Handbook of
General medicine
NEW ADVANCES AND CHALLENGES
Treatment Approaches • Drug-Class Overview
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HANDBOOK OF
GENERAL MEDICINE
VOLUME 1
NEW ADVANCES
AND CHALLENGES
Treatment Approaches • Drug-Class Overview
ii
Credits
Editor-in-Chief Dr Martin de Villiers
MBChB DOM FCFP (SA) MBL
Publishing Editor Lynette Strydom
Business Manager Silke Friedrich
Advertising Executives Barbara Milroy
Loren Chimes
Production Manager Mercy Baloyi
GM: Magazines Jocelyne Bayer
Printer CTP Printers, Cape
Publisher Tiso Blackstar Group (Pty) Ltd
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Parktown
Johannesburg 2193
Copyright 2019 MIMS (a division of Tiso Blackstar Group [Pty] Ltd)
This book is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or review, as permitted under the Copyright Act,
no part may be reproduced by any process without written permission from the Publisher.
The opinions expressed in MIMS Handbook of General Medicine – Volume 1 are those of the contributing authors and do not necessarily reflect the
opinion of the Publisher.
MIMS (a division of Tiso Blackstar Group [Pty] Ltd) is an independent company and is not affiliated to any pharmaceutical manufacturer or profes-
sional association. The advertising carried in MIMS Handbook of General Medicine – Volume 1 is independent of, and has no influence over, the edito-
rial content.
Although every effort has been made in compiling, editing and checking the information contained in this publication to ensure that it is accurate,
the authors, the editors, the Publisher and their employees or agents shall not be responsible for the continued currency of the information/images, or
for any errors, omissions or inaccuracies in this publication, whether arising from negligence or otherwise, or for any consequences arising therefrom.
The healthcare practitioner should rely on his or her medical knowledge and expertise when treating a patient, as well as on the pharmaceutical
manufacturer in the prescribing of any medication.
HANDBOOK OF GENERAL MEDICINE VOL 1
i3ii
Foreword
The MIMS Handbook of General Medicine – Volume 1 enters the picture when the disputing forces of
biotechnology and artificial intelligence brought about by the fourth industrial revolution are poised
radically to impact both health and healthcare, and change the daily practice of medicine. Electronic
patient records, wearable diagnostic devices and continuous health monitoring, as well as the appli-
cation of big data, algorithms and predictive modelling, will certainly not replace the doctor, but will
help to serve communities and patients better. Consequently, it is important for MIMS to embrace and
to explore these changes in our reference information as part of our quest to help keep our subscribers
abreast of innovations.
The articles in this publication, contributed by medical experts, cover an array of disciplines and topics
and aim to guide and update clinical decision-making and stimulate discussion. The focus is on health
challenges, including the role of the patient as a partner in healthcare in line with a patient/person-cen-
tred approach to care that is now in the forefront of change. The challenges posed by the contribution
of lifestyle and an ageing population to the growing burden of non-communicable diseases and asso-
ciated end-organ damage are covered comprehensively with new updates. The importance of com-
municable diseases relevant to South Africa and sub-Saharan Africa during an era when travel across
borders for business or leisure purposes has increased, places the focus clearly on those infections that
may not always be top-of-mind. The Handbook also covers frequently seen diseases and conditions to
assist in their management, and to keep patients and their families appropriately informed.
A huge vote of thanks goes to each and every author featured in this handbook, who took time out
of his or her busy professional schedule to contribute. I believe their commitment to serving their peers in
order to better serve the patient community is evident in the high quality of their review articles.
Both MIMS and I want to thank you, the clinician, for continuously serving the people of this beautiful
country and hope that this publication will contribute towards your ability to do so. I trust that you will
enjoy what is offered and would like to invite anyone with constructive input to contact me via MIMS so
that we can enhance future publications to better serve your professional needs.
Dr Martin de Villiers
email: [email protected]
HANDBOOK OF GENERAL MEDICINE VOL 1
iv
Contents
How to use this publication.................... vi RESPIRATORY SYSTEM
& EAR, NOSE AND THROAT
Important prescribing
information .............................................. vi Bronchospasm: diagnosis and treatment..........63
Treatment approaches Dr M Mukansi
GENERAL Chronic cough: therapeutic approach.............67
Obesity: one of the great medical challenges...1 Dr AD Black
Dr GA Hough Chronic obstructive pulmonary disease............71
Patients with multiple comorbidities and Dr A Peter
diabetes: management challenges..................11
Sinusitis and allergic rhinitis: understanding the
Dr A Kok disease process improves the outcomes..........76
The patient as partner in the non-allopathic Dr DB Vermaak
management of lifestyle-related diseases....... 13
Vestibular assessments: an update....................82
Dr DP van Velden, Prof MJ Kotze, Prof SJ van Rensburg
Ms LT Benigson, Dr LM Hofmeyr
CARDIOVASCULAR SYSTEM
GASTRO-INTESTINAL SYSTEM
Drugs for dyslipidaemia.......................................18 & UROGENITAL TRACT
Prof DJ Blom Functional/ulcer-negative dyspepsia: a
review of the consensus statements of
Management of heart failure with reduced leaders and workers in the field .........................87
ejection fraction (HFrEF).......................................22
Dr JAM Garisch
Dr MC Hendrickse
Gastro-intestinal infections..................................92
Statins: poison or panacea?...............................28
Dr SM Sithole
Dr J Singbo, Prof DJ Blom
Chronic kidney disease: prevention,
The patient with resistant hypertension: a diagnosis and management...............................96
practical approach..............................................32
Prof B Rayner
Prof B Rayner
Proteinuria – what does it mean? ....................100
The renin angiotensin aldosterone system
antagonism (RAAS) and clinical outcomes......37 Prof B Rayner
Dr JR Snyman CENTRAL NERVOUS SYSTEM
ENDOCRINE SYSTEM Management of chronic daily headaches ....103
Hyperthyroidism: causes and treatment............44 Dr EB Lee Pan
Dr EF Delport Alzheimer’s disease...........................................107
Hypothyroidism: risk factors and treatment.......51 Dr M West, Dr S van Heerden, Prof Dr JA Joska, Prof DJ Stein
Dr EF Delport MENTAL HEALTH
Recent advances in type II diabetes: newer The adult patient with attention deficit
drugs providing cardiovascular protection.......56 hyperactivity disorder........................................112
Prof P Joshi Dr NN Ngcobo, Prof B Chiliza
HANDBOOK OF GENERAL MEDICINE VOL 1 The primary management of depression as a
chronic disease .................................................116
Dr S Mashaphu
5v
INFECTIOUS DISEASES Inflammatory arthritis: a practical approach
to the diagnosis and management .................172
HIV management and antiretroviral
therapy in adults – an update...........................122 Dr K Makan
Dr CN Menezes, Dr DL Reddy Lower backache: pathologies, diagnosis
and treatment.....................................................183
Infectious diseases in returning travellers:
focus on dengue................................................130 Prof AJ Vlok, Prof GJ Vlok
Dr MBM Quam, Prof LH Blumberg OPHTHALMOLOGY
Fever of unknown origin....................................135 Decreasing eyesight in the elderly patient .....187
Dr K Pieton (Roberg) Dr J van Soelen
Listeriosis: clinical manifestation An overview of glaucoma.................................191
and management..............................................138
Dr H Abrahamse-Pillay
Dr J Thomas
DERMATOLOGY
Management and prevention of malaria........143
Acne vulgaris: prevention and treatment ....200
Prof LH Blumberg, Prof J Frean, Ms L Baker
Prof R Lehloenya, Dr T Isaacs, Prof RM Ngwanya
Rabies: prevention and management............ 150
Atopic dermatitis: diagnosis
Dr J Weyer, Prof LH Blumberg and management..............................................206
Tuberculosis IRIS .................................................157 Dr T Isaacs, Prof RM Ngwanya, Prof R Lehloenya
Dr JS Nel Psoriasis: diagnosis and treatment ..................214
MUSCULOSKELETAL SYSTEM Prof RM Ngwanya, Dr T Isaacs, Prof R Lehloenya
Fibromyalgia: diagnosis and management....161 Skin treatments for the patient who
wants to look younger.......................................219
Prof B Hodkinson
Dr M Smit
Gout: diagnosis and management .................166
Dr ET Cornelissen, Prof B Hodkinson
HANDBOOK OF GENERAL MEDICINE VOL 1
vi
How to use this publication
MIMS Handbook of General Medicine – Volume 1 comprises two main editorial sections.
Section 1: Treatment Approaches
These up-to-date, research-based review articles aim to inform the medical practitioner about the lat-
est diagnostic and treatment approaches.
The information provided from leading academics and opinion-leader specialists in the country will
enable the doctor to continue to be in the forefront of best practice and evidenced-based clinical
care pathways.
Section 2: Drug-Class Overview
This section features a comprehensive overview of a selection of drug classes relevant to various disci-
plines in general medicine. For each specified class and sub-classification thereof, the mechanism of
action and relevant “black box”-type warnings are given. Each class features a table, structured ac-
cording to active ingredient, which highlights important aspects, such as usual dosage range, dosage
forms available on the South African market, half-life, elimination, therapeutic area according to the
registered package insert, metabolism and drug- and dose-specific warnings
Expert pharmacology consultants compiled this section and it is essentially based on the latest avail-
able international medical information. The tables give registered indications for each product, as per
SAHPRA, and no reference is made to any “off-label” use of drugs. Off-label use may be beneficial to
the patient, but is subject to the prescribing healthcare practitioner’s judgement and expertise. The ta-
bles do not provide a comprehensive description of all the features and safety considerations of a class.
When in doubt, healthcare practitioners should consult the current manufacturer’s product literature for
registered indications and dosages, or should contact the manufacturer directly.
Important prescribing information
When prescribing any product mentioned in the MIMS Handbook of General Medicine – Volume 1,
doctors should be mindful of the important points listed below.
Hypersensitivity to the ingredient(s)/components of any medicine contra-indicates its use.
Medicines should not be prescribed to pregnant or lactating women unless the anticipated ben-
efit clearly outweighs any potential risk to the foetus.
The possibility of drug accumulation should be considered in the presence of significant
renal or hepatic impairment.
Tolerance to medicines is likely to be less with extremes of age.
Drug interferences with laboratory tests and physical incompatibilities common with parenteral
solutions have not been included.
Mono-amine oxidase inhibitors (MAOIs) have a prolonged action, so patients should not take
any of the foods or medicines known to cause reactions for at least 14 days after stopping
treatment.
Certain medicines (e.g. those that cause CNS depression) may lead to drowsiness and impaired
concentration, which may be aggravated by the simultaneous intake of alcohol or depression
agents.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 1
Obesity: one of the great medical challenges Treatment approaches
GA Hough lence are followed by increases in diabetes prevalence
in subsequent years (see Figure 3).2
MBChB (UCT) FCP(SA) Cert. Endocrinology & Metabolism (SA)
Obesity is the driving force behind the current diabe-
Specialist Physician/Endocrinologist/Diabetologist, Port Elizabeth tes epidemic sweeping the world. There is a close corre-
lation between increasing obesity and diabetes rates in
Obesity is perhaps the greatest medical challenge fac- the world. The burden of managing the impact of obe-
ing mankind today, with a rapidly accelerating preva- sity and its complications, such as diabetes, on health-
lence in developing nations. The cost of managing the care spending is a real threat to both established first
complications associated with obesity threatens na- world and emerging economies. Emerging economies,
tions’ economic growth and future.1 in particular, have to spend disproportionate amounts
of their healthcare budget on complications such as
Over the past 40 years, there has been a rapid in- type 2 diabetes (see Figure 4).3,4
crease in the global rates of obesity in both men and
women, with over 250 million men and over 350 million Definition and diagnosis
women estimated to have had Class I obesity (a BMI
[body mass index] of 30-35.0 kg/m2) in 2016 (see Figures The most widely used method of assessing obesity is to
1 and 2).1 measure the body mass index (BMI) of an individual,5
i.e. assess the appropriate weight for a particular height
Type 2 diabetes is perhaps the most visible complica- (see Figure 5). It has been criticised for being both too
tion of obesity. In most countries, particularly the United
States and the Middle East, increases in obesity preva-
M – million
Adapted from NCD Risk Factor Collaboration (NCD-RisC). Lancet. 2017;390:2627-42
Figure 1. Global obesity rates between 1975 and 20151
Age-standardised male and female adults
Adapted from NCD Risk Factor Collaboration (NCD-RisC). Lancet. 2017;390:2627-42
Figure 2. Global obesity prevalence in 20161
HANDBOOK OF GENERAL MEDICINE VOL 1
2 TREATMENT APPROACHES
Age-standardised global prevalence of obesity and diabetes
1. Adapted from NCD Risk Factor Collaboration (NCD-RisC). Lancet. 2017;390:2627-42 2. Adapted from NCD Risk Factor Collaboration (NCD-
RisC). Lancet. 2016;387:1513-30
Figure 3. Obesity and type 2 diabetes2
US annual medical expenditure
CI - confidence interval; US - United States
Cawley et al. Pharmacoeconomics. 2015;33:707-22
Obesity care expenditure and proportion of GDP attributed to obesity care differs globally
Australia 9.6 13.4 0.85
BrazilObesity care expenditure as a 1.05
proportion of total HE (%) 9.4
Canada Proportion of GDP used for9.7 0.92
Germany treating obesity (%)7.7
0.10
Israel 5.0 19.5 0.05
Mexico 21.7 0.11
Saudi Arabia 0.12
South Korea 22.6 0.03
18.7 0.09
Turkey 0.06
UAE 7.9 0.08
12.7
United Kingdom 2.00
United States
GDP - gross domestic product; HE - healthcare expenditure; UAE - United Arab Emirates
1. World Bank 2017. National GDP accounts data 2. World Obesity Federation. 2017
Figure 4. Obesity and healthcare costs3,4
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 3
Treatment approaches
WHO. Factsheet 311. 2014.
Figure 5. Defining and classifying obesity6
AMA – American Medical Association; NAFLD – non-alcoholic fatty liver disease
American Medical Association Resolution: 420 (A-13)
Figure 6. Obesity is a disease8
sensitive and for not being sensitive enough. Despite by both patients and physicians. The ACTION study, a
this, it remains the simplest and most easily accessible US-based survey which investigated barriers to obe-
measure to assess weight. Recent evidence shows a sity management, indicated that approximately 65%
particularly good relationship between BMI and mor- of people with obesity recognise obesity as a disease.
tality risk. The definition of normal weight is based on Moreover, all too often when the patient presents with
epidemiological studies showing no or minimal impact complications, he/she is not made aware that obesity is
on health outcomes for people with these BMIs. BMIs the underlying cause.7
above and below the norm show increasing adverse
health risks. Pathophysiology
Each level of obesity is associated with increased risk Obesity results when energy intake in the form of food
for both morbidity and mortality.6 In addition to the three or drink exceeds energy expenditure (see Figure 7). The
risk groups, many organisations make use of a fourth lev- excess energy is converted to fat, which is the most ef-
el of BMI, which is that greater than 50. This is known as ficient and dense form of energy storage. The excess
extreme obesity, with class 3 commonly referred to as fat is stored in different parts of the body, the amount in
morbid obesity. each being largely genetically determined.9
Obesity as a disease Understanding why differences in energy intake and
expenditure occur is the key to understanding obesity.
Obesity is not a lifestyle choice or an alternate way of About 70% of energy expenditure is accounted for by
living; it is recognised as a disease by all health authori- basic life processes of simply staying alive. Another 10%
ties and meets all criteria for the definition of a disease.7,8 of energy expenditure goes to thermogenesis and di-
(See Figure 6.) gestion of food. The remaining 20% is accounted for by
physical activity. Increased levels of physical activity do
Unfortunately, it is poorly recognised and diagnosed
HANDBOOK OF GENERAL MEDICINE VOL 1
4 TREATMENT APPROACHES
Badman MK, Flier SS. Science. 2005;307:1909-14.
Figure 7. Causes of obesity9,10
seem to protect against obesity, but once a person is It would seem that much of the increase in obesity we
obese, increasing physical activity has not been shown see in the world today is simply due to overfeeding and
to contribute to weight loss. activation of the hedonistic rewards mechanism asso-
ciated with particular foods.
Energy intake is largely unregulated, and there is no
homeostatic mechanism to regulate intake to maintain Complications of obesity
and stabilise BMI. There is also no energy waste gate to
get rid of excess energy intake. Therefore, as long as Each 5 kg/m2 increase in BMI results in an increase in mor-
energy intake exceeds energy expenditure even by the tality of around 30% (hazard ratio: 1.29 per 5 kg/m2 [95%
smallest amount, it will be converted to fat and stored. CI 1.27-1.32]). At a BMI of 30-35 kg/m2, median survival is
reduced by two to four years, and to eight to 10 years
Stimuli for energy intake include what we commonly with a BMI of 40-45 kg/m2. Obesity is a serious health risk.12
call appetite, hedonistic reward mechanisms in the brain
stimulated by food, as well as a multitude of other factors. In addition to its direct effect on mortality and life ex-
Unlike thirst, appetite is not a biological imperative; in fact, pectancy (see Figure 9)12, obesity is also responsible for
most of it seems to be an emotion which can be manipu- many other diseases. What is less often known and ap-
lated to both increase and decrease energy intake. preciated is the effect obesity has on cancer risk (see
Figure 10).
Finally, the human body is also designed to defend
against weight loss when confronted with minor de- The risk of these comorbidities increases as BMI in-
creases in energy intake. It does this primarily by increas- creases from the overweight classification to that of
ing stimuli for energy intake and can also reduce the Class 3 obesity (see Figure 11).
basal metabolic rate by up to 10%.
CCK – cholecystokinin; GLP-1 – glucagen-like peptide; PYY – peptide YY
1. Schwartz et al. Obes Rev. 2010;11:531-47 2. Sumithran et al. N Eng J Med. 2011;365:1597-604
Figure 8. Physiological responses to weight loss favour weight regain11
HANDBOOK OF GENERAL MEDICINE VOL 1
Life expectancy dTeREcArTeMaENsTeAsPPaRsOABCMHEIS increases 5
Proportion still alive (%)
Treatment approaches
100 Normal BMI =
almost 80% chance
80 of reaching age 70
60 BMI 35–40 =
~60% chance of reaching
40 BMI range (kg/m2)
22.5–25 age 70
25–30
BMI 40–50 =
20 30–35 ~50% chance of reaching
35–40
40–50 age 70
0
35 40 50 60 70 80 90 100
Age (years)
Data are based on male subjects; n=541,452
Prospective Studies Collaboration. Lancet 2009;373:1083–96
Figure 9. Life expectancy and BMI12
Figure 9. Life expectancy and BMI12
Treatment • Are there any contributing factors?
Perhaps the best treatment of obesity is prevention. Ac- - Exclude or treat diseases/disorders known to con-
knowledging the factors that we know are driving the cur- tribute to obesity.
rent worldwide obesity epidemic and addressing them
should prevent the next generation from following the • Assess for complications and comorbidities of obesity.
same path. We need to teach that appetite is mostly emo- - These must be managed and stabilised.
tion and not a biological imperative and that eating should - They are also useful to stratify and decide on the
appropriate level of intervention.
Given the high prevalence of obesity, it is difficult
be done mindfully with consideration of one’s physiological for healthcare systems to treat every single individual.
needs. We need to do more to encourage physical activity Therefore, it is important to be able to identify high-risk
and work at making lives less sedentary. Moreover, efforts individuals who would benefit most from treatment.
need to be stepped up to regulate the food industry with Disease-staging systems are useful methods to help
punitive taxes and restrictions on high, energy-dense, artifi- achieve this. Staging systems are not intended to sup-
cially-palatable foods that are designed to stimulate and plant treatment guidelines, but rather to act as an ad-
activate our hedonistic reward centres. ditional tool.
Secondly, we need to be able to recognise “at-risk” in- The Edmonton Obesity Staging System is one such
dividuals and intervene at an early stage. These include tool. It is designed to allow clinicians to describe the
low-birth-weight children, and those of obese parents, morbidity and functional limitations associated with
lower-income backgrounds and less educated families. excess weight and determine the appropriate clinical
management of that individual (see Figure 13).
