the incidence of type 2 diabetes mellitus, mainly diabetes has produced a wealth of studies in recent in patients with diabetes, a long-term condition …
The British Journal of Diabetes Vascular Disease
http://dvdsagepubcom The challenge of tackling cardiovascular outcomes
Anthony H Barnett British Journal of Diabetes Vascular Disease 2006; 6; S12 DOI: 101177/14746514060060020401 The online version of this article can be found at: http://dvdsagepubcom/cgi/content/abstract/6/2_suppl/S12
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The challenge of tackling cardiovascular outcomes
ANTHONY H BARNETT
Abstract
tice treatment guidelines and optimisation of targets in this population
I
Key words: type 2 diabetes, cardiovascular disease, landmark studies, evidence base, clinical practice
Introduction
Type 2 diabetes is associated
with a substantial increase in the risk of CVD, and this accounts for approximately 80 of deaths in this population1 Although only 3 of the population has diabetes, of patients admitted to hospital with an MI, 1015 have known diabetes and one in five deaths from an MI are recorded in patients with diabetes2 Diabetes, is therefore now considered as one of the major public health issues of our time The challenge facing physicians is to utilise optimal treatment to reduce the risk of CVD in patients with diabetes, a long-term condition that requires a coordinated approach from a multiprofessional team The treatment options for patients with type 2 diabetes have expanded based on evidence from clinical studies Several landmark studies have provided the basis for current best-prac-
Correspondence to: Professor Anthony Barnett Undergraduate Centre, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham, B9 5SS, UK Tel: 0121 424 3587; Fax: 0121 424 0593 E-mail: anthonybarnett@heartofenglandnhsuk
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The Heart Protection Study
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n
recent years there has been a dramatic increase in the incidence of type 2 diabetes mellitus, mainly attributed to the escalating prevalence of obesity and overweight in many populations worldwide, highlighting the need to tackle dietary and physical activity factors In people with type 2 diabetes, cardiovascular disease is the greatest cause of morbidity and premature mortality, imposing an ever-increasing burden on healthcare resources Our improved understanding of the pathophysiology of type 2 diabetes has produced a wealth of studies in recent years, leading to substantial advances in the management of diabetes This review will consider key landmark studies that have provided evidence to support the use of oral glucose-lowering agents, antihypertensives and lipid-lowering agents in this disease, highlighting the practical significance for clinicians Br J Diabetes Vasc Dis 2006;6suppl 2:S12S16
Statins The Scandinavian Simvastatin Survival Study
The 4S study was a secondary prevention trial that demonstrated a benefit in terms of cardiovascular events and mortality in favour of simvastatin compared with placebo3 During a median follow-up of 54 years, simvastatin was titrated to
40 mg daily The primary end point was total mortality, the secondary end point was major CHD events CHD death or non-fatal MI and the tertiary end points included any CHD event and any atherosclerotic event A post-hoc subgroup analysis of 4S was carried out to assess the effect of lowering cholesterol with simvastatin on mortality, the risk of CHD and other atherosclerotic events in patients with diabetes and CHD4 The results of this subgroup analysis showed a 43 reduction in total mortality p0087, a significant 55 reduction in major CHD events p0002 and a 37 reduction in any atherosclerotic event p0018 in patients with diabetes treated with simvastatin compared with placebo4 This subgroup analysis was the first trial-based evidence to demonstrate that cholesterol lowering with statins significantly reduces the risk of major CHD events and other atherosclerotic events in patients with diabetes and CHD
The more recent HPS investigated the effects of lowering cholesterol with a statin in patients with diabetes This trial compared the effects of 40 mg simvastatin daily with placebo in 5,963 patients with diabetes and 14,573 patients with occlusive arterial disease but no diabetes5
The primary end points were first major coronary event eg non-fatal MI or coronary death and first major vascular event eg major coronary event, stroke or revascularisation In patients with diabetes, there was a significant 22 reduction in major coronary events, stroke or revascularisation with simvastatin 40 mg compared with placebo p00001 The study demonstrated that this reduction was also evident in patients with diabetes who did not have any diagnosed occlusive arterial disease at entry: a 33 reduction with 40 mg simvastatin compared with placebo p00003 Furthermore, this reduction was also observed across all of the LDL-C subcategories examined, including a 27 reduction in patients with pre-treatment LDL-C levels of 30 mmol/L5 The evidence base for use of simvastatin is therefore, at a dose of 40 mg Unfortunately many patients are still started at
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Figure 1 The effect of cholesterol lowering with simvastatin in CARDS
Figure 2 Kaplan-Meier survival curve for participants with diabetes in the MICRO-HOPE Study
20 Primary end point cumulative hazard
Placebo Atorvastatin
025 Primary outcome Kaplan-Meier rates 020 015 010 005 0 0 500 1000
Placebo Ramipril
15
10
5
No at risk
0 1351 1392 1306 1361 1022 1074 651 694 305 328
Placebo 1410 Atorvastatin 1428
1500
Days of follow-up
