Hypertension is the most important cause of death globally, while the

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CARDIOMETABOLIC DISEASE Earn 3 CPD Points online This article was made possible by an unrestricted educational grant by Servier Laboratories.

1 CARDIOMETABOLIC DISEASE Earn 3 CPD Points online This article was made possible by an unrestricted educational grant by Servier Laboratories. New approaches to cardiometabolic disease Hypertension is the most important cause of death globally, while the global epidemic of diabetes continues unabated. 1,2 In clinical practice, hypertension and type 2 diabetes are progressive conditions that frequently co-exist as part of the cardiometabolic syndrome. 2 There is therefore an urgent need to improve the management of both hypertension and diabetes. In this CPD review, International and South African experts provide guidance on better care of these patients. Act today for tomorrow Key messages Prof Neil Poulter Professor of Preventative Cardiovascular Medicine Imperial College London, UK Hypertension is the most important cause of death globally. 1 Better management of hypertension is necessary. Monotherapy is usually inadequate therapy and at least two drugs are required it has even been suggested that two drugs should be used from the outset. The major options for combination therapy are: ACE-I or ARB plus CCB (A+C); ACE-I or ARB plus diuretic (A+D) or CCB plus diuretic (C+D). The ASCOT trial, specifically designed as a combination treatment trial, using the ACE-I, perindopril, and the CCB, amlodipine, provided significant evidence for an A+C combination using an ACE inhibitor and was stopped early because of a reduction in the risk of all-cause mortality. 3 A finding to emerge from the ASCOT trial was the role of blood pressure variability in predicting patients stroke and coronary heart disease (CHD) outcomes. Intermittent hypertension is more dangerous than average constant hypertension, something that has led to a sea change in how blood pressure is perceived and how it should be treated. The UK s National Institute for Health and Clinical Excellence (NICE) guidelines now recommend A+C as a first combination choice for treating patients with primary hypertension under the age of 55 years. The NICE guidelines are based on systematic review of published evidence. 4 If two agents can be given in a single pill it is beneficial since single-pill combinations have been shown to improve compliance by 21%. 9 Hypertension is the most important cause of death globally, with cardiovascular morbidity and mortality having a linear relationship with high blood pressure. 1 So it s crucial to optimise hypertension management, acting today for tomorrow. This is the view of Neil Poulter, Professor of Preventive Cardiovascular Medicine, Imperial College London, UK. He was speaking in Johannesburg as the guest of Servier Laboratories. Regardless of a country s income, whether low, middle or high, hypertension is the single biggest contributor to death and the problem is going to get worse. 2 We need to manage the condition better than we do currently. Monotherapy is usually inadequate therapy and at least two drugs are usually required. It is even recommended in some guidelines that two drugs should be used from the outset as initial therapy, he said. Whether you start with one or two drugs, a choice needs to be made among the possible combinations. The major drug classes are: Diuretics (but not low-dose thiazide diuretics, as there is no evidence to support their use) Angiotensin receptor blockers (ARBs) APRIL