Once an obese individual has been identified, the
It classifies individuals into one of five stages, accord-
management should shift to a more personalised ap-
ing to obesity-related risk factors or comorbidities, psy-
proach (see Figure 12). To do this, a little more informa- chological status and impact on quality of life. This ena-
tion is needed: Obesity is associated with mbleus tlhteipclilneiciacnotomidoenrtbifyidthoitseiepsatients with current
and complications
Metabolic, mechanical and mental Sleep apnoea
Metabolic Depression CVD and risk factors
Mechanical Anxiety • Stroke
Mental Asthma
NAFLD • Dyslipidaemia
• Hypertension
• Coronary artery disease
• Congestive heart failure
• Pulmonary embolism
Gallstones Chronic back pain
Cancers* Infertility Type 2 diabetes
Prediabetes
Physical functioning Incontinence Thrombosis
Arthrosis Gout
CVD, cardiovascular disease; NAFLD, non-alcoholic fatty liver disease
*Including breast, colorectal, endometrial, esophageal, kidney, ovarian, pancreatic and prostate
Adapted from Sharma AM. Obes Rev. 2010;11:808-9; Guh et al. BMC Public Health 2009;9:88; Luppino et al. Arch Gen Psychiatry 2010;67:220–9; Simon et al. Arch
Gen Psychiatry 2006;63:824–30; Church et al. Gastroenterology 2006;130:2023–30; Li et al. Prev Med 2010;51:18–23; Hosler. Prev Chronic Dis 2009;6:A48
Figure 10. Complications associated with obesity
HANDBOOK OF GENERAL MEDICINE VOL 1
6 TREATMENT APPROACHES
The risk of developing certain cancers is
increased at the highest BMI category1
Relative risk of developing cancers with BMI ≥40 kg/m2 vs BMI 18.5-24.9 kg/m2
* – postmenopausal; MM – multiple myeloma; RCC – renal cell carcinoma
1. Lauby-Secretan et al. N Eng J Med. 2016;375:794-8 2. Centre for Disease Control and Prevention
Figure 11. Cancer risk associated with high BMI
obesity-associated health problems who would most ences, while keeping calorie intake below the target
likely benefit from an intensive and resourceful weight- level. As a general guide, no person has been shown to
management programme. have a basal metabolic rate of less than 1 000 kcal per
day, so reducing calorie intake to this level will result in
Before starting any weight-loss intervention, it is essen- weight loss in all adults.
tial to consider what the actual outcome is intended to
be. Ideally, this should be to improve important health The rate of weight loss will be influenced by differ-
outcomes or comorbidities. With this in mind, a target ences between dietary calorie restriction and the es-
for weight loss should be identified at the start. This tar- timated basal metabolic rate. This again needs to be
get should be based on evidence that supports an im- planned and will depend on patient preferences and
provement in an identified health outcome. Different the need quickly to reverse comorbidities. For example,
comorbidities respond to different degrees of weight very low-calorie diets (VLCD) result in rapid weight loss
loss, as shown in Figure 14. and very quickly improve or reverse type 2 diabetes.
Diet is always the cornerstone of obesity treatment. When planning dietary interventions, healthcare pro-
The principle is the restriction of calorie intake to less fessionals need to be careful about not perpetuating
than expenditure, which will, of course, result in a nega- common myths and assumptions, and need to focus on
tive energy balance and weight loss. In order to do this, proven facts (see Tables 1 to 3). The NEJM published an
an estimate of daily calorie consumption is necessary, excellent review of this subject in 2017.
taking into account activity levels. The diet can then be
individually tailored to suit the patient’s dietary prefer- There is an entire gym industry built on the myth that
exercise leads to weight loss. Studies have consistently
* – Other measures include waist circumference and body-composition assessments; 1 – optional step
1. Jensen et al. Circulation. 2014;129(25 Suppl 2):S102-38 2. Yumuk et al. Obes Facts. 2015;8:402-424 3. Garvey et al. Endocr Pract. 2016;22(Suppl 3):1-203
Figure 12. Guidelines for obesity treatment
HANDBOOK OF GENERAL MEDICINE VOL 1
tools to identify patients at greatest risk 7
TREATMENT APPROACHES Treatment approaches
The Edmonton Obesity Staging System is one such tool, designed to allow clinicians to describe
the health impact associated with excess weight and determine appropriate clinical management
Stage Medical risk factors Psychological symptoms Functional limitations
0 No sign of obesity-related risk factors No symptoms No limitations
1 Obesity-related subclinical factors Mild obesity-related symptoms Mild impairment
2 Comorbidity requiring medical intervention Moderate obesity-related symptoms Moderate limitations
3 Significant end-organ damage Significant obesity-related symptoms Significant impairment
4 Severe obesity-related chronic disease Severe disabling symptoms Severe limitations
SShhaarrmmaa, ,KKuusshhnneer.r.InInttJJOObbeses(L(oLondn)d2).020090;93;33:32:8298–99-955
Figure 13. The Edmonton Obesity Staging System
* – Figure displays weight-loss ranges examined in the studies (impact of >10% weight on NAFLD, and sleep apnoea symptoms was not reported);
BP – blood pressure; TG – triglycerides; GERD – gastro-oesophageal reflux disease; NAFLD – non-alcoholic fatty liver disease; PCOS – polycystic ovary syndrome
Cefalu et al. Diabetes Care. 2015;38:1567-82; Lean et al. Lancet. 2018;391:541-51
Figure 14. Weight loss and improved obesity-related complications
shown this to be untrue, whether alone or in combina- use in obese patients. It is critically important to under-
tion with dietary calorie restriction. Exercise is helpful stand that none of the drugs has any long-term effects,
in the maintenance of weight loss achieved through and their effects on weight cease as soon as they are
dietary intervention. This does not mean that exercise stopped. Patients need to be counselled about this be-
should not be encouraged; it is well documented to re- fore starting the drugs so that they can prepare for the
duce hypertension, improve lipid metabolism and im- potential rebound if the medication is stopped. Most
prove glycaemic control and thereby improve obesity- of the medications have not been tested for long-term
induced comorbidities and mortality. However, it must use. Many obesity experts use the drugs long-term off-
be clearly explained to patients that exercise will not label, and there is emerging evidence that when done
assist with weight loss. Another myth is that exercise can carefully, this may be both safe and effective. Patients
compensate for the negative health impacts of obesity, should, however, be informed about any off-label use
the so-called “fit, fat patient”. Once again, studies have and be carefully made aware of potential side effects
consistently shown this to be untrue. Exercise cannot and the unknowns of long-term use.
compensate for the risks of obesity and is significantly
less effective than weight loss alone in reducing risk and The choice of the pharmaceutical agent needs to be
improving comorbidities. guided by pre-existing medical conditions, patient prefer-
ences and affordability. The latter is important since, ab-
For many patients, pharmaceutical treatment of obe- surdly, obesity drugs are not reimbursed by medical aids.
sity is an important adjunct to dietary calorie restric-
tion (see Figure 15). There is no wonder drug, and all Phentermine is the most widely prescribed pharmaco-
have limitations and side effects which may limit their logical agent for obesity, despite only being registered for
short-term use. Observational open-label studies suggest
HANDBOOK OF GENERAL MEDICINE VOL 1
8 TREATMENT APPROACHES
Table 1. Myths about obesity
Myth Basis of conjecture
Small sustained changes in energy intake or expenditure will National health guidelines and reputable websites advertise that
prod uce large, long-term weight changes. large changes in weight accumulate indefinitely after small sus
tained daily lifestyle modifications (e.g. walking for 20 minutes or
eating two additional potato chips).
Setting realistic goals in obesity treatment is important According to goal-setting theory, unattainable goals impair
because otherw ise patients will become frustrated and lose perform ance and discourage goal-attaining behaviour; in obesity
less weight. treatm ent, incongruence between desired and actual weight
loss is thought to undermine the patient’s perceived ability to
attain goals, which may lead to the discontinuation of behaviours
necessary for weight loss.
Large, rapid weight loss is associated with poorer long-term This notion probably emerged in reaction to the adverse effects of
weight outcomes than is slow, gradual weight loss. nutritionally insufficient very-low-calorie diets (<800 kcal per day)
in the 1960s; the belief has persisted, has been repeated in text
books and recommendations from health authorities, and has
been offered as a rule by dietitians.
Assessing the stage of change or diet readiness is important Many believe that patients who feel ready to lose weight are
in helping patients who seek weight-loss treatment. more likely to make the required lifestyle changes.
Physical-education classes in their current format play an The health benefits of physical activity of sufficient duration, fre
important role in preventing or reducing childhood obesity. quency, and intensity are well established and include reductions
in adiposity.
Breastfeeding is protective against obesity. The belief that breastfed children are less likely to become
obese has persisted for more than a century and is passionately
defended.
A bout of sexual activity bums 100 to 300 kcal for each Many sources state that substantial energy is expended in typical
person involved. sexual activity between two adults.
*We define myths as beliefs held true despite substantial evidence refuting them.
Table 2. Presumptions about obesity
Presumption Basis of conjecture
Regularly eating (vs. skipping) breakfast is protective against Skipping breakfast purportedly leads to overeating later in the
obesity. day.
Early childhood is the period during which we learn exercise Weight-for-height indices, eating behaviours, and preferences
and eating habits that influence our weight throughout life. that are present in early childhood are correlated with those
later in life.
Eating more fruits and vegetables will result in weight loss By eating more fruits and vegetables, a person presumably
or less weight gain, regardless of whether one intentionally spontaneously eats less of other foods, and the resulting
makes any other behavioural or environmental changes. reduction in calories is greater than the increase in calories from
the fruit and vegetables.
Weight cycling (i.e. yo-yo dieting) is associated with In observational studies, mortality rates have been lower among
increased mortality. persons with stable weight than among those with unstable
weight.
Snacking contributes to weight gain and obesity. Snack foods are presumed to be incompletely compensated for
at subsequent meals, leading to weight gain.
The built environment, in terms of sidewalk and park Neighborhood-environment features may promote or inhibit
availability, influences obesity. physical activity, thereby affecting obesity.
*We define presumption as an unproved yet commonly espoused proposition.
it may be safe for long-term use, but this would still be off- indulgence is higher, such as holidays or weekends. It is a
label. As a stimulant, it has the potential for all the typical relatively cheap drug which makes it accessible to many
side effects of tachycardia, mild elevation of blood pres- patients and it is therefore often used as first-line treatment.
sure, tremor, an increase in anxiety and sleep disturbance.
Patients should be counselled about these potential side Orlistat is a lipase inhibitor which decreases fat ab-
effects and told to discontinue the drug should they oc- sorption and results in energy-wasting. Although effec-
cur. Phentermine is a very short-acting drug and only exerts tive in clinical trials and approved for long-term use, it
its effect on the day it is taken. This means it can be used is not popular due to the GI side effects from the stea-
intermittently for short periods when the potential for over- torrhoea. Patients will also either consciously or uncon-
sciously adapt their diet to minimise these side effects,
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 9
Table 3. Facts about obesity Treatment approaches
Fact Implication
Although genetic factors play a large role, heritability is not If we can identify key environmental factors and successfully
destiny; calculations show that moderate environmental influence them, we can achieve clinically significant reductions
changes can promote as much weight loss as the most in obesity.
efficacious pharmaceutical agents available.26
Diets (i.e. reduced energy intake) very effectively reduce This seemingly obvious distinction is often missed, leading to erro
weight, but trying to go on a diet or recommending that neous conceptions regarding possible treatments for obesity;
someone go on a diet generally does not work well in the recognising this distinction helps our understanding that energy
long term.37 reduction is the ultimate dietary intervention required and ap
proaches such as eating more vegetables or eating breakfast
daily are likely to help only if they are accompanied by an
overall reduction in energy intake.
Regardless of body weight or weight loss, an increased level Exercise offers a way to mitigate the health-damaging effects of
of exerc ise increases health.28 obesity, even without weight loss.
Physical activity or exercise in a sufficient dose aids in long- Physical-activity programmes are important, especially for
term weight maintenance.28,29 children, but for physical activity to affect weight, there must be
a substantial quantity of movement, not mere participation.
Continuation of conditions that promote weight loss Obesity is best conceptualised as a chronic condition, requiring
promotes maintenance of lower weight.30 ongoing management to maintain long-term weight loss.
For overweight children, programmes that involve the Programmes provided only in schools or other out-of-home
parents and the home setting promote greater weight loss or structured settings may be convenient or politically expedient,
maintenance.31 but programmes including interventions that involve the parents
and are provided at home are likely to yield better outcomes.
Provision of meals and use of meal-replacement products More structure regarding meals is associated with greater weight
promote greater weight loss.32 loss, as compared with seemingly holistic programs that are
based on concepts of balance, variety, and moderation.
Some pharmaceutical agents can help patients achieve While we learn how to alter the environment and individual
clinically meaningful weight loss and maintain the reduction behaviours to prevent obesity, we can offer moderately
as long as the agents continue to be used.33 effective treatment to obese persons.
In appropriate patients, bariatric surgery results in long-term For severely obese persons, bariatric surgery can offer a life-
weight loss and reductions in the rate of incident diabetes changing, and in some cases lifesaving, treatment.
and mortality.14
*We classify the listed propositions as facts because there is insufficient evidence to consider them empirically proved.
replacing fat with carbohydrates or protein, while keep- Table 4. Eligibility for bariatric surgery
ing the overall calorie intake unchanged.
Eligibility for bariatric surgery
Liraglutide is a synthetic GLP1 inhibitor initially ap-
proved for the treatment of type 2 diabetes and later BMI Addition criteria
for the treatment of obesity after meeting the criteria for
registration at a dose of 3 mg daily (see Figure 16). Mild >40 No other criteria needed
gastro-intestinal upset and nausea are the major side ef-
fects, and it should not be used in patients with a prior his- 35-40 2 additional comorbidities
tory of pancreatitis. It has been well studied and is safe for
long-term use. Were it not for the prohibitively high price, 28-35 May be considered in particular
it would be an ideal weight-loss agent, especially where circumstances
long-term use is indicated. Its hypoglycaemic effects
and positive influence on lipids and blood pressure, as When to refer
well as cardiovascular-risk reduction, make it especially
attractive in a patient with obesity-related comorbidities. Patients should be referred to an obesity-focused cen-
tre when simple interventions have failed. These centres
Bariatric surgery is by far the most effective treatment are multidisciplinary, incorporating dieticians, psycholo-
for obesity measured by weight reduction, remission or gists, endocrinologists and surgical support for bariatric
improvement in comorbidities, mortality and life expec- surgery where indicated. Patients with poorly controlled
tancy. Ironically, beyond the initial surgical risk, long- type 2 diabetes on insulin with a BMI >35 should be
term data on morbidity and mortality suggest it is the strongly advised to consider bariatric surgery (see Table
safest intervention. It is the treatment of choice for high- 4). Patients with BMI >40 who have comorbidities and
ly insulin-resistant, poorly controlled type 2 diabetes. It have failed lifestyle and pharmacological intervention,
also rapidly improves comorbidities when they become should also be encouraged to consider bariatric sur-
life-threatening or are causing significant morbidity. gery (see Table 4). Patients with BMI >50 are extremely
high-risk, and pharmacological, dietary and lifestyle
treatments are usually futile; these patients should be
referred for bariatric surgery at the outset.
HANDBOOK OF GENERAL MEDICINE VOL 1
10 TREATMENT APPROACHES
* – Approved for short-term use.
FDA Drugs; EMA Medicines
Figure 15. Pharmacological treatment of obesity
GLP-1 RA – glucagen-like peptide-1 receptor agonist
Adapted from Campbell & Drucker. Cell Metabolism. 2013;17:819-37; Pratley & Gilbert. Rev Diabet Stud. 2008;5:73-94
Figure 16. Pharmacological effects of GLP-1 RAs
References 7. Kaplan LM, Golden A, Jinnett K, Kolotkin RL, Kyle TK, Look M, et al.
Perceptions of barriers to effective obesity care: Results from the
1. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in national ACTION study. Obesity Journal. 2018:26:61-69.
body-mass index, underweight, overweight, and obesity from 1975
to 2016: A pooled analysis of 2 416 population-based measurement 8. American Medical Association House of Delegates. Recognition of
studies in 128.9 million children, adolescents, and adults. Lancet. obesity as a disease. Resolution 2014. Available at http://www.npr.
2017:390:2627-2642. org/documents/2013/jun/ama-resolution-obesity.pdf. Accessed
May 2019.
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in dia-
betes since 1980: A pooled analysis of 751 population-based studies 9. Badman MK, Flier SS. The gut and energy balance: Visceral allies in
with 4.4 million participants. Lancet. 2016: 387:1513-1530. the obesity wars. Science. 2005:307(5717):1909-1914.
3. Cawley J, Meyerhoefer C, Biener A, Hammer M, Wintfield N. Savings 10. NHLBI. Clinical guidelines on the identification, evaluation and
in medical expenditures associated with reductions in Body Mass treatment of overweight and obesity in adults. NIH Publication.
Index among US adults with obesity, by diabetes status. Pharmo- 1998:98-4083.
economics. 2014:33(7):707-722.
11. Schwartz A, Doucet E. Relative changes in resting energy expendi-
4. Word Obesity. Global Obesity Observatory. Available at https:// ture during weight loss: A systematic review. Obesity Reviews.
www.worldobesitydata.org/country-profiles/. Accessed May 2019. 2010:11(7):531-547.
5. Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, Toplak H. 12. Prospective Studies Collaboration. Body-mass index and cause-
European guidelines for obesity management in adults. The Euro- specific mortality in 900 000 adults: Collaborative analyses of 57
pean Journal of Obesity. 2015:8: 402-424. prospective studies. Lancet. 2009:373(9669):1083-1096.
6. World Health Organization. Obesity and overweight. Available at
https://www.who.int/news-room/fact-sheets/detail/obesity-and-
overweight. Accessed May 2019.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 11
Patients with multiple comorbidities and diabetes: Treatment approaches
management challenges
A Kok In keeping with international and national guidelines,
RAAS blockers (ACE inhibitors and ARBs) should be
MBChB DipPec FCP (SA) MMed FACP BTheol FRCP (London) combined with calcium-channel blockers as therapy
for hypertension, whether the patient is diabetic or not.4
Specialist Physician in Private Practice, Johannesburg The blood-pressure targets have been adjusted to ac-
count for age and comorbidities. The risk of excessive
It has become clear in recent months that HIV/AIDS has blood-pressure reduction has become clear, especial-
moved to fifth place as a cause of mortality in South Af- ly the risk of falls and postural hypotension. The SPRINT
rica. It has been replaced by cardiovascular disease as study found that the greatest cardiovascular benefits
number one, while diabetes is number two. South Africa were achieved with systolic blood pressure <132 mmHg.
is facing an epidemic of lifestyle diseases and the need The trial was stopped early as there was a clear mortal-
to educate patients and their families accordingly be- ity benefit in the intensive treatment arm.6
comes paramount as this challenge is not always met
by medicines administration, but rather by the lifestyle The SA Hypertension Society guidelines echo interna-
choices people make. tional guidelines in that they advocate to keep blood
pressure below 130/80 mm Hg, to treat if blood pressure
The population is increasingly faced with comorbidi- is >140/90 mmHg and to avoid lowering blood pres-
ties in a single individual. There are no precise statistics sure below 120 mmHg systolic in the elderly (>65 years
on the true prevalence of all these conditions in the of age). The same targets apply in diabetes mellitus,
South African population, except for the SANHANES with the preferred drug classes being RAAS blockers,
data from 2012. In the IDF report of 2015, it became thiazide-like diuretics (indapamide) and non-dihydro-
clear that non-communicable diseases, with diabetes pyridine CCBs (verapamil, diltiazem).3
the most important, represent a worldwide problem.
Africa – especially sub-Saharan Africa – represents the The addition of DPP-4 inhibitors (vildagliptin, sitaglip-
biggest challenge as so many patients are undiag- tin and saxagliptin) has broadened the management
nosed or diagnosed late with resultant complications.1,2 of type II diabetes. Several studies have demonstrated
The prevalence of diabetes in South Africa in 2012 was their cardiovascular (CV) safety, and these drugs pro-
8% for blacks and whites, 13.4% for coloureds and 30% vide excellent glucose control when used in combina-
for the Indian population. tion with metformin. They can also be added to other
oral, as well as injectable, diabetic treatments.9-11 They
These numbers have major financial implications for have the benefit of posing low hypoglycaemic risk and
the future. Many patients with diabetes also suffer from are weight-neutral. There was, however, a potential
hypertension and lipid disorders (hyperlipidaemia), and negative cardiovascular effect in using saxagliptin in
as a group will incur significant healthcare costs in the patients with existing heart failure. Saxagliptin is, there-
future, especially in the context of an ageing popula- fore, contra-indicated in these patients, and there are
tion. These factors add to the challenge of comorbid limitations with the use of DPP-4 inhibitors in stage 3 renal
conditions. As complications develop, the costs similarly dysfunction.
escalate – for example, heart failure and end-stage re-
nal disease. The cardiovascular outcome studies (CVOTs) in type II
diabetes have added to our knowledge and now influ-
The cardiometabolic and renal intersect ence our choice of preferred treatment for those dia-
betic patients with cardiovascular disease, especially
The role of renal dysfunction in patients suffering from ischaemic heart disease. The update of the ADA/EASD
cardiovascular disease has been highlighted by re- guidelines now includes specific recommendations for
search relating to the SGLT2 inhibitor class of anti-dia- the SGLT2 inhibitors (empagliflozin, dapagliflozin) and
betic agents, as well as by new insights gained from the the GLP-1 receptor agonist (liraglutide) to be used as
development of the RAAS inhibitor, and the combina- first-line therapy in patients with existing cardiovascular
tion of valsartan, the neprilysin inhibitors and sacubitril disease.7,8
for the management of heart failure.
These agents are being used with increased fre-
The presence of renal dysfunction in diabetes and quency in the South African context to help prevent
cardiovascular disease implies accelerated atheroscle- future cardiovascular complications and especially be-
rosis and premature vascular ageing. The prevalence cause of their renal-protective effects. While the cost-
of hypertension in patients with impaired glucose tole- effectiveness of these agents must be considered, they
rance is 60,2%, but as high as 79,4% in those with con- have additional benefits in that they promote weight
comitant diabetes. This represents the need for treat- loss, pose a low hypoglycaemia risk and offer effective
ment that will protect against end-organ damage in glucose control. They have excellent glucose-lowering
addition to being metabolically favourable.5 For this effects, particularly in those patients who start at a high
reason, the SEMDSA guideline selected indapamide, HbA1c level.
as opposed to hydrochlorothiazide, as the diuretic of
choice.3 HANDBOOK OF GENERAL MEDICINE VOL 1
12 TREATMENT APPROACHES
Heart failure and diabetes to statin therapy should the HDLc targets (>1 mmol/L in
men, >1,2 mmol/L in women) and TG (<1,7 mmol/L) not
Heart failure has a bilateral interaction with diabetes. be reached. The effect on cardiovascular outcomes
Therefore, diabetic patients have a higher risk of devel- was disappointing in the FIELD study, but the trial design
oping cardiac failure, and heart-failure patients have a could have been responsible, as patients in both arms
higher risk of developing diabetes. Only metformin and received aggressive statin therapy which may have
the SGLT2 inhibitors act independently of insulin, and affected the lack of significant differences in MACE
therefore have unique benefits in the management of outcomes between the two arms. The ACCORD trial
the patient with both diabetes and heart failure. SGLT2 showed a similar benefit in diabetic retinopathy, using
inhibitors are beneficial in patients with heart failure as the micronised fenofibrate. It therefore has an addition-
they have a diuretic effect, and are cardio- as well as al benefit beyond lipid control that must be considered
renal-protective. They have significant benefits in reduc- in patients with diabetes.
ing mortality and morbidity not only in diabetic patients,
but also in heart-failure patients. For this reason, their in- Conclusion
clusion in the management algorithm for heart-failure
patients who may or may not be diabetic is under con- The management of any patient with diabetes requires
sideration.9,10 careful assessment of all the risk factors that could be
contributing to accelerated atherosclerosis, ischaemic
The development of the ARNI (angiotensin recep- heart disease, heart failure and the risk of renal dys-
tor blocker/neprilysin inhibitor) group of agents was function. Newer agents are now available to manage
ground-breaking. This agent has improved the outlook these patients with the best results possible. Excellent
for patients with heart failure, especially those with re- glycaemic control with agents that have been shown
duced ejection fraction (HF-rEF).12,13 It is equally effec- to reduce cardiovascular risk must be the treatment of
tive whether patients have diabetes or not. The results of choice. All risk factors must be addressed, although the
the PARADIGM study prompted the adjustment of the essential aspect of care remains good communication
European and other international guidelines for heart- with, and support of, patients to enable and empower
failure treatment to include the ARNIs and valsartan/sa- them to look after their health.
cubitril in the treatment algorithm for heart-failure man-
agement.14 These agents have the combined benefit References
of RAAS blockade and vasoconstriction, in addition to
their vasodilatory effect on the vaso-active peptide sys- 1. Shisana O, Labadarios D, Rehle T, et al. South African National
tem, including brain natriuretic peptide (BNP). The addi- Health and Nutrition Examination Survey, 2012. 2014th ed. Cape
tion of ARNIs will reduce hospitalisations for heart failure, Town HSRC press; 2014:1-397.
as well as heart failure in deterioration despite optimal
medical therapy. 2. International Diabetes Federation. IDF Diabetes Atlas, 7th ed. 2015.
3. SEMDSA 2017 Guidelines for the management of type 2 diabetes
Lipid control
mellitus. JEMDSA. 2017;22(1): S1-S196.
The lipid guidelines have also been updated, and in the 4. Bangalore S, Fakheri R, Toklu B, et al. Diabetes mellitus as a com-
setting of cardiovascular disease remain a critical as-
pect of treatment. The South African guidelines include pelling indication for the use of renin angiotensin system blockers:
an extensive assessment of the age and risk profile, as Systematic review and meta-analysis of randomized trials. BMJ.
well as existing risk factors for accelerated atheroscle- 2016;352:438
rosis. In this guideline, diabetes and renal impairment 5. UKPDS tight blood pressure control and risk of macrovascular and
are considered compelling reasons for the manage- microvascular complications in type 2 diabetes mellitus. UKPDS 38.
ment of dyslipidaemia with high-intensity statins, rosuv- BMJ. 1998;(317)703-713.
astatin and atorvastatin. If the LDLc is not at the target 6. SPRINT trial research group. A randomized trial of intensive versus
level of <1,8 mmol/L despite maximum statin dosages, standard blood-pressure control. N Engl J Med. Epub 2015 Nov 9.
ezetimibe should be added to achieve the target levels. 7. Zelniker TA, et al. SGLT2 inhibitors for primary and secondary pre-
The newer therapies that are available, e.g. PCSK9 inhi- vention of cardiovascular and renal outcomes in type 2 diabetes:
bitors, have proved extremely effective in lipid reduc- A systematic review and meta-analysis of cardiovascular outcome
tion specifically to block the LDL receptor, with the result trials. Lancet. 2019 Jan 5;393(10166):31-39.
that cardiovascular risk is significantly reduced.16,17,18 As 8. Marso SP, et al. Liraglutide and cardiovascular outcomes in type 2
the costs are high, there will be specific cases and indi- diabetes. N Engl J Med 2016; 375:311-322.
cations for their use, but their benefit has been demon- 9. White WB, et al. Alogliptin after acute coronary syndrome in pa-
strated using two different agents and in two individual tients with type 2 diabetes. N Engl J Med 2013; 369:1327-1335.
trials, both with significant CV MACE reduction. The 10. Scirica BM, et al. Insulin and glucose-lowering agents for treating people
high-intensity statins have to be used in the manage- with diabetes and chronic disease. N Engl J Med. 2013; 369: 1317-1326.
ment of dyslipidaemia in the patient with diabetes. 11. Green JB, et al. Effect of sitagliptin on cardiovascular outcomes in
type 2 diabetes. N Engl J Med. 2015 ; 373:232-242.
There remain questions regarding the addition of fi- 12. McMurray JJV, et al. Angiotensin-neprilysin inhibition versus enala-
brates to control HDLc and TG. The FIELD study showed pril in heart failure. N Engl J Med. 2014:371:993-1004.
benefit in reducing diabetic retinopathy – and this in the 13. Packer M. Angiotensin receptor neprilysin inhibition compared with
setting of existing early retinopathy. The use of a micro- enalapril on the risk of clinical progression in surviving patients with
nised fenofibrate has the most data and can be added heart failure. Circulation. 2015;131:54-61.
14. Ponikowski P. 2016 ESC Guidelines for the diagnosis and treatment
HANDBOOK OF GENERAL MEDICINE VOL 1 of acute and chronic heart failure. Eur Heart J. 2016;18:891-975.
15. Grundy SM, et al. Guidelines on the management of blood choles-
terol. Circulation. 2018; 139:1082-1143.
16. Schwartz GG, et al. Alirocumab and cardiovascular outcomes
after acute coronary syndrome. N Engl J Med. 2018;379:2097-2107.
17. Sabatine MS, et al. Evolocumab and clinical outcomes in patients
with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.
18. SA dyslipidaemia guideline consensus statement. SAMJ Nov.
2018 ;108 (11) part 2.
TREATMENT APPROACHES 13
The patient as partner in the non-allopathic Treatment approaches
management of lifestyle-related diseases
DP van Velden implications that may be of current or future concern,
based partly on the questionnaire-based assessment
MBChB, M Prax Med, M Phil (Journalism) performed at referral.
Retired Lecturer in Department of Family Medicine and Evidence-based, non-pharmacological and patient-
Primary Care, Faculty of Medicine and Health Sciences, centred interventions, including health education and
University of Stellenbosch, Stellenbosch promotion for self-management, as well as motivation
for aerobic and muscle-strengthening exercises, weight
MJ Kotze reduction, dietary interventions and smoking cessation,
are incorporated in the PSGT service. Lifestyle interven-
PhD (Human Genetics) tions are partly based on results from studies involving
a Mediterranean-type diet (including moderate wine
Division of Chemical Pathology, Department of Pathology, consumption), as well as an alkaline (plant-based) diet
Faculty of Medicine and Health Sciences, with a calcium-containing alkalinising agent. Statistical-
University of Stellenbosch, Stellenbosch ly significant improvement in the symptoms and signs of
certain chronic diseases were found with these limited
SJ van Rensburg lifestyle interventions. It is encouraging that such lifestyle
interventions alone, or in conjunction with allopathic
PhD (Biochemistry) medicines, may play an important role in the manage-
ment of NCDs.
Division of Chemical Pathology, Department of Pathology,
Faculty of Medicine and Health Sciences, Background and objective
University of Stellenbosch, Stellenbosch
The incidence of chronic and degenerative diseases in-
Most illnesses are managed with medical and surgical creases with age, and ageing patients present with co-
interventions that control the cause, symptoms and morbidities that add to the complexity of treatment. The
signs or alter the course of the disease. This disease-cen- aetiology of these diseases involves both environmental
tred approach for acute conditions is highly successful and genetic risk factors. Abundant evidence suggests
owing to the availability of effective medicines and safe that environmental risk factors interacting with genetic
surgical and anaesthetic techniques developed over abnormalities are important in NCDs, such as cancer,
the past few decades. However, modern therapeutic cardiovascular disease, diabetes, dementia, osteoar-
approaches using allopathic (Western) medicine only, thritis and osteoporosis. These risk factors include the
fail to prevent the initiation and progression of the chron- acidogenic (Western-type) diet with micro-nutrient defi-
ic and degenerative, lifestyle-related diseases. Some ciencies, obesity, smoking, and physical inactivity. Most
drugs have serious and unwanted adverse effects, and NCDs share common metabolic abnormalities linked to
long-term use could be prohibitively expensive and minor genetic abnormalities interacting with environ-
unaffordable for large sections of the community. We mental influences, a fact that needs to be taken into
need less invasive and more cost-effective treatment of consideration in the management of these conditions.1
illness, focused on avoidance of therapy-induced risk.
According to an innovative branch of science known
An integrated approach with a strong focus on stay- as epigenetics or epigenomics, specific lifestyle changes
ing healthy throughout life should be encouraged can alter gene expression. Epigenetics refers to biologi-
to stimulate the innate healing potential of the body. cal phenomena that circumvent the genetic code. The
There is good evidence that lifestyle-related cancers genes themselves do not change. What can change is
and other non-communicable diseases (NCDs) have how those genes are expressed or “switched on”. Some
several common symptoms and signs underlying meta- genes can be switched off as well. This is brought about
bolic abnormalities. This led to the implementation of a by a variety of environmental factors. There is thus an in-
pathway-based chronic disease/wellness screen (NCD terplay between genetic and epigenetic mechanisms.
assay) developed as a starting point for application This means that people can alter their genetic expres-
of pathology-supported genetic testing (PSGT). sion by applying easy lifestyle changes, such as ade-
quate intake of folate and other nutrients found to be
This is a novel concept developed in South Africa to essential for DNA methylation in a gene-specific man-
help distinguish between genetic and lifestyle-relat- ner. Since epigenetic marks are potentially reversible,
ed conditions requiring different treatment strategies. new opportunities for risk modification and prevention
When the boundaries between these two risk categories of NCDs become possible, using lifestyle changes and
are blurred, or the information obtained is insufficient to targeted medical treatment.2
address the health concerns of an individual, extended
genetic testing using whole genome/exome sequenc- Enormous sums of money are spent on helping peo-
ing can be performed. This allows for simultaneous as- ple to regain or maintain their health. However, the sig-
sessment of multiple gene variants for clinical relevance
to familial risk and lifestyle- or therapy-induced medical HANDBOOK OF GENERAL MEDICINE VOL 1
conditions. The PSGT reports include a summary page
focused on the reason for testing, accompanied by a
more detailed description of familial and personal risk
14 TREATMENT APPROACHES
nificant progress made over the past 50 years, particu- a month. Processed food was not part of the diet and
larly with regard to new medicines and more advanced foods with added sugar only rarely. One or two glasses
diagnostic techniques, has sometimes encouraged ill of local wine were consumed with meals.
health. The long-term use of symptomatic medications
may have undesirable iatrogenic side effects and does Following these results, Serge Renaud set up the Lyon
not necessarily stimulate healing of underlying metabol- Diet Heart Study7 in 1985. This was a clinical trial to test
ic and functional abnormalities. Also, long-term use is the effect of a Cretan-style Mediterranean diet on sur-
unaffordable for large sections of the community. vival and the recurrence of heart attacks in patients
who had already suffered one heart attack. After four
Over the past few decades, several extensive studies years, fatal and non-fatal coronary events had been
have been performed to identify the factors that distin- reduced by half in those following the Mediterranean-
guish societies with longer-than-average life expectancy style diet.
from those with a high prevalence of chronic diseases.
Life expectancy and quality of life are far more closely Several recent surveys have further supported the
linked to diet and lifestyle than previously realised.3 The Mediterranean diet as a way to help maintain optimum
global epidemic of obesity, type-2 diabetes and related health in old age. Those combining all four lifestyle fac-
diseases are having a significant impact on the health of tors (the Mediterranean diet, daily exercise, no smoking
millions. Medical scientists, such as biochemists and ge- and regular, responsible alcohol consumption) reduced
neticists, realised that patients would have to become mortality from heart disease by almost 70%.8,9 This high-
involved in the healing process by taking co-responsibil- lights the importance of nutrition and lifestyle to stay
ity for their health. This led Kotze and van Rensburg4 to healthy and live longer.
implement PSGT of disease pathways shared by many
NCDs with a genetic component. The integrative PSGT Exercise and a change of diet are closely linked to pre-
approach aims to improve quality of life across the dis- venting a host of diseases. There is abundant evidence
ease spectrum, ranging from monogenic disorders with a that physical activity lowers blood pressure, increases
Mendelian inheritance pattern to complex multi-factorial insulin sensitivity, and improves blood-lipid levels and vas-
diseases with a genetic component. Referral to a physi- cular function. Exercise is essential for losing abdominal
cal therapist or genetic counsellor based on disease se- fat that is a major cause of chronic inflammation and
verity forms an integral part of the PSGT service. Potential diabetes due to cytokine secretion. In people who have
benefits include early detection of genetic risk factors already had a heart attack, daily moderate exercise
for cardiovascular disease and the prevention of Alzhei- has proved more successful than any medical treat-
mer’s disease through lifestyle modifications before the ment for preventing heart failure.10 Research has shown
disease becomes manifest.4,5 that the effect of alcohol consumption on biochemical
markers and metabolic processes involved in heart dis-
Under- and post-graduate education in the health ease may be beneficial in some people, while harmful
sciences concentrates mainly on the management of in others, depending on individual differences in genetic
acute medical and surgical conditions that could be background.11 By comparing the effects of alternative,
life-threatening. The individual’s role in managing future moderate consumption of red wine and brandy on the
disease risk is paramount, especially in an ageing socie- lipoprotein profile in the same experimental population
ty that relies heavily on medical or surgical interventions of healthy adults, genetic risk factors that may contrib-
to cure the disease. ute to differences in response were identified. Moderate
alcohol consumption has a protective effect on cardio-
Cardiovascular diseases vascular disease risk factors by increasing HDL-choles-
terol. This study provided additional evidence that red
Heart disease is the primary cause of death in the de- wine, containing more non-alcoholic components than
veloped world, and is a growing problem in develop- brandy, has greater health benefits. Red wine reduced
ing countries, as the population adopts a westernised platelet aggregation that is ascribed to the presence of
lifestyle. The World Health Organization predicted that polyphenol antioxidants in the wine.
heart disease would soon be responsible for 60% of all
deaths worldwide by 2015. This confirms what Sir William Since alcohol intake may be contra-indicated in indi-
Osler wrote in 1862: “A man is only as old as his arteries”. viduals with specific genetic alterations that occur rela-
tively frequently in the general population, a multi-gene
The American nutritionist Ancel Keys initiated the NCD assay was developed aimed at early detection of
Seven Countries Study6 in the 1960s, that explored the genetic markers correlating with known biochemical
relationship between diet and coronary heart disease pathological cardiovascular risk factors, to enable the
in the USA, Finland, the Netherlands, Italy, Yugoslavia, development of individually tailored preventive pro-
Greece and Japan. After 15 years’ observation, there grammes.12 Genetic testing is used to diagnose treat-
was clear evidence of a much lower death rate due able subtypes of complex chronic diseases, to facilitate
to heart disease on the island of Crete. The Cretan diet prevention of cumulative risks and to formulate inter-
consisted mainly of fruit and vegetables, bread and vention programmes tailored to the individual.4,13
grains, nuts and seeds. Olive oil was the primary fat,
and low- to moderate amounts of dairy products, such The researchers also studied the effects of an alkaline
as cheese and yoghurt, were eaten daily. Eggs were Mediterranean-type diet complemented with red wine
eaten once or twice a week and fish and poultry about on the criteria related to the metabolic syndrome. The
twice a week. Red meat was eaten only once or twice Mediterranean-type diet had a protective effect on the
metabolic syndrome, and more specifically on the im-
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 15
paired glucose regulation, by significantly lowering the plementation with an alkaline powder for relief of osteo- Treatment approaches
fasting glucose level after the diet-plus-wine period. This arthritis symptoms. The research was conducted in two
indicates that lifestyle changes can significantly influ- stages.18 An open, interventional study (n=40) confirmed
ence the impaired response to the physiological effects the notion that Multiforce® Alkaline Powder, 7.5 g twice
of insulin, including those on glucose and lipid meta- daily, is likely to be an effective alternative or adjunct
bolism.14 for the relief of symptoms of osteoarthritis of the hands.
Thereupon, the main study was conducted with 100
The adverse effects of the cholesterol-lowering drugs eligible, consenting volunteers (47-89 years), accord-
are a serious concern for medical practitioners. Hydroxy ing to a randomised, placebo-controlled, crossover de-
methyl glutaryl coenzyme A reductase inhibitors, com- sign (n=50) per treatment group. Study duration was 56
monly called statins, are some of the most commonly days, 28 days per regimen. Crossover to alternate regi-
prescribed medications worldwide. Evidence suggests mens took place on day 28. Clinic visits were fortnightly.
that statin therapy has significant mortality and morbid-
ity benefit for both primary and secondary prevention Compared to placebo, Multiforce® Alkaline Powder
from cardiovascular disease. Reservations have been intake over 28 days was associated with significant re-
expressed regarding the adverse effects of long-term ductions (p <0.005) in pain, tenderness and stiffness of
statin use. interphalangeal and metacarpophalangeal joints of
the hand. Confirmation of systemic alkalinisation by an
Myalgia is the most common side effect of statin use, alkaline powder, rich in organic anions in the form of cit-
with documented rates from 1-10%. Rhabdomyolysis is rate salts, was reflected by a significant and sustained
the most serious adverse effect from statin use, though increase in urine pH. The ingestion of the alkaline pow-
it occurs quite rarely (less than 0.1%). The most com- der was well tolerated. The study demonstrated that the
mon risk factors for statin-related myopathy include dietary supplementation with an alkaline powder, con-
hypothyroidism, polypharmacy and alcohol abuse. De- taining organic anions in the form of citrate salts, signifi-
rangement in liver function tests is common, affecting cantly relieved the symptoms and signs of osteoarthritis
up to 1% of patients. Some statin drugs are potentially of the hands.18
diabetogenic, and there is concern that statins may be
associated with increased risk of cognitive decline and Based on the study outcome, the alkalinisation of the
dementia. Statins do have multiple drug interactions, diet may be considered a safe and effective, non-allo-
primarily those which interact with the cytochrome pathic, therapeutic modality to be used alone or as an
p450 enzyme group.15 adjunct to other interventions in the management of this
common degenerative disease, mainly in the elderly.