2 None of the ACE-Inhibitors has as much evidence as perindopril in different clinical settings. Prof Poulter Earn 3 CPD points at Click on Accredited Education Programmes Angiotensin-converting enzyme inhibitors (ACE-Is) Calcium channel blockers (CCBs) Beta-blockers Pointing out that ACE-Is should not be combined with ARB s, 4 Professor Poulter laid out the following options for combining drugs of different classes as recommended in several sets of guidelines: ACE-I or ARB plus CCB (A+C) ACE-I or ARB plus diuretic (A+D) CCB plus diuretic (C+D) Reviewing the various A+D trials (LIFE, VALUE, PROGRESS, HYVET and ADVANCE), Professor Poulter noted that whilst more than one trial had shown a benefit for this combination in respect of stroke risk reduction, effects on coronary protection were inconsistent across the trials. 5 Both HYVET 16 and ADVANCE 15 trials also showed benefits in respect of all-cause mortality, something not often improved in hypertension trials. Turning to A+C trials, and the ASCOT trial 3 in particular, Professor Poulter observed that the blood pressure-lowering arm of this landmark study, specifically designed as a combination treatment trial, had evaluated an A+C strategy using the CCB, amlodipine and the ACE-I perindopril. All outcomes favoured the A+C combination, which showed such a significant reduction in the risk over a beta-blocker ± thiazide diuretic combination when it came to all-cause mortality that the trial was stopped early. ACE Inhibitors may have benefits beyond blood pressure when it comes to coronary protection, and in the ASCOT trial we also saw significant reductions in the risk of stroke. Every cardiovascular risk factor apart from heart rate was positively impacted, highly statistically significantly so, by amlodipine ± perindopril and some of the small biochemical differences observed in this A +C arm may well matter at the population level. But one novel finding to emerge from the ASCOT trial was the role of blood pressure variability in predicting patients stroke and coronary heart disease (CHD) outcomes, a finding borne out in a subsequent study. 6 Mean achieved blood pressure has a minimal association with stroke and CHD outcomes, but increasing variability is a powerful predictor of the risk of both, said Professor Poulter. In the ASCOT trial, no measure of BP predicted both risks better than long-term variability, i.e. over several years. The implications of this are that intermittent hypertension is more dangerous than average constant hypertension, something that has led to a sea change in how we perceive blood pressure risk and how we should treat it. The amlodipine ± perindopril combination used in the ASCOT study reduced blood pressure variability differentially relative to the beta-blocker ± thiazide combination, and adjusting for its effect on variability could explain the results observed. 6 The ACCOMPLISH trial evaluated a single-pill combination of the ACEinhibitor, benazapril and amlodipine versus an A+D strategy. 7 A significant reduction in the risk of cardiovascular events was observed with the single-pill A+C strategy. The UK s National Institute for Health and Clinical Excellence (NICE) guidelines now recommends A+C as the best choice based on a systematic review of the evidence. 4 CCBs perform better than diuretics in respect of stroke outcomes and cause less new-onset diabetes, which gives them a clear edge. But which A do you choose? Only the ONTARGET trial compared an ACE-I and an ARB head-to -head and showed no significant differences between the two. However, I am persuaded in favour of ACE-Is further to a subsequent meta-analysis in which ACE-Is were associated with a 10% reduction in the risk of all-cause mortality versus no effect for ARBs. 8 ARBs can be used as a second-line A in those patients intolerant of ACE Inhibitors, said Professor Poulter. Wrapping up, he underscored again that there is no evidence for the use of lowdose thiazide diuretics in the treatment of hypertension. He added the rider that there is good evidence of cardiovascular benefit for high-dose thiazides, chlorthalidone and indapamide, however. If we are going to use two drugs and they can be given in a single pill, we should do so, he said. Single-pill combinations have been shown to improve compliance by 21%. 9 The vast majority of patients require two agents. A+C is the preferred strategy and you know my thoughts as to which A. And of those, none has as much evidence as perindopril, he concluded. 2 APRIL 2014

Prof Brian Rayner Head of Division of Hypertension and senior consultant in the Division of Nephrology at Groote Schuur Hospital and University of Cape Town Issues and answers in hypertension How do

ANSWER 1: Prof Neil Poulter One could be guided by the ASCOT trial, which was a combination trial (although a single pill did not exist at that time).

3 Prof Brian Rayner Head of Division of Hypertension and senior consultant in the Division of Nephrology at Groote Schuur Hospital and University of Cape Town Issues and answers in hypertension How do we decide on the correct dose of the combination of perindopril/ amlodipine to use? ANSWER 1: Prof Neil Poulter One could be guided by the ASCOT trial, which was a combination trial (although a single pill did not exist at that time). In my clinical practice using non-combination agents, I start with amlodipine 5mg, and then add perindopril at a starting dose of 4mg or 5mg (new perindopril salt). 17 I then double the perindopril and increase the amlodipine to 10mg to get to target. I also do this to minimise oedema. Your own clinical practice should be followed when using the new combinations, he noted. The forthcoming guidance from the British Hypertension Society is likely to stress the value of starting with drug combinations in high-risk patients with severe hypertension. The latest American Hypertension Society guidelines, published in February, 2014, recommend initiating therapy with a combination pill in patients with high blood pressure (160/100mmHg or higher) and in those at high cardiovascular risk. The exception is the elderly (above 80 years) where one should still start low and go slow to avoid complications such as postural hypotension ANSWER 2: Prof Brian Rayner One should remember that in the frail elderly (above 75 years) treatment of hypertension is discretionary. Also when we treat, we should be aiming for higher levels of around mmHg. The HYVET trial was a useful study of healthy elderly people and should not be used as general guidance for the compromised elderly. What blood pressure target should we be aiming for in diabetic patients? ANSWER: Prof Neil Poulter The overall guidance before the ACCORD trial was 130/80mmHg based on no evidence. In the ACCORD trial, they tried to test a suitable lower level and actually succeeded in lowering blood pressure to around 119mmHg systolic, but they were not able to show any cardiovascular benefit. Thereafter diabetic organisations in the US suggested a return to 140mmHg systolic for the diabetic patient. I think this is wrong. After all, the ADVANCE trial showed that at levels of 134mmHg systolic, there was an 18% reduction in the risk of cardiovascular mortality. If I were diabetic, this is closer to the level I would want my blood pressure to be. Tried and trusted now improved Key messages Prof Richard Donnelly Professor of Medicine, head, School of Graduate- Entry Medicine & Health University of Nottingham, UK The evidence from a large number of clinical trials relating to a large number of new therapies means there is no reason for healthcare professionals not to provide good diabetes care. 11 Type 2 diabetes is being diagnosed in younger and younger individuals, which is going to have an even greater impact in terms of reduced life expectancy. 10 While the link between diabetes and cardiovascular disease is well recognised, diabetes also confers an additional risk for certain cancers and for death from renal disease. Good management requires individualisation of HbA 1c targets and a multifactorial approach. 11 Because type 2 diabetes is a progressive condition, titration and escalation of therapy are necessary, along with combination therapy. However, in clinical practice, doctors are often slow in anticipating the progressive nature of type 2 diabetes and hence slow to titrate. 13 According to the UK s National Institute for Health and Clinical Excellence (NICE) guidelines, metformin is the first-line treatment with sulphonylureas as second line. The sulphonylureas are a heterogeneous group of drugs. This means the best choice requires careful evaluation. Based on the findings of the ADVANCE trial,where a strategy based on gliclazide MR was used, the sulphonylurea of first choice should be gliclazide MR. 12 APRIL