The primary prevention of cardiovascular disease
without drugs is high on the agenda of clinicians be- Osteoporosis
cause of the potentially serious adverse effects of some
of the medications used for the primary and secondary Bone is a living tissue that renews and remodels itself
prevention of coronary artery disease. continuously. This process is very intricate, involving
many cellular and biological mechanisms – including
Osteoarthritis gene-expression patterns which account for the activity
of bone cells. Research points to the interplay between
Osteoarthritis is a chronic condition and a major cause genetic and epigenetic mechanisms involved in bone
of morbidity, affecting 60% of men and 70% of wom- health. This is brought about by a variety of environmen-
en over the age of 65 years.16 Current therapeutic ap- tal factors, including diet and exercise. Diet and exer-
proaches, including allopathic (Western) medicine, fail cise can dramatically improve bone health, possibly
to prevent initiation and progression of the disease, and reversing osteoporosis.19
some approaches have life-threatening side effects.
Degeneration of joint cartilage is still the most important Although mainstream medicine is desperate to find
pathophysiological feature of osteoarthritis. Nonsteroi- the “miracle” osteoporosis drug, it becomes clear that
dal anti-inflammatory drugs (NSAIDs) – the mainstay of drugs alone are not the answer to better bone health.
symptomatic relief – could cause serious adverse ef- The adverse effects of bisphosphonates and the im-
fects, especially in the elderly. Pharmacological treat- plications for osteoporosis management highlighted
ments consist of paracetamol, systemic and topical the importance to investigate alternative methods to
cyclo-oxygenase-2 (COX-2) non-selective and selective prevent bone loss and to stimulate bone formation.20
inhibitors, classified as NSAIDs; topical capsaicin; intra- Adopting a regimen of regular exercise, in harmony
articular corticosteroids and hyaluronates; glucosamine with the body’s natural processes, helps to build strong,
and/or chondroitin sulphate and diacerein for possible flexible bones that resist fracture. The correct mechani-
structure-modifying effects; and the use of opioid an- cal bone stimulation increases proliferation and differ-
algesics and tramadol for the treatment of refractory entiation of osteoblasts. This increases bone stimulation,
pain. Studies with disease-modifying drugs in the man- which translates into denser and stronger bones.21
agement of osteoarthritis, such as bisphosphonates to
inhibit increased bone turnover, and methotrexate, The typical "Western diet" is considered to be acido-
which has anti-inflammatory effects, may have serious genic owing to the greater acid load contained in ani-
side effects.17 mal products and the deficiency in fruit and vegetable
content. This results in a state of overlooked low-grade,
A compelling body of anecdotal evidence alerted chronic, compensated metabolic acidosis. It was pos-
the authors to the therapeutic potential of dietary sup- tulated that the ensuing acidotic stress might play a
HANDBOOK OF GENERAL MEDICINE VOL 1
16 TREATMENT APPROACHES
role in the pathophysiology of osteoporosis. In responseBone Spec Alk Dementia – protecting against cognitive decline
to states of diet-derived metabolic acidosis, the kidney
implements compensating mechanisms to restore the While there is currently no treatment that can prevent or
acid-base balance. The latter condition was suggested, cure dementia, researchers have identified some fac-
more than 40 years ago, to predispose to numerous sys- tors that may help protect against cognitive decline.
temic disorders, including osteoporosis, osteomalacia, Exercise offers an impressive array of health benefits.
hypercalciuria and renal stone disease. Chronic aci- It may help ward off cognitive decline and dementia.
dosis is buffered by the skeleton, resulting in increased Regular, moderately strenuous exercise helps to create
osteoclastic bone resorption with ultimate renal calci- a positive self-image and increases self-confidence. It is
um-wasting, as well as a decrease in osteoblastic bone also a valid form of stress relief, helps relieve insomnia,
formation, culminating in decreased bone-mineral den- and works well as an alternative prescription for treating
sity. Existing evidence suggests the clinical importance people with depression. Some studies have shown that
of the so-called nutritional acid-load hypothesis of oste- engaging in a programme of regular exercise improved
oporosis, and the need to treat the “latent” metabolic cognitive function in people who already had memory
acidosis induced by the typical Western diet.22,23 problems. Exercise may be particularly advantageous
for people with the genetic risk associated with suscep-
Concurrent with the research on the influence of tibility to Alzheimer’s disease.24
the alkaline diet on osteoarthritis of the hands,18 the re-
searchers at the University of Stellenbosch identified 30 A Mediterranean-style diet also appears to lower the
candidates with osteopenia. A pilot interventional study risk of developing mild cognitive impairment and slow
on (n=30) volunteers to assess the effects of an alkaline the progression to dementia in people who have the
powder (Multiforce® Alkaline Powder) on biomarkers condition. Also, there is some evidence that moderate
of bone resorption and bone formation was also per- consumption of alcohol reduces the risk of cognitive
formed. Urine deoxypyridinoline (DPD) (expressed as a decline and dementia.25 However, experts do not rec-
function of creatinine), and serum bone-specific alka- ommend drinking alcohol to prevent cognitive decline.
line phosphatase (BSAP) were measured as parameters We can enjoy an occasional alcoholic beverage, but
of resorption and formation respectively, at baseline should limit our consumption to no more than two drinks
and again after three and six months. per day for males or one drink for women.
No difference in urinary DPD (resorption marker) Consistent, good quality sleep is known to improve
could be demonstrated, but a highly significant change overall health and may prevent cognitive decline. Our
(p=0.0007) in serum BSAP (formation marker) was in- bodies rely on a certain amount of regular sleep for a
duced by the study medication (see Figure 1). Any sup- variety of essential functions of the brain. Studies have
pression in the resorption marker (DPD/creatinine) might shown that people who regularly sleep less than the rec-
be ascribable to the calcium content of the alkaline ommended seven to eight hours a night score lower on
powder. However, this was not observed in the pilot tests of mental function. A study by Spira et al26 showed
study. Instead, a stimulation in serum levels of the bone- that the brain concentration of beta-amyloid (a marker
formation marker BSAP was documented – this cannot for Alzheimer’s disease) was lower in patients who slept
readily be ascribed to the calcium content of the pow- for longer. Lim et al27 showed that older adults who were
der and more likely reflects its alkalinising activity. This carriers of the APOE 4 genotype had a reduced risk of
finding is promising, but since an appropriate compara- Alzheimer’s disease or cognitive decline if they had reg-
tor was not included in this pilot study, further studies ular, unfragmented sleep. These results are explained
over longer periods are required. by the findings of Nedergaard and colleagues that the
brain has a glymphatic system that removes metabolic
Visit; LS Means waste products.28 During sleep, the interstitial spaces in
Current effect: F(2, 53)=8.3169, p=.00072 the brain increase by about 60% and neurotoxins are
cleared via a glial-dependent perivascular network
Type III decomposition that drives perivenous drainage.29 In patients with multi-
Vertical bars denote 0.95 confidence intervals ple sclerosis, Nelson et al in 2014 found that smokers had
36 significantly smaller jugular vein diameters than non-
smokers.30 The glymphatic function is improved by low
34 alcohol exposure, but high alcohol intake has adverse
effects, leading to a higher risk of dementia in heavy
a drinkers.31
32 Many researchers believe that mental stimulation as
you age is more important than an education level in
30 maintaining a healthy brain. Activities that require ac-
28 b tive mental engagement, such as reading, writing, do-
ing crossword puzzles, playing board or card games,
26 engaging in group discussions, and playing music, may
24 b protect against cognitive impairment.
22 Social interaction can have profound effects on
health and longevity. There is evidence that secure so-
20 cial connections may be as important as physical activ-
18
16
14
12
10
123
Vi si t
Figure 1. Bone-specific alkaline phosphatase measured
over three visits in volunteers (n=30) taking a calcium-
containing alkaline powder
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 17
ity and a healthy diet to protect memory and cognitive 9. Renaud S, De Lorgeril M. Wine, alcohol, platelets, and the French Treatment approaches
function in several ways with ageing. Social activities paradox for coronary heart disease. Lancet. 1992;339:1523-6.
require you to engage in several important mental pro-
cesses, including attention and memory, which can 10. Ornish D. Dr Dean Ornish’s Program for Reversing Heart Disease.
bolster cognition. It may also help strengthen cognitive New York: Random House; 1993. Eat More, Weigh Less. New York:
reserve, which can delay the onset of dementia. Harper Collins Publishers; 2001.
Conclusions 11. Kotze MJ, Marnewick JL, Kidd M, et al. Assessment of the impact
of hereditary factors on biochemical parameters of cardiovascular
Public health, governmental, as well as public, private risk in relation to moderate alcohol consumption. Nutr Aging.
and medical institutions interested in stemming the glob- 2014;2:189-195.
al epidemic of chronic disease must take into considera-
tion the interface of physiology, human behaviour and 12. Kotze MJ, Van Velden DP, Botha K, et al. Pathology-supported ge-
the obesogenic environment of modern industrialised netic testing directed at shared disease pathways for optimized
societies. The atherogenic and obesogenic environment health in later life. Personalized Med. 2013;10:497-507.
of inactivity, highly palatable foods with hidden fats and
sugars can promote metabolic syndrome, obesity, and 13. Kotze MJ, Badenhorst CH. Chronic disease risk management: Com-
related conditions, whereas fruit and vegetables with an- bining genetic testing with medical and nutritional therapy. SA Fam
ti-inflammatory phytochemicals and an alkaline pH, can Pract. 2005;47:43-44.
counteract these chronic and degenerative diseases.
14. Van Velden DP, Van der Merwe S, Fourie E, et al. The influence of a
Research points to an interplay between genetic Mediterranean-like diet with and without red wine on patients with
and epigenetic mechanisms involved in health main- the metabolic syndrome. S Afr J Enol Vitic. 2007;28:44-49.
tenance and disease prevention. This is brought about
by a variety of environmental factors, including diet 15. Ramkumar S, Raghunath A, Raghunath S. Statin therapy: Review
and exercise, which can dramatically improve cardio- of safety and potential side effects. Acta Cardiol Sin. 2016 Nov;
vascular-, mental-, and bone health, and even prevent 32(6):631-639.
certain cancers. While there is currently no treatment
that can prevent or cure most chronic and degenera- 16. Golding MB. Update on the biology of the chondrocyte and new
tive diseases associated with an ageing society, re- approaches to treating cartilage diseases. Best Pract Res Clin Rheu-
searchers have identified some lifestyle-related factors matol. 2006;20(5):1003-1025
that may help protect against declining health.
17. Schellak N. Cardiovascular effects and the use of nonsteroidal anti-
Genetic tests are developed to diagnose treatable inflammatory drugs. S Afr Fam Pract. 2014;56(1):16-20.
subtypes of complex chronic diseases, to facilitate the
prevention of cumulative risks and to formulate inter- 18. Van Velden DP, Reuter H, Kidd M, et al. Non-allopathic adjuvant
vention programmes tailored to the individual. This in- management of osteoarthritis by alkalinisation of the diet. Afr J Prm
novation paves the way to stimulate healing in the fu- Health Care Fam Med. 2015;7(1).
ture, rather than to treat the symptoms with potentially
harmful allopathic medicines only. The patient will have 19. Delgado-Calle J, Garmilla P, Riancho JA. Do epigenetic marks
to become actively involved in the management of his govern bone mass and homeostasis? Current Genomics. May
or her health by accepting responsibility for healthy, ev- 2012;12(3):252-236.
idence-based lifestyle choices based on family history
and his or her personal genetic profile.3 20. Kennel KA, Drake MT. Adverse effects of bisphosphonates: Implications
for osteoporosis management. Mayo Clin Proc. 2009 Jul;84(7):632-7.
References
21. Denham J, et al. Exercise: Putting action into our epigenome. Sports
1. Kotze MJ, Lückhoff HK, Peeters AV, et al. Genomic medicine and Medicine. 2014 Feb; 44(2):189-209.
risk prediction across the disease spectrum. Crit Rev Clin Lab Sci.
2015;52(3):120-37. 22. Adeva MM, Souto G. Diet-induced metabolic acidosis. Clin Nutr.
2011;30: 416-421.
2. Kim YI. Nutritional epigenetics: Impact of folate deficiency on DNA
methylation and colon cancer susceptibility. J Nutr. 2005;135(11):2703-9. 22. MacDonald HM, Black AJ, Aucott L, et al. Effect of potassium citrate
supplementation or increased fruit and vegetable intake on bone
3. Van Velden, DP. Die pasiënt as vennoot. Pretoria: Protea Boekhuis; 2018. metabolism in healthy postmenopausal women: A randomized
4. Kotze MJ, Van Rensburg SJ. Pathology supported genetic testing controlled trial. Am J Clin Nutr. 2008;88:465-74.
and treatment of cardiovascular disease in middle age for preven- 24. Lückhoff HK, Brand T, van Velden DP, et al. Clinical relevance of
tion of Alzheimer’s disease. Metab Brain Dis. 2012;27(3):255-66. apolipoprotein E genotyping based on a family history of Alzhei-
5. Lückhoff HK, Kidd M, van Rensburg SJ, et al. Apolipoprotein E geno- mer’s disease. Curr Alzheimer Res. 2015;12(3):210-217.
typing and questionnaire-based assessment of lifestyle risk factors
in dyslipidemic patients with a family history of Alzheimer’s disease: 25. Smith D, Yaffe K. Dementia (including Alzheimer’s disease) can be
Test development for clinical application. Metab Brain Dis. 2016 prevented: Statement supported by international experts – 109 Ex-
31(1):213-224. perts from 36 countries – including SJ van Rensburg (South Africa).
6. Keys AB. Seven Countries: A multivariate analysis of death and Journal of Alzheimer’s Disease 38. 2014;699-703.
coronary heart disease. A Commonwealth Fund Book. Cambridge:
Harvard University Press; 1980:1-381. 26. Spira AP, Gamaldo AA, An Y. Self-reported sleep and β-amyloid
7. De Lorgeril M, Salen P, Martin JL, et al. Mediterranean diet, tradi- deposition in community-dwelling older adults. JAMA Neurol. 2013
tional risk factors and the rate of cardiovascular complications af- Dec;70(12):1537-43. doi: 10.1001/jamaneurol.2013.4258.
ter myocardial infarction. Final report of the Lyon Diet Heart Study.
Circulation. 1999;99:779-785. 27. Lim AS, Yu L, Kowgier M, et al. Modification of the relationship
8. Van Velden DP, Mansvelt EPG, Fourie E, et al. The cardioprotec- of the apolipoprotein E ε4 allele to the risk of Alzheimer disease
tive effect of wine on human blood chemistry. Ann NY Acad Sci. and neurofibrillary tangle density by sleep. JAMA Neurol. 2013
2002;957:337-40. Dec;70(12):1544-51. doi: 10.1001/jamaneurol.2013.4215
28. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from
the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/
science.1241224
29. Plog BA, Nedergaard M. The glymphatic system in central nervous
system health and disease: Past, present, and future. Ann Rev Pathol.
2018 Jan 24;13:379-394. doi: 10.1146/annurev-pathol-051217-111018
30. Nelson MC, Isaacs F, Hassan MS, et al. Prevalence of abnormal blood
flow patterns and effects of biochemistry and lifestyle factors on the
major neck vessels in patients with Multiple Sclerosis in the Western
Cape, South Africa. Medical Technology SA. 2014;28(1):26-33
31. Lundgaard I, Wang W, Eberhardt A, et al. Beneficial effects of low
alcohol exposure, but adverse effects of high alcohol intake on
glymphatic function. Sci Rep. 2018 Feb 2;8(1):2246. doi: 10.1038/
s41598-018-20424-y.
HANDBOOK OF GENERAL MEDICINE VOL 1
18 TREATMENT APPROACHES
Drugs for dyslipidaemia
DJ Blom complications due to dyslipidaemia. The major clinical
consequences of dyslipidaemia are atherosclerosis (is-
MBChB, MMed, FCP (SA), PhD. chaemic heart disease, cerebrovascular disease, peri-
pheral arterial disease, aortic aneurysms) and acute
Head of Division of Lipidology, Department of Medicine, pancreatitis. Dyslipidaemia management is therefore
University of Cape Town, Cape Town primarily risk management: reducing the risk of a cardio-
vascular event in those patients with predominant hy-
The vast majority of dyslipidaemic patients have no percholesterolaemia or reducing the risk of an episode
symptoms directly referable to dyslipidaemia. The pri- of acute pancreatitis in those with severe hypertriglyc-
mary goal of drug therapy for dyslipidaemia is therefore
not alleviation of symptoms, but reducing the risk of
Table 1. Classes of lipid-modifying drugs
Drug class Examples1 Main clinical indication Effect on lipids
% change % change % change
LDLC HDLC TG
HMG CoA reductase Atorvastatin Primary agent for cardiovascular risk reduction ¯25-60 ↑5-15 ¯10 -35
inhibitors Fluvastatin
(statins) Lovastatin
Pravastatin
Simvastatin
Rosuvastatin
Bile acid sequestrants Cholestyramine Additional LDLC reduction for inadequate statin ¯15-25 ↑3-8 ¯0-10
response or statin intolerance ¯15-20 ↑3-5 ¯3-5
¯10-25 ↑5-30 ¯20-50
Cholesterol Ezetimibe Additional LDLC reduction for inadequate statin
response or statin intolerance
absorption inhibitors
Hormone-sensitive Niacin Triglyceride reduction
lipase inhibitors2 Acipimox HDLC elevation
LDLC reduction, LDL particle size
Fibrates Bezafibrate Hypertriglyceridaemia ¯5-20 ↑10-35 ¯20-50
Fenofibrate
Gemfibrozil
1 – The table lists drugs available in South Africa
2 – These agents have complex mechanisms of action that extend beyond hormone-sensitive lipase inhibition.
Table 2. Single-tablet combination lipid-modifying therapies
Component 1 Component 2 Main clinical indication Comments
Simvastatin Ezetimibe
Cardiovascular risk reduction (simvastatin) Combination of statin + cholesterol absorption
Niacin Laropiprant Additional LDLC reduction (combination) inhibitor synergistically lowers LDLC
Treatment of mixed hyperlipidaemia (TG↑, HDLC¯, Laropiprant inhibits the prostaglandin receptor DP1
↑LDLC despite statin therapy) and reduces the flushing associated with niacin
Table 3. Lipid-modifying drugs and their roles in treating various lipid phenotypes
Drug Hypercholesterolaemia Mixed hyper Hypertriglyceridaemia
lipidaemia
Extreme Severe Moderate Severe Moderate
Statins +++ +++ +++ ++ x+
+ x xx
Cholestyramine1 +++ ++ + + xx
+ ++ ++ ++
Ezetimibe1 +++ +++ x ++ +++ +++
Niacin ++
Fibrates xx
+++ – central role, drug of choice
++ – very useful
+ – can consider using in special circumstances
x – not generally useful in this condition
1 – most effective in combination with a statin, modest effect as monotherapy
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 19
Table 4. Statins currently marketed in South Africa Treatment approaches
Statin Starting dose Maximal dose Lipid effects at starting dose
HDLC
Rosuvastatin 5 mg 40 mg LDLC TG
Atorvastatin 10 mg 80 mg % change % change % change
Simvastatin 10 mg 40 mg +13
Pravastatin 10 mg 80 mg -45 +6 -15
Fluvastatin 20 mg 80 mg -38 +8 -19
Lovastatin 20 mg 80 mg -28 +2 -19
-19 +3 -11
-22 +5 -12
-29 -8
eridaemia (triglycerides >10-15 mmol/L). Lipid-lowering The baseline LDLC and the target LDLC determine
treatment is just one aspect of risk reduction and treat- the statin dosage. In South Africa, the current LDLC tar-
ment is not complete without advice on lifestyle modi- get is <1.8 mmol/L for those with clinically overt cardio-
fication (smoking cessation, diet, exercise) and control vascular disease and most type II diabetics. In primary
of other risk factors, such as hypertension. Almost all pa- prevention patients with a 10-year risk of 15-30%, the
tients will require long-term therapy for optimal benefit. target is <2.5 mmol/L, while the target is <3.0 mmol/L if
the risk is less than 15%. Statins have a non-linear dose-
Risk assessment always precedes the initiation of lipid- response curve and doubling the dose of a statin only
lowering treatment and as cardiovascular risk in par- lowers LDLC by a further 6%.
ticular may be affected by many variables, there are
no absolute lipid values at which treatment is indicated. The choice of statin is largely dictated by the required
Patients with multiple risk factors, such as smoking, dia- reduction in LDLC, potential for drug interactions and cost.
betes and hypertension, will need treatment at much
lower lipid values than those in whom hypercholesterol- The drugs most likely to interact with statins by inhib-
aemia is the only problem. iting their hepatic metabolism, are azole antifungals,
cyclosporine, macrolides, protease inhibitors and ami-
Lipid-modifying drugs odarone. Rosuvastatin and pravastatin are least affect-
ed by inhibition of cytochrome p450 enzymes.