Among the many agents available to control glucose levels in diabetes, our preferred agents should be safe, effective and have proven protective actions, particularly with regard to microvascular

4 Among the many agents available to control glucose levels in diabetes, our preferred agents should be safe, effective and have proven protective actions, particularly with regard to microvascular complications. Prof James Ker, Emeritus Professor, University of Pretoria Earn 3 CPD points at Click on Accredited Education Programmes When it comes to diabetes, the evidence from a large number of clinical trials relating to a large number of new therapies means there is no reason for healthcare professionals not to provide good diabetes care. This is the view of Richard Donnelly, Professor in Medicine, Head, School of Graduate-Entry Medicine & Health, University of Nottingham, UK. He was speaking in Johannesburg as the guest of Servier Laboratories. There is a global epidemic of diabetes and the prevalence is projected to rise from 366 million in 2011 to 552 million by Of even more concern is that we re diagnosing type 2 diabetes in younger and younger individuals, 10 and this is going to have an even greater impact in terms of reduced life expectancy, as those diagnosed with diabetes can expect a year reduction in this regard. Recent findings suggest that younger type 2 diabetes patients have even worse outcomes and mortality than type 1 diabetic patients. 10 And while the link between diabetes and cardiovascular disease is well recognised, diabetes also confers an additional risk for certain cancers and for death from renal disease. There is a continuous linear relationship between elevated glycosylated haemoglobin levels and cardiovascular disease, said Professor Donnelly, while diabetic renal disease carries a substantially higher risk of death from macrovascular causes. The following are important considerations in providing good management 11 : Individualisation of HbA 1c targets Long-term safety and cardiovascular outcomes Microvascular complications, which can be costly and fatal Clinical efficacy and cost-effectiveness of treatment strategies A multi-factorial approach Professor Donnelly underscored that HbA 1c is an unreliable surrogate endpoint and that clinical cardiovascular outcomes are what matter most. Type 2 diabetes is a syndrome and there is much more to it than high blood glucose. Dyslipidaemia, obesity and hypertension need to be taken into account too, hence the need for a multifactorial approach. Type 2 diabetes is a progressive condition, which means that over time it becomes more and more difficult for patients to maintain glycaemic control. Titration and escalation of therapy are therefore necessary, along with combination therapy, he said. However, in clinical practice we are often slow in anticipating the progressive nature of type 2 diabetes and hence slow to titrate. 13 According to the UK s National Institute for Health and Clinical Excellence (NICE) guidelines, metformin is the first-line treatment with sulphonylureas as second line. DPP-4 inhibitors are recommended when there is good reason not to use a sulphonylurea. The metformin/sulphonylurea combination is strongly recommended as the most clinically cost-effective strategy. The sulphonylureas are effective and bring about prompt HbA 1c reduction. Professor Donnelly cautioned, however, that while the sulphonylureas generally have good long-term safety data, especially gliclazide, they are nonetheless a heterogeneous group of agents. Several large clinical outcome trials have evaluated the role of intensive therapy in slowing macro- and microvascular complications. In the ADVANCE trial of a patient population well controlled at baseline, four out of five achieved an HbA 1c 7% using titrated metformin and gliclazide modified-release (MR). With the addition of other antidiabetic agents as necessary to achieve glycaemic targets, this approach conferred a very worthwhile clinical benefit, in respect of a positive impact on both renal protection and blood glucose control. There was no net gain in body weight and the incidence of hypoglycaemia was very low. 12 So which sulphonylurea should you choose, given their aforementioned heterogeneity? Professor Donnelly thought that hypoglycaemic events could provide useful guidance. He cited a study 14 that compared sulphonylureas to the DPP-4 inhibitor, sitagliptin with regard to hypoglcaemia and found a similar incidence with gliclazide/ Gliclazide MR and sitagliptin in this regard. Gliclazide has the lowest risk of cardiovascular disease, he noted, and there is also evidence to suggest that switching pre-emptively to insulin is not the answer to addressing reduced life expectancy. Summing up, he reiterated that the ADVANCE trial provides data that more intensive glucose-lowering using a strategy based on gliclazide MR provides effective glycaemic control with a low risk of hypoglycaemia. 4 APRIL 2014