There are five major classes of lipid-modifying drugs that
are listed in Table 1. Table 2 summarises single-tablet There is no convincing evidence that any one statin
combination therapies available in South Africa. There offers superior risk reduction when compared to other
are also two food supplements or “nutraceuticals” statins, as long as equivalent reductions in LDLC are
which influence lipid metabolism. Plant sterols or stanols achieved. Table 4 provides further details on the statins
can be added to foods such as margarine or yoghurt available in South Africa.
and achieve modest LDLC-lowering in the range of
6-15%. Omega-3 fatty acids (fish oil supplements) have The most frequent side effect of statins is muscle toxi-
a modest triglyceride-lowering effect in mild hyper city. Patients may experience predominantly proximal
triglyceridaemia and have been shown to reduce sud- muscle pain, with or without evidence of muscle break-
den cardiac death in high-risk individuals. down, as seen by elevation of the creatinine kinase. In
the worst-case scenario, this may progress to rhabdo-
The choice of a lipid-modifying agent for a particular myolysis and renal failure due to myoglobinuria.
patient is based on the following criteria:
• Lipid phenotype: What is the primary lipid abnormal- Muscle toxicity is dose-related and is seen more fre-
quently in the elderly, those with renal failure, untreated
ity? (See Table 3.) hypothyroidism and when statins are co-prescribed with
• Therapeutic goal: cardiovascular risk reduction or fibrates or drugs that inhibit their metabolism. Recently,
an increased risk of myopathy has been found with the
prevention of pancreatitis? 80 mg dose of simvastatin and simvastatin should not be
• Outcome data of drug for specified goal uptitrated beyond 40 mg per day. Patients who have
• Risk of interaction with other drugs the patient is taking taken simvastatin 80 mg per day for more than a year
• Side-effect profile of drug without muscle-related side effects may continue on
• Cost this dose.2
Statins Ezetimibe
Statins are the best-known and most widely prescribed Ezetimibe is a cholesterol-absorption inhibitor. It de-
lipid-modifying drugs. Their efficacy and safety has creases LDLC by 15-25% as monotherapy. The maximal
been well documented in multiple large studies.1 Statins benefit is seen at a dose of 10 mg/day and this is the
primarily reduce LDLC and have been shown to reduce only marketed dose. Ezetimibe is generally well toler-
cardiovascular events in long-term studies. ated. The effect of ezetimibe is additive to that of statins
and its main use is as add-on treatment for patients who
They are therefore the drugs of choice in hypercholes- are not reaching LDLC targets at maximal doses of a
terolaemic patients where cardiovascular risk reduction potent statin or are statin-intolerant.
is the primary goal of therapy.
HANDBOOK OF GENERAL MEDICINE VOL 1
20 TREATMENT APPROACHES
Cholestyramine Conclusion
Cholestyramine works by binding bile acids in the in- With our current armamentarium of lipid-lowering medi-
testine and reducing the endogenous bile-acid pool. cation, it is possible to manage dyslipidaemia safely and
Cholestyramine is not absorbed systemically and is effectively in the vast majority of patients. Lipid-modifying
therefore very safe. Gastro-intestinal side effects in the drugs only prevent a proportion of cardiovascular events
form of nausea, bloating and constipation are frequent and research into further “anti-atherosclerotic” drugs is
and many patients tolerate cholestyramine poorly. ongoing. The bigger challenge is, however, implement-
Cholestyramine may also interfere significantly with the ing the evidence we currently have: making these drugs
absorption of other medications and should be dosed available and affordable to the patients who need them
well apart from other medications. and then securing long-term adherence.
Cholestyramine should not be used in patients with hy- REFERENCES
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cations and cholestyramine is now rarely prescribed. 2. Egan A, Colman E. N Engl J Med. 2011;365(4):285-287.
3. Keech A, Simes RJ, Barter P, Best J, Scott R, et al. Lancet. 2005;
Fibrates
366(9500):1849-1861.
Fibrates activate the peroxisome proliferator-activated 4. Ginsberg HN, Elam MB, Lovato LC, et al. N Engl J Med. 2010; 362
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ways in lipoprotein metabolism. Fibrates reduce tri- (17):1563-1574.
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hyperlipidaemia where both cholesterol and triglycerides 6. Boden WE, Probstfield JL, Anderson T, et al. N Engl J Med. 2011;
are elevated. Fibrates are often prescribed in combina-
tion with statins for the latter indication, but combination 365(24):2255-2267.
therapy is associated with a higher risk of side effects 7. Goldberg RB, Jacobson TA. Mayo Clin Proc. 2008;83(4):470-4784.
(myopathy) and should be initiated and monitored by
specialists. Renal clearance is important in fibrate meta-
bolism and great care must be taken in patients with
impaired renal function. The currently available fibrates
are bezafibrate, fenofibrate and gemfibrozil. Gemfibrozil
should not be prescribed in combination with statins due
to a higher risk of interactions. Fenofibrate has shown in-
triguing benefits on diabetic microvascular disease in a
recent study.3 Routine addition of fenofibrate to simva-
statin in another study of diabetics with very high cardio-
vascular risk did not improve cardiovascular outcomes,
except possibly in the subgroup with the highest triglycer-
ides and lowest HDLC.4
Nicotinic acid
Nicotinic acid (or niacin) is a B-group vitamin that influ-
ences lipid metabolism in pharmacological dosages. It
decreases triglycerides, increases HDLC and modestly
lowers LDLC. Flushing is a problematic and frequent side
effect. Extended-release preparations are associated
with less flushing. Flushing is also reduced by co-admin-
istering nicotinic acid with a specific prostaglandin D2
receptor subtype 1 blocker (laropiprant).5 There is cur-
rently renewed interest in this old drug as it has multi-
ple beneficial effects on the lipid profile and newer for-
mulations are better tolerated. In a recently published,
relatively small study, niacin therapy did not improve
cardiovascular outcomes when added to intensive sta-
tin therapy and the results of a larger trial are awaited to
clarify the role of niacin in cardiovascular risk reduction.6
Although niacin can increase glucose, this is usually not
clinically problematic.7
HANDBOOK OF GENERAL MEDICINE VOL 1
Combination fenofibrate plus simvastatin therapy in patients with:
Mixed dyslipidaemias
• Significantly improves TG, non-HDL-C and HDL-C levels vs simvastatin monotherapy (p < 0.001) 1
Type 2 diabetes mellitus
• Reduces CV events by 31 % vs simvastatin monotherapy *3
Lipanthyl® has a good safety profile in combination with a statin 2
Dosage and directions for use: 4
Adults One 200 mg capsule daily with food
* In a subgroup of patients with TG ≥ 2,30 mmol/L + HDL-C ≤ 0,88 mmol/L
TG, triglycerides; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol, CV, cardiovascular
Reference: 1. Grundy SM, Vega GL, Yuan Z, Battisti WP, Brady WE, Palmisano J. Effectiveness and Tolerability of Simvastatin Plus Fenofibrate for Combined Hyperlipidemia
(The SAFARI Trial). Am J Cardiol 2005;95:462-468. 2. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. The FIELD Study Investigators. Effects
of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised, controlled trial. Lancet
2005;366:1849-1861. 3.Elam MB, Lovato LC, Byington RP, et al. Hypertriglyceridemia and Low HDL-C Predicts Fenofibrate Response in The ACCORD-Lipid Trial.
Circ 2010;122:A19724. 4. Lipanthyl® Package Insert. Abbott Laboratories (Pty) Ltd, South Africa. 23 September 2005.
S3 LipanthyL 200 mg capSuLeS. Pack size/s: 30 capsules. Each capsule contains 200 mg fenofibrate (micronised). Pharmacological classification a
7.5 serum cholesterol reducers. Registration number 30/7.5/0494. Namibia: NS2. 10/7.5/0333. For full prescribing information refer to the package insert
approved by the Medicines Regulatory Authority. Further information is available on request from the holder of the registration. Abbott Laboratories
S.A. (Pty) Ltd. Co. Reg. No. 1940/014043/07. Abbott Place, 219 Golf Club Terrace, Constantia Kloof, 1709. Tel: (011) 858 2000. Date of
Publication of this promotional material: June 2019. Promo. No. ZAELIL190123
22 TREATMENT APPROACHES
Management of heart failure with reduced
ejection fraction (HFrEF)
MC Hendrickse Stable heart failure describes a patient with symptoms
remaining unchanged for at least one month. Decom-
MBChB (UCT), FCP (SA), Cert. Cardio pensated chronic heart failure often results in hospital
admission and has a bearing on prognosis.
Specialist Cardiologist in Private Practice, Cape Town
The New York Heart Association Functional Classifica-
Heart failure is a clinical syndrome characterised by tion of cardiac failure is used to differentiate among
typical symptoms (e.g. breathlessness, ankle-swelling various classes of cardiac failure, depending on symp-
and fatigue) that may be accompanied by signs (e.g., toms. It also determines eventual therapy (see Table 1).
elevated jugular venous pressure, pulmonary crackles
and peripheral oedema) caused by a structural and/or Table 1. Functional classification of cardiac failure
functional cardiac abnormality, resulting in a reduced
cardiac output and/or elevated intracardiac pressures Class I No limitation of physical activity. Ordinary
at rest or during stress. physical activity does not cause undue
breathlessness, fatigue, or palpitations.
The clinical syndrome is characterised by progressive
fluid overload, resulting from the maladaptations to car- Class II Slight limitation of physical activity.
diac dysfunction stemming from a multitude of causes, Comfortable at rest, but ordinary physical
including hypertension, ischaemia, valvular heart dis- activity results in undue breathlessness,
ease, intrinsic muscle disease and pericardial disease. fatigue or palpitations.
Heart failure includes a broad spectrum of patients
– from those with normal left ventricular systolic func- Class III Marked limitation of physical activity.
tion (EF >50%) to those with mid-range ejection fraction Comfortable at rest, but less than
(EF 40-49%) and reduced left ventricular ejection frac- ordinary physical activity results in undue
tion (EF ≤40%). This article focuses mainly on the man- breathlessness, fatigue or palpitations.
agement of patients with heart failure and reduced left
ventricular ejection fraction, HFrEF (EF ≤40%). Class IV Unable to carry on any physical activity
without discomfort. Symptoms at rest
In modern practice, the ejection fraction is usually can be present. If any physical activity is
assessed using echocardiography. However, radionu- undertaken, discomfort is increased.
cleotide techniques, cardiac magnetic resonance im-
aging (CMR) and CT-scanning may also be used, with Source: New York Heart Association
the added advantage of picking up various aetiologi-
cal factors resulting in cardiac dysfunction. Cardiac MR Treatment objectives
is effective in delineating pathology that may otherwise
be missed using conventional echocardiographic tech- The objectives of correctly managing heart failure are
niques, such as infiltrative conditions, i.e. sarcoidosis. to improve the clinical status, functional capacity, qual-
Functional MRI has become increasingly popular as a ity of life and to prevent hospital admissions. Treatment
non-invasive method for assessing myocardial viability is targeted at modifying maladaptive neurohumoral
and perfusion. responses, thereby improving symptoms and survival. It
is of utmost importance to treat patients appropriately
Patients with heart failure are often very complex to di- and timeously, as recurrent hospital admissions impact
agnose as they often have a range of other comorbidi- on morbidity, mortality and ultimately prognosis.
ties, including hypertension, diabetes mellitus, cancer
and other general medical conditions. Initial investiga- Pharmacological treatment of heart
tion and treatment of heart failure with reduced ejec- failure with reduced ejection fraction
tion fraction differs according to the duration of symp-
toms and whether the heart failure is of new onset (de Angiotensin-converting enzyme inhibitors (ACEIs), an-
novo) or chronic. De novo heart failure may emanate giotensin receptor blockers (ARBs), mineralocorticoid
from an acute condition, such as an acute ischaemic antagonists (MRAs) and beta-blockers (BBs) form the
event or myocarditis, or acutely decompensated di- cornerstone of cardiac-failure treatment for patients
lated cardiomyopathy that has developed over weeks with reduced ejection fraction.
to years, becoming evident once a precipitating factor
“tips” the balance. Angiotensin receptor blocker-neprilysin inhibitors
(ARNIs), combine the effects of valsartan and sacu-
Heart failure may be completely reversible, i.e. in the bitril in boosting plasma levels of BNP, and have been
setting of acute viral myocarditis, tachycardia-induced shown to be superior to ACE inhibitors, i.e. enalapril, by
cardiomyopathy or Takotsubo (stress-induced cardio- reducing hospitalisation for heart failure (21% RRR), and
myopathy), and therefore it is of utmost importance significantly reducing cardiovascular death (20 % RRR)
to define the aetiological mechanism which may then and all-cause mortality (16% RRR). This drug has been
have a bearing on initial therapy, maintenance treat- an exciting development in the field of heart-failure
ment and prognosis. management.
HANDBOOK OF GENERAL MEDICINE VOL 1
ß
RESTORE
cardiac function
CARVEDILOL:
• is indicated twice daily for
mild to moderate stable
symptomatic congestive
heart failure
• is indicated once daily for
essential mild to moderate
hypertension
• has a positive effect
on metabolic parameters.1
C A R V E D I L O L 6,25 mg 12,5 mg 25 mg
For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898
Email [email protected] CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za
CARVETREND 6,25, 12,5, 25 mg. Each tablet contains 6,25, 12,5, 25 mg carvedilol respectively. S3 A37/7.1.3/0276, 0277, 0278. NAM NS2 08/7.1.3/0105, 0104, 0103. BOT S2 BOT1101790, 1791, 1792. For full prescribing
information, refer to the professional information approved by SAHPRA, December 2014. 1) Panagiotis C Stafylas, Pantelis A Sarafidis. Carvedilol in hypertension treatment. Vascular Health and Risk Management 2008;4(1):23-30.
CDE479/07/2018.
24 TREATMENT APPROACHES
Diuretic therapy has its place in reducing signs and Mineralocorticoid inhibitors
symptoms of heart failure, but little data exist to support
mortality benefit. Mineralocorticoid inhibitor (MRA) therapy (i.e. spirono-
lactone and eplerenone) is recommended in all symp-
Ivabradine has been shown to improve clinical out- tomatic patients with heart failure with reduced ejection
comes and should be considered in patients with a rest- fraction (ejection fraction of less than 35%; NYHA II+),
ing tachycardia, despite the maximally tolerated beta in addition to ACE inhibitors and beta-blockers, to re-
blockade. duce hospitalisation and mortality. Caution should be
exercised in patients with hyperkalaemia and those
Angiotensin-converting enzyme inhibitors with impaired renal function. Potassium levels should be
monitored. Gynaecomastia is an important complica-
Data show that ACE inhibitors reduce morbidity and tion to discuss with patients because mineralocorticoid
mortality in patients with heart failure with reduced ejec- antagonists have an affinity for steroid-binding proteins,
tion fraction. These agents inhibit the renin-angiotensin- which may affect androgen-, oestrogen- and corticos-
aldosterone system (RAAS), and it is recommended teroid-binding. In male subjects, eplerenone has a lesser
that they are titrated to the maximum tolerated doses propensity for the development for gynaecomastia,
to achieve the desired therapeutic effect. Angio-oede-
ma, renal dysfunction and hypotension may limit tole- Studies related to mineralocorticoid antagonist effi-
rance and uptitration. Asymptomatic patients should cacy refer to the RALES trial (NYHA III+) and EMPHASIS
also be placed on ACE inhibitor therapy to reduce the trial (NYHA II+). Patients with ischaemic heart disease
risk of decompensation, hospitalisation and death. (Tri- and heart failure may also benefit from the addition
als relating to ACE inhibitors include CONSENSUS and of a mineralocorticoid antagonist. Mineralocorticoid
SOLVD.) antagonists are also of great benefit in the post-ST eleva-
tion myocardial infarction setting, where the LVEF ≤40%.
ACE inhibitors, in addition to beta-blocker therapy,
are a class IA-indicated combination – it reduces both Angiotensin receptor blocker-neprilysin inhibitors
hospitalisation and death.
Angiotensin receptor blocker-neprilysin inhibitors (ARNIs)
Angiotensin receptor blockers (CHARM and ValHeFT constitute a new therapeutic class of drugs acting on
trials) are similarly indicated in patients who are intoler- the renin-angiotensin aldosterone system (RAAS) and
ant to ACE inhibitors, and have an analogous effect in the natriuretic peptide system. The original molecule,
reducing the negative outcomes in patients with heart LCZ 696, now traded as Entresto®, is a composite of
failure. valsartan and sacubitril, a neuropeptidase inhibitor
(neprilysin inhibitor).3 Neprilysin breaks down BNP (brain
ARBs are recommended to replace ACE inhibitors in natriuretic protein), potentially decreasing its beneficial
patients who are ACE inhibitor-intolerant. The CHARM effect. Neprilysin also breaks down angiotensin I and
trial demonstrated the benefit of candesartan in reduc- angiotensin II. By inhibiting neprilysin, angiotensin levels
ing cardiovascular mortality. Reduced hospitalisation increase, negating the beneficial effects of an elevated
was also noted in the ValHeft trial (valsartan). BNP. The addition of valsartan, therefore, inhibits the an-
giotensin 1 receptor (the receptor for angiotensin II), re-
At the GP level, the combination of ACE inhibitors and sponsible for vasoconstriction, sodium and water reten-
ARBs is not recommended, although this combination tion, including myocardial hypertrophy. The beneficial
has been used in restricted patients who are unable to effects of BNP are then able to take effect, including
use mineralocorticoid antagonists (not recommended potentiating sodium and water loss, reducing aldoster-
outside of the specialist realm). one and renin secretion, reducing sympathetic outflow,
decreasing vasopressin secretion, and reducting salt
Beta-blockers appetite and water intake. It also reduces myocardial
hypertrophy and fibroblast proliferation, augments va-
Beta-blockers reduce mortality (CIBIS-II and COMET trials) sodilatation and reduces systemic vascular resistance.
in symptomatic patients with heart failure and reduced The beneficial effects of natriuretic peptides (BNP and
ejection fraction. Beta-blockers are usually withheld in ANP) also reduce pulmonary artery pressure, pulmonary
the initial phase of stabilisation during heart-failure treat- artery wedge pressure and right atrial pressures.
ment until adequate diuresis has occurred. Doses may
then be uptitrated slowly to maximum doses, at times The PARADIGM-HF trial1,2 was an active-controlled
requiring a few weeks to months to achieve these maxi- study that evaluated the superiority of Entresto® versus
mum doses. Common cardio-selective (B1-selective) enalapril on rates of heart-failure hospitalisation and
beta-blockers in the South African setting include aten- mortality reduction in patients with chronic HFrEF, and
olol, bisoprolol, metoprolol, and carvedilol (alpha- and provided evidence to support the replacement of ACE
beta-selective). ACE inhibitors and beta-blockers may inhibitors or ARBs with Entresto® in the management of
be started simultaneously, or in a staggered fashion with chronic HFrEF. Seventy per cent of the study population
either an ACE inhibitor or a beta-blocker as the initial were NYHA Class II (slight limitation of physical activity –
agent of choice. As mentioned, patients should be clini- comfortable at rest, but ordinary physical activity caus-
cally stable with medications uptitrated to maximum es symptoms of heart failure). The primary endpoint was
doses if tolerated. the first event in the composite of cardiovascular death
or heart-failure hospitalisation.
Beta-blockers are especially useful in the setting of
heart failure with co-existent atrial fibrillation, ischaemic The pharmaceutical agent Entresto®, is currently pre-
heart disease and in the setting of cardiac failure with
other underlying arrhythmias.