Prof Larry Distiller Specialist Physician/ Endocrinologist Centre for Diabetes and Endocrinology, Houghton, Johannesburg Issues and answers in diabetes In practice, we see older patients (over 65

ANSWER: Prof Larry Distiller You need to use sulphonylureas that are compatible with the patient, as all sulphonylureas are not the same. Gliclazide MR is least likely to cause hypoglycaemic events.

5 Prof Larry Distiller Specialist Physician/ Endocrinologist Centre for Diabetes and Endocrinology, Houghton, Johannesburg Issues and answers in diabetes In practice, we see older patients (over 65 years) on gliclazide MR experiencing hypoglycaemic episodes. What should we do? ANSWER: Prof Larry Distiller You need to use sulphonylureas that are compatible with the patient, as all sulphonylureas are not the same. Gliclazide MR is least likely to cause hypoglycaemic events. However, if your patient is experiencing them on this agent, then the dose is too high. In elderly patients with impaired renal function, the dose should be marginally smaller. Also, we need to note that the SEMDSA guidelines recommend that glibenclamide should not be used, with the single exception of its use in pregnant women. Should we be pushing for gliclazide MR in the state sector? ANSWER: Prof Richard Donnelly The tolerability of the MR version of gliclazide is favourable, due to the reduced peak-trough variations in drug concentration, which could possibly lead to a lower risk of hypoglycaemia. This could be a compelling argument for the use of this agent also in the public sector. References 1. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: Danaei G, Singh GM, Paciorek CJ et al. The global cardiovascular risk transition:association of 4 metabolic risk factors with national income, urbanisation and Western Diet in 1980 and Circulation 2013; 127(14): Dahlof B, Sever PS, Poulter NR, et al for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial- Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: NICE hypertension guidance 127, 2011.Clinical management of primary hypertension in adults.(update to NICE clinical guidance 34.( 5. Wright JM.First-line drugs for hypertension. Database Syst Rev 2009; 8(3): CD Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010; 375: Jamerson K, Weber MA, Bakris GA, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008; 359: Van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduces mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J 2012; 33: Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010; 55: The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011; 364: American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2013: 36: S11-S ADVANCE collaborative group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358(24): Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies MJ. Clinical inertia in people with type 2 diabetes: A retrospective cohort study of more than people Diabetes Care 2013: 36(11): Al Sifri SA, Basiounny A, Echtay A, et al. The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial. Int J Clin Pract 2011; 65(11): Patel A. The ADVANCE Trial. Lancet 2007; 370: Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358(18): Telejko E. Perindopril arginine: Benefits of a new salt of the ACE inhibitor perindopril. Current Medical Research and Opinion. 2007; 23(5): (8) Diabetes Atlas, 5 th Edition; CPD How to earn CPD points: Visit click on Accredited Educational Programmes, Click on registration, then answer the relevant questionnaire. Your Certificate will be ed to you. Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) I info@denovomedica.com APRIL

The underestimated risk of

Earn 3 CPD Points online The underestimated risk of hypertension Dr David Webb Johannesburg Introduction The high and increasing worldwide burden of hypertension is a major global health challenge. Hypertension