HANDBOOK OF GENERAL MEDICINE VOL 1
“CHAINED”DON’T LET YOUR PATIENTS BE A potent short-acting diuretic1
TO THE NEAREST TOILET SET YOUR PATIENTS FREE FROM OEDEMA
WITHOUT MAJOR INTERRUPTIONS TO THEIR
DAILY ROUTINE.2
BURINEX is a potent, short-acting diuretic with a reduced period of urinary frequency to
minimise disruption of daily routine1,2
BURINEX is completely absorbed (≥ 80 %), which results in predictable diuresis3,4
BURINEX offers the flexibility of once daily or more frequent dosing for individualised
treatment1
BURINEX is the only loop diuretic that can be directly switched from IV to oral without a
change in dose3,4
LEPETTA 082 382 4645 11350J References: 1. Burinex® approved package insert,1985. 2. Bennion-Pedley J, Postlethwaite DL, Lomas DM, et al. The Effect of Bumetanide and Frusemide on Frequency of Microtitration. Journal of International Medical Research 1975;3:241-244. 3. Brater DC. Pharmacology of Diuretics. American
Journal of Medical Science 2000;319(1):38-50. 4. Buggey J, Mentz RJ, Pitt B, et al. A reappraisal of loop diuretic choice in heart failure patients. American Heart Journal 2015;169(3):323 -333.
S3 Burinex® 1 mg Tablets. Each tablet contains bumetanide 1 mg. Reg. No. G/18.1/94. S3 Burinex® 2 mg 0,5 mg/ml 4 ml Injection. Each ampoule contains bumetanide 0,5 mg/ml in a neutral isotonic solution (phosphate buffer). Reg. No. P/18.1/145. For full prescribing information, refer to the
package insert approved by the medicines regulatory authority. 2019053010141430
Adcock Ingram Limited. Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021, South Africa. Telephone + 27 11 635 0000. www.adcock.com.
26 TREATMENT APPROACHES
scribed in combination with other heart-failure thera- monitoring of renal failure and hypokalaemia. Com-
pies, excluding ACE inhibitors and ARBs. In the South monly used loop diuretics include furosemide, torasem-
African setting, Entresto® is indicated as second-line ide and bumetanide.
therapy, replacing ACE inhibitors or ARBs in the treat-
ment of symptomatic heart failure Class II to Class IV for Thiazide/thiazide-like diuretics typically include hydro-
patients with HFrEF.3 chlorothiazide and indapamide. Potassium-sparing
diuretics have also been used, including amiloride and
Entresto® resulted in a 20% reduction in death from triamterene. Again, exercise caution when using com-
cardiovascular causes and a 21% reduction in hospitali- bination therapy, as significant electrolyte disturbances
sation for heart failure. There was also a 16% relative risk may occur.
reduction in all-cause mortality. The risk of sudden death
was also reduced by 20%. There were 30% fewer pres- Ivabradine
entations to the emergency unit, 18% fewer admissions
to ICU and 12% lower risk of all-cause hospitalisation in Ivabradine has been shown to reduce the combined
patients treated. The use of Entresto® also significantly endpoint of hospitalisation and mortality in heart failure
improved quality of life.1 in patients with symptomatic heart failure with an LVEF
<35% and patients in sinus rhythm with a heart rate over
The PARADIGM-HF trial,1 therefore, represents a signifi- 70 beats/minute (SHIFT trial). Survival benefit was noted
cant landmark in the study of heart-failure therapy. in patients with a heart rate in excess of 75 beats per
minute. This agent should not be used in patients in atrial
When initiating Entresto®, it is essential to stop the ACE fibrillation.
inhibitor and ARB for 36 hours before administration.
The initial dose in most patients will be 100 mg twice Hydralazine and isosorbide dinitrate combination
a day. After three to four weeks, therapeutic doses of
200 mg twice daily may be used, if tolerated. Should In black patients of African descent, the combination
the patients be on low doses of an ARB or ACE inhibi- of hydralazine and isosorbide dinitrate has been shown
tor, the same process of stopping these agents within to reduce hospitalisation and death in patients with a
36 hours applies. Then start with a slightly lower dose of left ventricular ejection fraction <35%. This combination
Entresto®, 50 mg twice a day, gradually uptitrating to a may furthermore be used in patients unable to tolerate
maximum of 200 mg twice a day over four to six weeks, ACE inhibitors or ARBs. This combination should not be
if tolerated. Hypotension and renal dysfunction may oc- used routinely in all patients with heart failure, as sup-
cur in the initial stages of treatment; however, with the portive studies were small and mainly centred on pa-
continuation of treatment, these effects are expected tients of African descent. These agents are usually add-
gradually to decrease in frequency. The initial 36-hour ed to conventional therapy.
wait before administration is owing to the potential risk
of angio-oedema and hypotension with dual blockade Other treatments
of the RAAS.
Other treatments with a less certain benefit in sympto-
Close attention to liver function, potassium levels, matic patients with heart failure with reduced ejection
symptomatic hypotension, renal dysfunction and angio- fraction include digoxin and other digitalis glycosides.
oedema are important considerations when initiating Recent studies suggest a higher risk of events (heart
Entresto®, preferably under specialist supervision. Dose failure, hospitalisation and death) in patients who have
adjustment may be required, depending on adverse atrial fibrillation with heart failure, and receive digoxin.
events. There is no robust evidence linking Entresto® to However, this has been a highly controversial topic as
an increased incidence of dementia. Currently, Entres- other studies have found no harmful effects in the same
to® is indicated as second-line therapy after failure of clinical setting. Digoxin is best avoided in cases of renal
ARBs and ACE inhibitor therapy for patients with HFrEF. failure and a history of toxicity. Digoxin may be explored
when other therapeutic options cannot be pursued. Di-
Diuretics goxin should be prescribed under specialist supervision
and the monitoring of digoxin levels.
Diuretics reduce symptoms related to cardiac con-
gestion. How they affect mortality has not been com- Non-pharmacological treatment
prehensively studied in randomised control trials. A
Cochrane meta-analysis has shown that patients with Cardiac resynchronisation therapy, with or without an
chronic heart failure treated with diuretics had a de- intracardiac defibrillator (CRT/CRT-D), is supported by
creased risk of worsening heart failure and death when a host of clinical trials for mortality benefit, reduction in
compared to controls. Optimal diuretic therapy also im- hospital admissions and improvement in the quality of
proves exercise capacity. life. Cardiac resynchronisation devices (specialised bi-
ventricular pacemakers) are indicated, in the presence
A combination of loop and thiazide/thiazide-like of specific criteria, i.e. in the presence of a left bundle
diuretics is used to treat challenging patients. Howev- branch block, where symptoms are functionally limiting,
er, the risk of electrolyte disturbance, renal failure and despite optimal pharmacological therapy. Implantable
hypotension should always be kept in mind, and be pre- defibrillator devices prevent sudden cardiac death due
vented. to malignant arrhythmias (ventricular tachycardia or
Loop diuretics are classically labelled as high-ceiling
diuretics, as they may be used in high doses, with mini-
mal side effects. As mentioned, there should be close
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 27
ventricular fibrillation) and may be indicated in primary Treatment approaches
and secondary prevention scenarios.
Left ventricular assisting devices and cardiac trans-
plantation are alternatives for bridging and destination
therapy respectively.
Additional notes
The use of n-3 polyunsaturated fatty acids (n-3-PUFA)
may be considered in the symptomatic heart-failure
patient to reduce the risk of cardiovascular hospitalisa-
tion and death, against a background of optimal anti-
failure therapy.
Antiplatelet therapy offers no benefit to the patient
with heart failure, in the absence of associated coro-
nary artery disease. Likewise, anticoagulation, in the ab-
sence of atrial fibrillation/flutter, and active ventricular
or atrial thrombus, has no effect in reducing morbidity
and mortality, compared with placebo or aspirin.
Long-acting calcium-channel blockers, e.g. diltiazem
and verapamil, should be avoided (negatively inotrop-
ic) in patients with heart failure with reduced ejection
fraction. Amlodipine is safe in patients with heart failure.
Felodipine would be a secondary alternative.
references
1. McMurray JJV, Packer M, Desai AS, et al. Baseline characteristics and
treatment of patients in prospective comparison of ARNI with ACEI to
determine impact on global mortality and morbidity in heart failure
trial (PARADIGM-HF). Eur J Heart Fail. 2014;16(7):817-825.
2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhi-
bition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-
1004.
3. Entresto [prescribing information]. East Hanover, NJ: Novartis Phar-
maceuticals Corp; November 2017.
further reading
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for
the management of heart failure: A report of the American College
of Cardiology Foundation/American Heart Association Task Force on
Practice Guidelines. Circulation. 2013;128(16):e240-e327.
- European Society of Cardiology. Clinical Practice Guidelines. 2018.
https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
HANDBOOK OF GENERAL MEDICINE VOL 1
28 TREATMENT APPROACHES
Statins: poison or panacea?
J Singbo and dangerous drugs – for example, a Google search
(14 Jan 2019) using the term “statin side effect” had
MBChB, FCP (SA) more than 26 million hits. Some of the most commonly
perceived problems include:
Senior Registrar, Division of Endocrinology, Department
of Medicine, University of Cape Town, Cape Town Neurocognitive problems
DJ Blom Case reports, social media and the popular press have
raised concerns about cognitive adverse events, such
MBChB, MMed, FCP (SA), PhD. as cognitive dysfunction, memory loss, severe irritability,
aggression, confusion, suicide attempts and depres-
Head of Division of Lipidology, Department of Medicine, sion, that apparently improved upon discontinuation
University of Cape Town, Cape Town of statins.2-4 This fear surrounding the potential cogni-
tive side effects of statins was exacerbated by the FDA,
Patients with dyslipidemias are at an increased risk of which in 2012 ruled that an additional warning be in-
developing atherosclerotic cardiovascular disease (AS- cluded in the package insert of statins, indicating that
CVD). In the early 1990s, the availability of the 3-hydroxy- statins may have adverse effects on cognition. How-
3-methylglutaryl coenzyme A (HMG-CoA) reductase ever, this FDA decision was not supported by reliable
inhibitors (“statins”) revolutionised the treatment of lipid data. For instance, a study of spontaneous reports of
abnormalities and the prevention of ASCVD. With ever- cognitive adverse events for statins in the FDA data-
increasing evidence regarding their safety and effica- base showed that the frequency of such reports was
cy, we have witnessed a remarkable growth in the num- very similar to those for other drugs used in the manage-
ber of patients eligible for statins, in addition to a move ment of ASCVD. Between November 1997 and February
towards lower low-density lipoprotein (LDL) cholesterol 2002, there were 60 reports of patients who had memo-
targets and, consequently, higher statin doses. Despite ry loss attributed to statin use in the FDA database.5 This
overwhelming proof of efficacy and safety, statins are is equivalent to 1.9 cases of cognitive adverse events
still frequently utilised suboptimally and “statin phobia” per million statin prescriptions, identical to the rate for
is an important contributor to their underutilisation. clopidogrel and virtually the same as the 1.6-cases-per-
million rate for losartan.6 Although there has been some
Statins act primarily by competitively inhibiting HMG- debate in the literature, with some studies reporting
CoA reductase, the rate-limiting enzyme in the choles- mild cognitive dysfunction, as measured by neuropsy-
terol synthetic pathway. Lower intracellular cholesterol chological testing7,8, and others not finding any cogni-
results in the cell upregulating LDL-receptors, which in tive impairment in either cognitively normal patients
turn leads to the lowering of plasma LDL cholesterol. or those with Alzheimer’s disease, the balance of the
Inhibiting HMG-CoA reductase also affects the syn- evidence does not suggest that statins cause cognitive
thesis of isoprenoids. Altered levels of isoprenoids and dysfunction. The Heart Protection Study was the largest
changes in protein prenylation may explain many of double-blind, placebo-controlled, randomised trial to
the effects of statins thought to be independent of lipid- systematically assess memory in statin-treated patients.
lowering.1 These so-called pleiotropic effects include a Memory was assessed using a validated telephonic
beneficial influence on endothelial function; the stabili- questionnaire in more than 20 000 patients at the end of
sation of atherosclerotic plaques; anti-oxidative, anti-in- the study. Cognitive function did not differ significantly
flammatory and antithrombotic effects; and effects on between patients assigned simvastatin or those as-
the immune system and bone metabolism. The clinical signed a placebo. The pooled results of eight long-term
importance of these pleiotropic effects – either benefi- studies, involving more than 23 000 patients, showed a
cial or harmful – is somewhat controversial. Neverthe- significant reduction (29%) in new-onset dementia in
less, statins are being explored as potential treatments statin-treated patients, although not all studies show
in such inflammatory disorders as systemic lupus ery- changes in the same direction.9 Current guidelines do
thematosus and rheumatoid arthritis. Reduction of LDL not support the prescription of statins for the sole indi-
cholesterol seems to be the primary mechanism respon- cation of reducing the risk of dementia. Statins also do
sible for cardiovascular risk reduction as there is a close not appear to be associated with an increased risk of
relationship between the degree of LDL cholesterol re- suicide or depression.5
duction and cardiovascular event reduction. Addition-
ally, equivalent reductions in LDL cholesterol generally Statin-associated muscle symptoms
reduce cardiovascular event rates, irrespective of the
LDL-lowering mechanism. Muscle symptoms are by far the most frequent adverse
reports among statin-treated patients and are the big-
Side effects and statin phobia gest impediment to effective statin therapy in clinical
Despite overwhelming proof of efficacy and safety,
many patients and some clinicians fear the use of
statins. Statins are frequently perceived as highly toxic
HANDBOOK OF GENERAL MEDICINE VOL 1
UNCLOG PIPES THE
• Primary Hypercholesterolemia • Hypercholesterolaemia
• Mixed Dyslipidaemia • Coronary Heart Disease
S4 ADCO-SIMVASTATIN 10 mg. Each tablet contains 10 mg simvastatin and butylhydroxyanisole 0,02 % m/m as an antioxidant. Reg. No. 35/7.5/0277. S4 ADCO-SIMVASTATIN 20 mg. Each tablet contains 20 mg simvastatin and
butylhydroxyanisole 0,02 % m/m as an antioxidant. Reg. No. 35/7.5/0278. S4 ADCO-SIMVASTATIN 40 mg. Each tablet contains 40 mg simvastatin and butylhydroxyanisole 0,02 % m/m as an antioxidant. Reg. No. 35/7.5/0279. S4 ADCO-
ATORVASTATIN 10 mg. Each film-coated tablet contains atorvastatin calcium 10,36 mg equivalent to 10 mg atorvastatin. Reg. No. 43/7.5/1116. S4 ADCO-ATORVASTATIN 20 mg. Each film-coated tablet contains atorvastatin calcium 20,72 mg
equivalent to 20 mg atorvastatin. Reg. No. 43/7.5/1117. S4 ADCO-ATORVASTATIN 40 mg. Each film-coated tablet contains atorvastatin calcium 41,44 mg equivalent to 40 mg atorvastatin. Reg. No. 43/7.5/1118.
For full prescribing information refer to the package insert approved by the medicines regulatory authority. Adcock Ingram Limited.
Reg. No. 1949/034385/06. Private Bag X69, Bryanston, 2021. Tel. +27 11 635 0000 www.adcock.com 201808151093170
30 TREATMENT APPROACHES
practice. Symptoms generally occur within four to six estimate that high-dose statin therapy (e.g. atorvastatin
weeks of starting therapy, but may occasionally occur 40 mg daily) may cause an excess of approximately 50
after several years of treatment. Classically, symptoms to 100 cases of NOD in 10 000 treated individuals.12 How-
tend to be symmetrical and proximal, affecting mainly ever, the net benefit remains positive, both in patients at
the muscles of the shoulder and hip girdles.10 high risk of developing diabetes or patients with estab-
lished diabetes. It is essential to explain to patients that
Although there is no universally agreed upon defini- NOD associated with statin therapy occurs in patients
tion for statin-associated muscle symptoms (SAMS), the with a high baseline risk of becoming diabetic – in other
following terms are frequently used. Myalgia can cause words, patients with normal glycaemia and no insulin re-
unexplained muscle discomfort often described as "flu- sistance will not suddenly become diabetic if they take
like" symptoms with normal creatine kinase (CK) levels. a statin. Also, statins do not have a measurable nega-
Complaints may include muscle aches, soreness, stiff- tive effect on glycaemic control in diabetic patients.
ness, tenderness, and cramps with or shortly after exer- Starting a statin in a patient with diabetes will, therefore,
cise (not nocturnal cramping). Similar symptoms may reduce cardiovascular risk without significantly impact-
occur in patients with minor elevations in CK (approxi- ing glycaemic control.
mately four to 10 times the upper limit of normal [ULN]).
Regulators frequently use the term "myopathy" in patients Haemorrhagic stroke
with muscle symptoms and CK levels more than 10 times
the ULN. Patients with very marked elevations in CK (usu- In observational studies, low cholesterol is associated
ally more than 40 times the ULN) and evidence of renal with a slightly increased risk of intracranial bleed-
impairment or myoglobinuria have rhabdomyolysis – a ing. However, some confusion may be present as low
serious disorder that requires rapid medical intervention. cholesterol is often a marker of poor general health.
Occasionally, patients have elevated CK levels in the In the SPARCL study, patients with a stroke one to six
absence of any muscle symptoms. This should no longer months before enrolment were randomised either to
be a frequent finding as guidelines advise against routine atorvastatin 80 mg/day or placebo. Atorvastatin mark-
monitoring of CK in asymptomatic patients. Exercise and edly reduced the overall stroke risk, and this was due
thyroid disorders are common explanations for inciden- to a decrease in ischaemic strokes. The incidence of
tally discovered elevated CK levels. haemorrhagic stroke was 2.3% in patients on atorvas-
tatin, compared with 1.4% in placebo-treated controls,
The risk of statin-associated muscle adverse events in- but most haemorrhagic strokes occurred in the small
creases if statins are used with enzyme inhibitors. Simva- number of patients randomised to the trial with a base-
statin, and to a lesser extent atorvastatin, are meta- line haemorrhagic stroke. Subsequent cardiovascular
bolised by the hepatic isoenzyme CYP3A4. CYP3A4 outcome studies with statins and other lipid-lowering
Inhibitors may increase the plasma concentration of medications have not found a consistent increase in
these statins, increasing the risk of adverse reactions. haemorrhagic stroke. Statins should thus not be with-
If a potent CYP3A4 inhibitor, such as erythromycin, is held in patients with an ischaemic stroke for fear of con-
called for, then simvastatin or atorvastatin should be verting this to a haemorrhagic stroke. In patients with a
stopped for the duration of therapy. Fluvastatin, pravas- strong indication for a statin (e.g. established coronary
tatin and rosuvastatin are not significantly metabolised artery disease), statins should not be discontinued, even
by CYP3A4 and are less susceptible to CYP interactions. if patients experience a haemorrhagic stroke.
Simvastatin is now contra-indicated with cyclosporin,
danazol and gemfibrozil. The maximum recommended Hepatic dysfunction
dose of simvastatin in conjunction with amlodipine or
diltiazem is 20 mg/day.11 Statins very infrequently cause severe liver disease, and
routine monitoring of liver function tests is not required
There is no doubt that many patients experience mus- in patients on statins. In patients with elevated liver en-
cle symptoms while taking a statin. However, it is not zymes on statins, it is important not to ascribe the abnor-
always clear that these symptoms are causally related mality to statin therapy, but to consider other possible
to statins. For instance, muscle symptoms are reported explanations, such as alcohol, non-alcoholic fatty liver
very commonly in observational studies, but in double- disease, iron overload or viral hepatitis.
blind, placebo-controlled studies, the rates of muscle
symptoms were very similar in the statin and placebo Risks in pregnancy and breastfeeding
group. When PCSK9 inhibitors were studied as an alter-
native therapy for patients with statin intolerance, many Statins are rated as category X in pregnancy and must
patients with a history of not tolerating a minimum of be discontinued before conception, whenever possible.
two statins were either able to tolerate a statin during However, should a patient inadvertently conceive while
the double-blind crossover statin challenge or reported taking a statin, the risk to the foetus is very small, and
muscle symptoms while on placebo.10 there is no need to terminate the pregnancy. Data on
the safety of statins in breastfeeding are minimal. Gener-
Diabetes ally, the use of statins by breastfeeding mothers is discour-
aged, although more recent literature has questioned
Statin therapy is associated with a small, but definite, in- this, especially for hydrophilic statins like rosuvastatin.13
crease in the risk of new-onset diabetes (NOD), and the
risk of intensive statin therapy is slightly higher than that
of moderate statin therapy. Using modelling, one can
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 31
Absolute risk versus absolute benefit Take-home messages Treatment approaches
When explaining the merits of statin use to a patient, The benefits of statins prescribed according to guide-
it is often helpful to spell out the concepts of absolute lines substantially outweigh the risk of adverse effects.
versus relative risk and absolute versus relative benefit. The harm done by negative statin publicity and sub-
sequent treatment discontinuation exceeds any harm
The absolute benefits of statin therapy depend on an done by statins themselves. Statins should be prescribed
individual’s absolute risk of occlusive vascular events with a positive attitude as patients who fear statins are
(which will be influenced by factors such as age, gen- more likely to experience side effects.
der, smoking status and concomitant diseases – e.g.
hypertension or diabetes) and the reduction in LDL Statins are no panacea; neither are they poison. They
cholesterol that is achieved. Patients with the highest are one of the pharmaceutical pillars of cardiovascular
absolute risk also benefit the most from statin treatment risk reduction and are an essential component of a well-
or, to put it differently, the lowest number needed to designed therapeutic plan for patients at high cardio-
treat. For example, lowering LDL cholesterol by 2 mmol/L vascular risk.
with an effective low-cost statin regimen (e.g. atorvas-
tatin 40 mg daily) in 10 000 patients for five years would References
typically prevent major vascular events from occur-
ring in about 1 000 patients (10% absolute benefit) with 1. Goldstein JL, Brown MS. Regulation of the mevalonate pathway.
pre-existing occlusive vascular disease (secondary pre- Nature. 1990;343(6257):425-30.
vention) and in 500 patients (5% absolute benefit) who
are at increased risk, but have not yet had a vascular 2. Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with
event (primary prevention).14 Long-term statin therapy statin cholesterol-lowering drugs. QJM. 2004; 97(4):229-35
has been shown to reduce vascular disease risk during
each year of continued use, so more substantial abso- 3. News C. 76. CGS News. 2005:07 March, 2005.
lute benefits would accrue with prolonged therapy. 4. Graveline D. Lipitor: Thief of memory: Statin drugs and the misguid-
To summarise, the potential major adverse effects of ed war on cholesterol. Pennsylvania: Infinity Publishing; 2006.
long-term statin use are myopathy, NOD, and probably 5. Yang CC, Jick SS, Jick H. Lipid-lowering drugs and the risk of depres-
a small increase in the risk of haemorrhagic stroke. Treat-
ing 10 000 patients for five years with an effective regi- sion and suicidal behavior. Arch Intern Med. 2003; 163:1926.
men (e.g. atorvastatin 40 mg daily) may cause about 6. Richardson K, Schoen M, et al. Statins and cognitive function: A sys-
five cases of myopathy (one of which might progress,
if the statin therapy is not stopped, to the more severe tematic review. Ann Intern Med. 2013 Nov 19;159:688-97.
condition of rhabdomyolysis), 50-100 cases of NOD, and 7. Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on
approximately 5-10 haemorrhagic strokes. However,
any adverse impact of these side effects on major vas- cognitive function and psychological well-being. Am J Med.
cular events has already been taken into account in 2000;108(7)538-546.
the estimates of the absolute benefits of statin therapy. 8. Muldoon MF RC, Sereika SM, et al. Randomized trial of the effects
of simvastatin on cognitive functioning in hypercholesterolemic
Overall, statins are still prescribed in inadequate dos- adults. Am J Med. 2004;117(11):823-829.
es or not being taken by many patients at high cardio- 9. Swiger KJ, Manalac RJ, Blumenthal RS, et al. Statins and cognition:
vascular risk. Although many factors contribute to this, A systematic review and meta-analysis of short- and long-term cog-
unfounded and often irrational fear of statins is un- nitive effects. Mayo Clin Proc. 2013;88(11):1213-21.
doubtedly a significant contributor. A negative percep- 10. Nissen SE, Dent-Acosta RE, Rosenson RS, et al. GAUSS-3 Investiga-
tion of statins, or the expectation that adverse effects tors. Efficacy and tolerability of evolocumab vs ezetimibe in pa-
will occur, may increase the likelihood of experiencing tients with muscle-related statin intolerance: The GAUSS-3 rand-
side effects. As doctors, we should not strengthen or en- omized clinical trial. JAMA. 2016;315(15):1580-90.
courage this nocebo effect.15 A relatively simple mes- 11. Team AMM. New MHRA recommendations on simvastatin interac-
sage for patients is that taking an adequate statin dose tions – implications for patients taking amlodipine & simvastatin
can reduce their relative risk of having a heart attack 40mg/day. New MHRA recommendations. 2012.
or stroke by approximately 50% and the higher their ab- 12. Collins R, Reith C, Emberson J, et al. Interpretation of the evi-
solute risk, the greater the absolute benefits. The prov- dence for the efficacy and safety of statin therapy. Lancet. 2016;
en benefits of statins substantially outweigh their risk of 388(10059):2532-61.
causing harm. Furthermore, many symptoms attributed 13. Lwin EMP, Ritchie U, Gerber C, et al. Transfer of rosuvastatin into
to statins (e.g. muscle symptoms with a normal CK) are breast milk: Liquid chromatography-mass spectrometry meth-
often incidental and not causally related to the statin odology and clinical recommendations. Drug Des Devel Ther.
therapy. The decision to initiate statin therapy should 2018;12:3645-3651
be made after an informed discussion between the cli- 14. Ridker PM, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular bene-
nician and the patient about the risks and benefits of fits and diabetes risks of statin therapy in primary prevention: An
statin treatment, taking into account additional factors, analysis from the JUPITER trial. Lancet. 2012;380 (9841):565-71.
such as potential benefits from lifestyle modifications, 15. Gupta A, Whitehouse A, Collier T, et al. ASCOT Investigators. Ad-
informed patient preference, comorbidities, polyphar- verse events associated with unblinded, but not with blinded, statin
macy, general frailty and life expectancy. therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-
Lowering Arm (ASCOT-LLA): A randomised double-blind placebo-
controlled trial and its non-randomised non-blind extension phase.
Lancet. 2017;389:2473-81.
HANDBOOK OF GENERAL MEDICINE VOL 1
32 TREATMENT APPROACHES
The patient with resistant hypertension:
a practical approach
B Rayner to South African hypertension guidelines in the appro-
priate way, with a validated and calibrated BP-meas-
MBChB, FCP, MMed, PhD uring device.
Emeritus Professor, Division of Nephrology and Hypertension, Patients at risk
Department of Medicine, University of Cape Town, Cape Town
Demographic correlates of RH include black race, old-
Hypertension is the world’s leading risk factor for cardio- er age, visceral obesity, CKD, diabetes mellitus, higher
vascular disease (CVD), stroke, disability, and death. Framingham 10-year risk and male sex.4 Patients with RH
Despite a steady improvement in control rates over the are also more likely to have non-dipping/reverse hyper-
past 30 years, a significant percentage of patients are tension, increased sympathetic nervous system over-
treatment-resistant and fail to meet blood-pressure (BP) activity, and excess aldosterone. Contrary to reports
targets despite appropriate treatment. Resistant hyper- about a study in South Africa done predominately in
tension (RH) is common, with the prevalence ranging black and mixed-ancestry patients, RH was found to be
from 12-15% of population-based studies to 15-18% in more common in leaner subjects.5
clinic-based reports.1,2 The prognosis for RH is adverse as
these individuals remain at increased risk for target or- Practical approach
gan damage, morbidity, and mortality. For example, in
a large retrospective study of more than 200 000 patients A practical guide to the approach to RH is outlined
with incident hypertension, those with resistant hyper- in Figure 1, but for a detailed review of the topic the
tension were 47% more likely to suffer the combined reader is referred to the following reference: Resistant
outcomes of death, myocardial infarction, heart failure, Hypertension: Detection, Evaluation and Management:
stroke, or chronic kidney disease (CKD).3 It is therefore A Scientific Statement from the American Heart Asso-
critical that general practitioners and specialists have a ciation.4 Once apparent treatment resistance has been
sound clinical approach to this important problem. excluded, referral to a specialist is recommended.
Definition Exclusion of apparent
treatment resistance
Resistant hypertension is defined as the blood pressure
of a hypertensive patient that remains elevated above The four most important causes of apparent treatment
goal (>140/90 in South Africa) despite the concurrent resistance are incorrect BP measurement (discussed
use of ≥3 antihypertensive agents of different classes, above), treatment inertia, non-adherence and super-
that include a long-acting calcium-channel blocker added white-coat effect.
(CCB), an angiotensin-converting enzyme (ACE) inhibi-
tor or angiotensin receptor blocker (ARB), and a diuretic Non-adherence
(thiazide or thiazide-like).4 All agents should be adminis- Non-adherence is a major issue in achieving BP con-
tered at maximum or maximally tolerated doses and at trol. In newly diagnosed hypertensives, up to 50% are
the appropriate dosing frequency. non-adherent in the first year.6 Factors contributing to
poor adherence are myriad and multilevel, and the ap-
Implicit in this definition is that the BP is taken correctly proach is multifaceted and beyond the scope of this
as errors in office BP measurement are common. It is short article. However, the detection of non-adherence
essential that BP is measured and recorded according
Evaluation of patient BP not at goal Superadded white coating
Appropriate treatment Physician inertia
Patient, funder Non-adherence
BP at goal +/- 85% or physician Lack of lifestyle changes
failure Interfering drugs
Inappropriate formularies
Secondary causes
True resistance 2% No single-pill combinations
Figure 1. Approach to the patient with resistant hypertension
HANDBOOK OF GENERAL MEDICINE VOL 1
Mild to Moderate
essential hypertension 3,5
Provides effective BP control with mono-or combination therapy 1,2
• Improves insulin sensitivity in insulin resistant patients, ideal for patients with metabolic syndrome 4
• Well tolerated with a low potential for drug interactions 2
Dosage and directions for use: 3
Adults 0,2 mg in the morning
The dose may be titrated after 3 weeks to 0,4 mg, given as one dose or as divided
doses (morning and evening) until a satisfactory response has been achieved.
* In a subgroup of patients with TG ≥ 2,30 mmol/L + HDL-C ≤ 0,88 mmol/L
Reference: 1. Waters J, Ashford J, Jäger B, Verboom CN, Wonnacott S. Use of moxonidine as initial therapy and in combination in the treatment of essential hypertension – results of the TOPIC (Trial of Physiotens In
Combination) Study. J Clin Basic Cardiol 1999;2(2):219-224. 2. Fenton C, Keating GM, Lyseng-Williamson KA. Moxonidine: A Review of its Use in Essential Hypertension. Drugs 2006;66(4):477-496. 3. Physiotens®
Package Insert. Abbott Laboratories (Pty) Ltd, South Africa. 15 April 2011. 4. Haenni A, Lithell H. Moxonidine improves insulin sensitivity in insuline-resistant hpertensives. J Hypertens 1999;17(3):S29-S35 5. Cynt®
Package Insert. Abbott Laboratories (Pty) Ltd, South Africa. 15 April 2011. S3 PHYSIOTENS® 0,2. Each filmcoated tablet contains 0,2 mg moxonidine. Reg. No. 32/7.1.3/0139. S3 PHYSIOTENS® 0,4. Each fi lm-coated
tablet contains 0,4 mg moxonidine. Reg. No. 32/7.1.3/0141. S3 CYNT® 0,2. Each fi lm-coated tablet contains 0,2 mg moxonidine. Reg, No.: 32/7.1.3/0136. S3 CYNT® 0,4. Each film-coated tablet contains 0,4 mg
moxonidine. Reg, No.: 32/7.1.3/0138
For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority. Further information is available on request from the holder of the registration. Abbott Laboratories S.A. (Pty) Ltd.
Co. Reg. No. 1940/014043/07. Abbott Place, 219 Golf Club Terrace, Constantia Kloof, 1709. Tel: (011) 858 2000. Date of Publication of this promotional material: June 2019. Promo. No. ZAEPHS190124
34 TREATMENT APPROACHES
is the first critical step. Self-reporting, pill counts and is a worldwide phenomenon and may account for up
pharmacy refills may be useful. Unfortunately, patients to 50% of hypertensives with apparent treatment resist-
are not always forthcoming about lack of adherence, ance.2 This is due most commonly to the prescribing
which may be partial or complete. Inappropriate esca- of antihypertensives at suboptimal doses, especially
lation of therapy has the potential for harm. diuretics in patients, despite not achieving BP goal.
The education of healthcare professionals and audit-
Increasingly, it has become clear that the use of ing of practices are probably the most effective ways
methods to detect antihypertensive drugs or their of reducing this problem. For example, rewarding phy-
metabolites in either the urine or blood are the critical sicians in the United Kingdom for an increased number
first step forward. However, this is not generally available of patients at goal has resulted in an improvement in
to practitioners outside large institutions. Amlodipine is BP control.
taken by most patients with RH, and in conjunction with
the Division of Pharmacology, the Hypertension Clinic Failure to adhere to lifestyle changes
at Groote Schuur Hospital has developed an amlodi-
pine assay. In a study performed in the clinic, 20% of Lifestyle changes are not only important in reducing
patients with RH were fully non-adherent and another cardiovascular risk, but have an important synergistic
20% partially adherent, and amlodipine levels were di- effect with antihypertensive medication. The most im-
rectly linked to the degree of BP control.7 As amlodipine portant measures to undertake are: loss of weight, re-
has a very long half-life, it is able to detect both partial duction in dietary sodium and alcohol, increased po-
and full non-adherence. The assay is available to the tassium intake and regular exercise. Achieving weight
private sector. reduction is always difficult, but limiting sugar intake is
a simple and effective method. Reducing the addition
Another useful method to detect non-adherence is to of salt to food is important, although 70% of consumed
perform a 24-hour BP-monitoring after directly observing salt is from processed foods. Thus, it is important to eat
the taking and swallowing of BP medication. unprocessed foods (fresh fruit and vegetables), which
has the important effect of increasing potassium intake
Once non-adherence has been diagnosed, the rea- that may offset the harmful effects of salt. Regular walk-
sons can be explored and acted upon. Patient- and ing for 30 minutes 5 x per week is effective in reducing
family-member education is essential. The unrecog- BP. Binge-drinking must be avoided and alcohol limited
nised side effects of medication may reduce patient to 1 to 2 standard drinks per day.
adherence and should be actively explored. Pill bur-
dens must be reduced by using single-pill combinations, Interfering medication
which have been shown to reduce non-adherence
and improve BP control. Triple-combination tablets with There is a wide range of medication and recreational
diuretic, ACE inhibitor or ARB, and amlodipine are now drugs that induce and exacerbate RH (see Table 1). A
generally available. The use of affordable generic an- detailed drug history is essential. NSAIDs may be taken
tihypertensive drugs is also important to avoid co-pay- over the counter for a variety of reasons unbeknown to
ments and non-adherence due to the inability to pay. the medical practitioner. The use of oral contraceptives
can be easily overlooked in young women and in rare
Superadded white-coating cases induce malignant hypertension. The VEGF inhibi-
tors are a new class of drugs used for cancer and the
The white-coat effect refers to the rise in BP during BP- practitioner may be unaware of their marked effects on
measurement due to an alerting phenomenon. This is BP. A syndrome closely resembling pre-eclampsia may-
more commonly described in normotensive individuals be induced. Patients may not be forthcoming about
whose BP rises into the hypertensive range during meas- recreational drug abuse, and screening for ampheta-
urement (termed white-coat or office hypertension), mines and cocaine should be considered in selected
and is a generally benign condition. This also occurs in cases.
patients with treated hypertension, resulting in appar-
ent treatment resistance. It is often more marked in the Table 1. Common drugs that induce and exacerbate RH
elderly and should be suspected in low-risk individuals
with minimal or no target organ damage. This should be Oral contraceptives
excluded before embarking on extensive investigations Sympathomimetics
for secondary causes of hypertension by performing 24- Cyclosporin, tacrolimus
hour BP-monitoring or home BP-monitoring with a vali- Erythropoetin
dated device. Another method to exclude white-coat- VEGF inhibitors
ing that is becoming increasingly popular is automated Alcohol
office BP. This is preferably performed in the absence of Cocaine, amphetamines
the medical practitioner, and it closely correlates with Antidepressants
24-hour daytime BP.8 Three to five measurements are Steroids
taken one minute apart. The first reading is discarded,
and the mean calculated from the remaining readings.
Physician inertia
Suboptimal antihypertensive therapy accounts for a
large subset of patients not achieving BP targets. This
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 35
Secondary causes a loop diuretic is advised. High doses may also be re- Treatment approaches
quired, especially if the CKD is stage 4 or 5.
Table 2 lists the common causes of secondary hyper-
tension, and very rare causes of secondary hypertension Other forms of secondary hypertension need to be
have not been included. Secondary causes should be treated on their merits and are beyond the scope of
considered based on a detailed history of symptoms, this article.
examination and special investigations. This should not
be embarked on in the first instance unless there is a Pharmacological treatment of RH
strong clinical suspicion. The most common causes are
primary aldosteronism, CKD, and sleep apnoea. In RH, Further pharmacological treatment of RH needs to be
up to 20% of patients may have primary aldosteronism instituted only after consideration of the factors de-
and it is worthwhile performing an aldosterone-to-renin scribed above. Recent evidence suggests that the next
ratio even if the potassium is normal. This test will also step in treatment is the use of low-dose spironolactone
identify patients with Liddle phenotype where both the (12.5 mg-25 mg) and that this is superior to beta- and
aldosterone and renin are suppressed. Primary aldo- alpha blockers.10 Response is predicted by a low re-
steronism will respond to spironolactone or adrenalecto- nin level and normal-to-high aldosterone.11 Spirono-
my if an adenoma is identified, while a Liddle syndrome lactone should be avoided if the eGFR <45 ml/min or K+
will respond to amiloride. Unfortunately, pure amiloride >5 mmol/L. Monitoring of serum K+ is essential to detect
is not registered in South Africa, and it is suggested the occasional hyperkalaemia.
practitioner try half-dose amiloride complex with a thia-
zide in patients with low renin/aldosterone and RH. As these studies were done in largely European popu-
lations and where the Liddle phenotype is rare, we have
Some authorities consider routinely screening patients developed an alternative approach to RH in Africa by
for sleep apnoea in RH, but in the author’s experience a physiological phenotyping on the basis of the renin and
positive test is rarely found if there are no clinical clues. aldosterone profile (see Table 3). Patients with low renin/
Always remember that apnoea may occur in non- normal-to-high aldosterone receive spironolactone, those
obese patients. with low renin/low aldosterone receive amiloride and
those with high renin/variable aldosterone receive other
Renal artery stenosis (RAS) due to fibromuscular dys- antihypertensives like beta- and alpha blockers. This per-
plasia responds well to percutaneous renal artery dila- sonalised approach was confirmed to be successful in a
tation with up to 70% cure rates. Takayasu’s arteritis study done in Africa.12 The main disadvantage is that pure
does not respond to renal artery dilatation or stenting, amiloride is not available in South Africa and Amiloride Co
and good responses can be obtained by vascular re- maybe a useful alternative in half dose (see above).
construction or transplanting the affected kidney to the
iliac artery, for example. Results of percutaneous stent- In the author’s experience, the final drug to be used if
ing for atherosclerotic RAS have been disappointing all else fails, is a trial of minoxidil. This is especially useful
and this should be reserved for selected cases.9 Sleep in black patients, particularly those with CKD. However,
apnoea responds well to nocturnal CPAP, but patient unwanted hair growth – especially in females – limits its
adherence is problematical. Funding from medical use. A rare side effect is chemical pericarditis.
schemes and health authorities is also restricted despite
hypertension being a prescribed minimum benefit. Newer approaches
Patients with CKD often require four or more antihy- There was initial excitement about the use of renal
pertensive drugs, and if eGFR <45 ml/min, switching to denervation for the treatment of RH. Unblinded studies
Table 2. Common causes of secondary hypertension
Condition Clinical context Screening tests
Kidney disease Screen all hypertensives Dipstick +ve for protein and/or blood,
renal ultrasound
Renal artery stenosis – fibromuscular Bruits, discrepant pulses in older Kidney ultrasound, captopril renogram,
CT angiography
dysplasia, atherosclerotic, takayasu’s arteritis vasculopath or young female, CKD 24-hour nor-meta-adrenaline
Phaeochromocytoma Sweating, palpations, headaches, labile Low K+, aldosterone renin ratio (ratio
Primary aldosteronism >70, and aldosterone >500 pmol/L highly
BP, weight loss (rare if symptoms absent) suggestive)
+ Low K+, renin and aldosterone
Refer
Resistant hypertension or low K TSH
Liddle syndrome Resistant hypertension or low K+ Calcium, PTH
Sleep apnoea Snoring, day-time somnolence, obesity 24-hour urine cortisol
Thyroid disease Symptoms and signs of hypo- or Chest radiograph, echocardiography
hyperthyroidism
Parathyroid disease Rare
Cushing’s syndrome Rapid weight gain, features of Cushing’s
Coarctation of the aorta Young hypertensive with radio-femoral
delay
HANDBOOK OF GENERAL MEDICINE VOL 1
36 TREATMENT APPROACHES
Table 3. Renin- and aldosterone-profiling for RH
Condition Plasma renin level Plasma aldosterone Primary treatment
Primary aldosteronism low Normal to high Spironolactone, rarely surgery
Liddle phenotype low Low Amiloride
Renal, renovascular, other high Generally high Beta blockers, alpha blockers,
other
showed profound and long-lasting improvements in BP. 12. Akintunde A, Nondi J, Gogo K, Jones ESW, Rayner BL, Hackam DG,
However, in the Simplicity 3 study, where patients were et al. Physiological phenotyping for personalized therapy of uncon-
randomised and the placebo group underwent sham trolled hypertension in Africa. American Journal of Hypertension.
procedures, there were no differences in BP.13 Currently, 2017;30(9):923-30.
renal denervation is not recommended for RH.
13. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT,
Baroreceptor stimulation is another procedure under et al. A controlled trial of renal denervation for resistant hypertension.
investigation for RH, but it is too early to make a judge- The New England Journal of Medicine. 2014;370(15):1393-401.
ment on its efficacy and safety.
Conclusion
RH is a common clinical problem associated with ad-
verse morbidity and mortality. Apparent treatment re-
sistance is a major issue and needs to be addressed in
the first instance. Thereafter, a detailed investigation
into the reasons for resistance to therapy may include
but should not be limited to the failure to institute life-
style changes, interfering drugs and secondary causes.
An approach to pharmacological treatment of RH is
outlined.
REFERENCES
1. Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncon-
trolled and apparent treatment resistant hypertension in the United
States, 1988 to 2008. Circulation. 2011;124(9):1046-58.
2. Egan BM, Zhao Y, Li J, Brzezinski WA, Todoran TM, Brook RD, et al.
Prevalence of optimal treatment regimens in patients with appar-
ent treatment-resistant hypertension based on office blood pres-
sure in a community-based practice network. Hypertension (Dallas,
Tex: 1979). 2013;62(4):691-7.
3. Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis
KL, et al. Incidence and prognosis of resistant hypertension in hyper-
tensive patients. Circulation. 2012;125(13):1635-42.
4. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-
Himmelfarb CR, et al. Resistant hypertension: Detection, evaluation,
and management: A scientific statement srom the American Heart
Association. Hypertension (Dallas, Tex: 1979). 2018;72(5):e53-e90.
5. Moosa MS, Kuttschreuter LS, Rayner BL. Evaluation and manage-
ment of patients referred to a tertiary-level hypertension clinic
in Cape Town, South Africa. South African Medical Journal.
2016;106(8):797-800.
6. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to
prescribed antihypertensive drug treatments: Longitudinal study of
electronically compiled dosing histories. BMJ (clinical research ed).
2008;336(7653):1114-7.
7. Jones ESW, Lesosky M, Blockman M, Castel S, Decloedt EH, Schwa-
ger SLU, et al. Therapeutic drug monitoring of amlodipine and the
Z-FHL/HHL ratio: Adherence tools in patients referred for apparent
treatment-resistant hypertension. South African Medical Journal.
2017;107(10):887-91.
8. Myers MG, Godwin M, Dawes M, Kiss A, Tobe SW, Kaczorowski J.
Measurement of blood pressure in the office: Recognizing the prob-
lem and proposing the solution. Hypertension. 2010;55(2):195-200.
9. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid DM,
et al. Stenting and medical therapy for atherosclerotic renal-artery
stenosis. The New England Journal of Medicine. 2014;370(1):13-22.
10. Banegas JR, Ruilope LM, de la Sierra A, Vinyoles E, Gorostidi M, de
la Cruz JJ, et al. Clinic versus daytime ambulatory blood pressure
difference in hypertensive patients: The impact of age and clinic
blood pressure. Hypertension. 2017;69(2):211-9.
11. Williams B, MacDonald TM, Morant SV, Webb DJ, Sever P, McInnes
GT, et al. Endocrine and haemodynamic changes in resistant
hypertension, and blood pressure responses to spironolactone or
amiloride: The PATHWAY-2 mechanisms substudies. The Lancet Dia-
betes & Endocrinology. 2018;6(6):464-75.
HANDBOOK OF GENERAL MEDICINE VOL 1
TREATMENT APPROACHES 37
The renin angiotensin aldosterone system Treatment approaches
antagonism (RAAS) and clinical outcomes
JR Snyman or the aldosterone receptors or combinations of these,
should translate into clinical benefit and a reduction in
MBChB (Pret), MPharmMed, MD mortality. Unfortunately, it took years for the develop-
ment of non-peptide renin and angiotensin receptor
Medical Specialist Holdings (Pty) Ltd, Cape Town blockers. The first products developed were the ACEIs
in the early 1980s, followed by the ARBs in the 1990s and
Clinical outcomes are often distant from the time of renin blockers which were only registered in early 2000.
treatment initiation and the clinician may fall into the The big question then was “did it benefit the patient?”
trap of trying something new as the true clinical benefit and were combinations better as so-called ACEI es-
of treatment is not always proximal to the intervention cape and upregulation of angiotensin II in the presence
prescribed. Lowering blood pressure is easy and can be of ARBs occurred. The different disease manifestations
done with a myriad of medicines. The challenge for the are highlighted below with the current evidence for
clinician is which one will best protect the patient’s end clinical outcomes.
organs over time, resulting in a reduction in mortality.
This is even more relevant when the patient suffers mul- Hypertension1
tiple comorbidities, such as diabetes mellitus, renal dis-
ease and cognitive impairment. The renin angiotensin All the currently available ACEIs, ARBs and renin blockers
aldosterone system (RAAS) has been identified as the effectively lower blood pressure, i.e. 10 mm Hg on aver-
major contributor to the pathology of many of the vas- age as all have flat dose-response curves. This means
cular and even non-vascular-related conditions (meta- that if the blood-pressure reduction required is more
bolic disorders), often closely associated with elevated than 10 mm Hg, these medications should be combined
blood pressure. Blocking the effect of the RAAS has with either diuretics or calcium-channel blockers (CCBs)
been the focus of extensive research, first with the an- which will add an additional 5-10 mm Hg reduction. Of-
giotensin-converting enzyme inhibitors (ACEIs), followed ten patients with higher blood pressure need to start on
by the angiotensin-1-receptor blockers (ARBs), then by combinations. The initial starting drug is usually an ACEI,
combinations of the two. The latter was in turn followed but if not tolerated, an ARB is indicated. ACEIs or ARBs
by renin antagonists and combinations with the ARBs or combine well with CCBs (e.g. amlodipine) and diuretics
ACEIs. Direct aldosterone antagonists were also added such as indapamide (metabolically neutral). The type
to the mix, with good results in selected patients. The of ACEI or ARB is perhaps less important if the problem
research studies firstly aimed to address hypertension, is restricted to hypertension. When blood pressure (BP)
after which their focus shifted to end-organ protection variability is important, then a longer-acting agent, such
involving, for example, the kidneys (renal failure) and as perindopril (ACEI) or telmisartan (ARB), makes more
cardiovascular system (myocardial infarction, heart fail- sense. Adding a diuretic to either an ACE or an ARB
ure, atherosclerosis, stroke), and finally to disease-spe- also increases the duration of action and reduces BP
cific or all-cause mortality reduction. variability. Only in step 4 would one add an aldosterone
antagonist as a diuretic, provided the serum potassium
RAAS’s role in disease is below 4.5 mmol/L. All ACEIs and ARBs are registered
for hypertension.
Figure 1 displays the many important areas where angi-
otensin II plays a role in driving end-organ pathology. Im- Heart failure2
paired kidney perfusion signals renin production which
converts angiotensinogen to angiotensin I which is then Activation of the RAAS is pivotal in heart failure (HF),
changed to angiotensin II by the so-called angiotensin- again making a RAAS antagonist a logical choice, and
converting enzyme (ACE). Angiotensin II triggers an ar- most ACEIs have been researched for this indication.
ray of reactions, ranging from direct vasoconstriction Ramipril, perindopril, trandolapril and lisinopril can be
by stimulating angiotensin-1 (AT1) receptors; it acts as a given once daily, whereas captopril should be taken
growth signal for fibrosis and cell proliferation (ventricu- three times per day and enalapril and quinapril twice
lar hypertrophy and fibrosis), renal mesangial cell hyper- daily. Although well researched, fewer ARBs record a
trophy, endothelial inflammation and atherosclerosis, registered indication for treating heart failure; those in-
sympathetic nervous system activation (increased sym- dicated are valsartan, candesartan and losartan. Most
pathetic tone and nor-adrenalin circulation), reduction patients (>50%) did not reach the study target dosages
in pre-adipocyte differentiation, reduction in insulin sen- of either medicine type, mostly due to tolerance. A re-
sitivity and release of aldosterone. The latter also causes cent meta-analysis demonstrated that the idea of start-
vasoconstriction and sodium and water retention with ing with a lower dose and titrating to the highest toler-
putative potassium loss by stimulating up-regulation of able dose of either agent is actually acceptable.3 The
the transporter system in the distal convoluted tube of authors state that higher dosages of ACEIs and ARBs re-
the kidney. It is therefore easy to deduce that reducing duce the risk of HF worsening compared to lower doses,
renin activity and blocking the ACE or the AT1 receptor
HANDBOOK OF GENERAL MEDICINE VOL 1
38 TREATMENT APPROACHES
Ace – angiotensin-converting enzyme; CNS – central nervous system; CV – cardiovascular; NO – nitric oxide;
RAS – renin-angiotensin system; SNS – sympathetic nervous system; R-R – resting rate;
ROS – reactive oxygen species; VSMC – vascular smooth muscle cells; ↑ – increase, ↓ – decrease
Adapted from McFarlane et al4 and Sharma et al7
Figure 1. The role of angiotensin II in cardiovascular and metabolic dysregulation
and higher doses of ARBs also reduce the risk of HF hos- medication, does not significantly reduce the all-cause
pitalisation. Giving higher dosages increases the risk of mortality or cardiovascular mortality of heart-failure
hypotension and adverse effects (e.g. hyperkalaemia, patients.5 Therefore aliskiren is not a RAAS blocker of
cough, rise in creatinine and so on), compared to lower choice, either alone or in combination with other RAAS
dosages. antagonists.
The renin antagonist, aliskiren, did not demonstrate Myocardial infarction
any advantage when given alone or in combination
with an ACEI for heart failure. In patients with chronic Guidelines indicate the role of ACEIs in the prevention
heart failure, the addition of aliskiren to enalapril led of myocardial infarction (MI), especially in patients
to more adverse events without an increase in benefit. post-MI and in patients with poor left ventricular func-
Non-inferiority was not shown for aliskiren when com- tion. Early controversy existed over the use of ARBs in the
pared to enalapril.4 same setting. The reason being that AT1 blockade results
in upregulation of angiotensin II production and stimu-
In a systematic review, the authors point out that
aliskiren, either used alone or combined with standard
HANDBOOK OF GENERAL MEDICINE VOL 1
Need endurance
when treating CVS disease?
Perindopril has proven outcomes in:
• Coronary Artery Disease1
• Acute Myocardial Infarction2
• Stroke3
• End-stage Renal Failure4
the endurance ACE-inhibitor
For further product information contact PHARMA DYNAMICS P O Box 30958 Tokai Cape Town 7966 Fax +27 21 701 5898
Email [email protected] CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000 www.pharmadynamics.co.za
PEARINDA 4, 8. Each tablet contains 4, 8 mg perindopril tert-butylamine respectively. S3 A41/7.1.3/0649, 0650. NAM NS2 10/7.1.3/0476, 0477. For full prescribing information, refer to the professional information
approved by SAHPRA, April 2009. PEARINDA PLUS 4. Each tablet contains 4 mg perindopril tert-butylamine and 1,25 mg indapamide. S3 A41/7.1.3/0633. NAM NS2 10/7.1.3/0611. For full prescribing information, refer
to the professional information approved by SAHPRA, April 2010. 1) The EUROPA study Investigators. “Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease:
randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study)”. The Lancet 2003;362:782-788. 2) The PREAMI study Investigators. “Effects of angiotensin-converting enzyme inhibition with
perindopril on left ventricular remodelling and clinical outcome. Results of the randomized perindopril and remodelling in elderly with acute myocardial infarction (PREAMI) study”. Arch Intern Med 2006;166:659-666.
3) PROGRESS Collaborative Group. “Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack”. The Lancet 2001;358:1033-41.
4) Guerin AP, et al. “Impact of Aortic Stiffness Attenuation on Survival of Patients in End-Stage Renal Failure”. Circulation 2001;103;987-992. PAI594/04/2019.
40 TREATMENT APPROACHES
lation of the AT2 receptor, which is associated with cell betes is likely to be more important in high-risk patients.
proliferation, fibrosis and inflammation.6 However, there In a combined analysis of three trials, HOPE, EUROPA
was no evidence found in a recent meta-analysis that and PEACE, on the benefits of ACEIs in high-risk patients,
ARBs increase the risk of MI.7 This large and comprehen- a risk reduction of new-onset diabetes of 0.86 (95% CI
sive analysis produced evidence to debunk the hypoth- 0.78-0.95) was reported.11
esis that ARBs increase the risk of myocardial infarction.
Compared with controls, ARBs reduce the risk of stroke, In the ASCOT-BPLA trial, 27% of patients had co-ex-
heart failure, and new-onset diabetes with a neutral isting type II diabetes. Patients were randomised to re-
outcome in MI. ceive amlodipine/perindopril or atenolol/diuretic, with
perindopril being added to the amlodipine regimen
Systematic reviews of ARBs that include meta-analy- and bendroflumethiazide + potassium to the atenolol
ses indicate that ARBs lack the cardiovascular-protec- regimen as required in order to achieve pre-defined
tive effects of ACEIs. This is independent of the BP-lower- blood-pressure goals. Patients were followed up for a
ing effect and that ACEIs consistently reduce mortality, median of 5.5 years. This study was stopped early be-
whereas not all ARB studies demonstrate the latter. cause of a significant 11% decrease of total mortality, a
24% reduction in cardiovascular death, a 16% reduction
The ESC 2017 guidelines recommend the use of ACEIs in cardiovascular events and procedures, a 23% reduc-
after ST-segment elevation myocardial infarction (STE- tion in stroke, and a 15% reduction in renal impairment in
MI) and only if ARBs are not tolerated in patients with favour of the amlodipine/perindopril-based regimen.12
low ejection fraction heart failure. Treatment with ACE Further analysis of patients who developed diabetes
inhibitors is recommended in patients with systolic LV during the trial revealed that of the subgroup of patients
dysfunction or heart failure, hypertension, or diabetes, who did not have diabetes at baseline, 11.4% (n=794) of
and should be considered in all STEMI patients. In the patients assigned to the atenolol/thiazide-based treat-
context of STEMI, valsartan was found to be non-inferior ment arm and 8% (n=567) of patients assigned to am-
to captopril in the VALsartan In Acute myocardial iN- lodipine/perindopril-based treatment, developed type
farcTion study. II diabetes during the five years of follow-up.
Mineralocorticoid receptor antagonist (MRA) therapy Several meta-analyses demonstrate the value of ACEI
is recommended in patients with LV dysfunction (LVEF and ARB treatment, resulting in the delay or reduction in
<40%) and heart failure after STEMI. Eplerenone (selec- onset of TIIDM.13 In 10 large clinical trials, the incidence
tive aldosterone receptor antagonist) reduced the mor- of new T2DM was 9.6% in individuals taking non-RAAS
bidity and mortality in these patients.8 blockers, i.e. thiazides, CCBs and or beta blockers, com-
pared with 7.4% in those receiving ACE inhibitors or ARBs
Metabolic syndrome (22% reduction, P<.00001). Forty-five patients needed
and diabetes mellitus to be treated for four to five years to prevent one new
case of TIIDM. In studies with nondiabetic patients, ARB
Impaired insulin sensitivity and hypertension are risk fac- therapy reduced the incidence of new-onset diabetes
tors for atherosclerosis. Impaired insulin sensitivity is also a by 17% compared with placebo, by 27% compared
precursor for type II diabetes mellitus (TIIDM). The RAAS is with beta blockers, and by 24% compared with calci-
pivotal in the development of both hypertension and in- um-channel blockers.
sulin resistance. RAAS inhibitors, such as ACEIs and ARBs,
may therefore improve insulin sensitivity and prevent the It is therefore obvious that RAAS blockade using either
sequelae of insulin resistance, TIIDM and its effects on an ACEI or an ARB treatment results in a protective ef-
the cardiovascular system. ACEIs improve insulin sensi- fect against the development of diabetes.
tivity in patients with hypertension and insulin resistance,
including diabetes. End-organ protection
The exact mechanisms by which insulin sensitivity itself The heart, kidney, retina and brain are the end organs
becomes impaired are not fully understood. Angioten- for disease development in patients with hypertension
sin II plays an important role, as a result of its inhibition and/or diabetes mellitus. Both ACEIs and ARBs have
of adipocyte differentiation, via the AT1 receptor, which been shown to reduce the incidence of cardiovascular
leads to accumulation of lipids in muscle, liver and events, micro and macro-albuminuria (a reduction in
pancreas, with a putative reduction in insulin sensitivity. the progression or development of end-stage kidney
Angiotensin II is also known to impair insulin intracellular disease), diabetic retinopathy and stroke. There is some
signalling and disrupt the pancreatic islet structure. It research pointing to a reduction of the incidence of de-
has been suggested that angiotensin II may have a del- mentia. The effect on dementia has, however, not been
eterious effect on glucose metabolism by increasing re- confirmed in large clinical trials.
active oxygen species and inducing inflammation, de-
creasing blood flow in many tissue beds, and stimulating Studies confirmed equivalence between ACEIs and
the sympathetic nervous system.9 ARBs with regard to reno-protection. Telmisartan was
shown to be non-inferior to enalapril in providing long-
ACEIs and ARBs reduce insulin sensitivity and prevent term renoprotection in those with type II diabetes. This
the onset of TIIDM.10 ACEIs have a beneficial effect on finding supports the clinical equivalence of angioten-
insulin sensitivity and they prevent the development of sin II receptor blockers and ACE inhibitors in patients
new-onset type II diabetes in patients with hypertension, suffering from conditions at high risk for cardiovascular
compared with conventional antihypertensive agents, events.14
such as diuretics and β-blockers. The beneficial effects
of RAAS blockade on the incidence of new-onset dia-
HANDBOOK OF GENERAL MEDICINE VOL 1
Antihypertensive treatment to feel better
10/10
10/20
S3 Zaneril 10/10. Each tablet contains: 10,0 mg Lercanidipine hydrochloride, 10,0 mg Enalapril maleate. Reg. no. 41/7.1/0935.
S3 Zaneril 10/20. Each tablet contains: 10,0 mg Lercanidipine hydrochloride, 20,0 mg Enalapril maleate. Reg. no. 41/7.1/0936.
For full prescribing information refer to package insert approved by the medicines regulatory authority. Further information
available on request to the holder of registration. Litha Pharma (Pty) Ltd. Reg. no.: 1994/008717/07. 106 16th Rd, Midrand.
LP 2202 07/2019
STILL THE NO 1 low dose
aspirin prescribed by cardiologists1
Enteric coated shell provides
protection from gastric discomfort2
References: 1. IMS Data May 2019 2. H.G. Dammann, F. Burkhardt & N. Wolf. Enteric coating of aspirin significantly decreases
gastroduodenal mucosal lesions. Ailment Pharmacol Ther 1999; 13: 1109-1114.
S2 Ecotrin 81mg. Each tablet contains Aspirin 81mg. Reg. no.: 29/2.7/0767
For full prescribing information refer to package insert approved by the medicines regulatory authority. Further information is available on
request to the holder of registration. Litha Pharma (Pty) Ltd. Reg. no.: 1994/008717/07. 106 16th Rd, Midrand. 087 742-1860.
www.lithahealthcare.co.za
LP 2788 07/2019
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