lower doses with no attempt to titrate up to the evidence base dose In addition, the results from this study show that patients with diabetes, with or without high cholesterol levels, derive the same benefit from treatment with a statin This suggests that, since all patients with type 2 diabetes are at increased cardiovascular risk, they should all be prescribed a statin agent unless there is a contraindication or tolerability problem, regardless of their initial cholesterol concentrations supported by CARDS see below
The Collaborative Atorvastatin Diabetes Study
The CARDS study assessed the effectiveness of atorvastatin 10 mg daily versus placebo in the primary prevention of major cardiovascular events in patients with type 2 diabetes without particularly high concentrations of LDL-C6 Participants had no history of cardiovascular disease and were randomly assigned to placebo or atorvastatin The primary end point was time to first occurrence
of an acute CHD event, coronary revascularisation or stroke The median follow-up was 39 years since the trial was stopped two years early due to a significant difference in the primary end points in favour of atorvastatin Patients who received atorvastatin had a significant 37 reduction in the risk of first cardiovascular disease event compared with placebo p0001 figure 16 Treatment with atorvastatin was associated with reductions in acute CHD, coronary revascularisations and the rate of stroke Atorvastatin also demonstrated a 27 reduction in the death rate compared with placebo p0059,6 concluding that atorvastatin 10 mg daily is well tolerated and efficacious in reducing the risk of first cardiovascular disease events in patients with type 2 diabetes without high LDL-C levels This landmark study confirms that all adult patients with type 2 diabetes should be given treatment with a statin, regardless of their level of LDL-C There does not appear to be any justification for having a particular threshold level of LDL-C at which patients with type 2 diabetes should receive this therapy, unless there is a contraindication or tolerability problem Indeed, the question
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clinicians should be asking is why is this patient with type 2 diabetes not on a statin?, rather than should this patient with type 2 diabetes be on a statin?
The Fenofibrate Intervention and Event Lowering in Diabetes study
Patients with type 2 diabetes commonly have dyslipidaemia, which includes low HDL-C and raised triglycerides The FIELD study investigated the effect of fenofibrate on cardiovascular events in patients with type 2 diabetes and low-to-moderate CVD risk This was a disappointing study since the 11 relative risk reduction in the primary end point of CHD or non-fatal MI was not significant7 As might have been predicted, the confounding factor may have been the increased use of other lipid treatments, predominantly statins, in the placebo group p000017 The role of fibrates in the management of type 2 diabetes remains unclear, except in patients with very high triglycerides, where there is a danger of acute pancreatitis
Renin-angiotensin-aldosterone system inhibitors The Heart Outcomes Prevention and Evaluation study: subgroup study
The
MICRO-HOPE study investigated whether the ACE inhibitor ramipril, could lower the risk of cardiovascular and renal disease in patients with diabetes This study compared ramipril 10 mg daily with placebo in 3,577 patients with diabetes who had a previous cardiovascular event or at least one other cardiovascular risk factor The combined primary outcome was MI, stroke or cardiovascular death8 The median duration of follow-up was 45 years, six months less than planned as the study was terminated early Treatment with ramipril was associated with a significant 25 reduction in the combined primary end point compared with placebo p00004 figure 28 However, since blood pressure decreased slightly more among patients who were treated with ramipril, it had been argued as to whether this reduction in cardiovascular events was due to a specific effect from inhibi-
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Table 1
Secondary end point results from the ASCOT trial Amlodipine-based regimen n9,639 Number Rate per 1,000 Atenolol-based regimen n9,618 Number Rate per 1,000 444 5 852 9 1602 17 820 9
342 4 422 4 159 2 85 168 328 155 65 81 30
Unadjusted HR 95 CI 087 076100 087 079096 084 078090 089 081099 076 065090 077 066089 084 066105
p-value 00458 00070 00001 00247 00010 00003 01257
Non-fatal MI excluding silent fatal CHD Total coronary end point Total cardiovascular events and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure
390 4 753 8 1362 14 738 8 263 3 327 3 134 1
74 146 274 139 49 62 25
tion of the RAAS or due to its effect on reducing blood pressure
The Losartan Intervention For End point reduction in hypertension study
The LIFE study aimed to address the ongoing question of which antihypertensive drug is most suitable to reduce the risk of CVD in patients with hypertension and diabetes? Patients with diabetes, hypertension and signs of left ventricular hypertrophy were randomised to receive either losartan or atenolol9 The primary end point was a composite of cardiovascular morbidity and mortality Patients treated with losartan had a 24 risk reduction in the primary end point compared with atenolol p00319 Since systolic blood pressure was reduced substantially in both treatment groups,
adjustment for this factor had little effect on the end point results This suggests that the beneficial effects seen with losartan are over and above that of blood pressurelowering alone, and may be attributed to its inhibitory effect on the RAAS Alternatively, the apparent benefits with losartan could be due to the detrimental effect of the beta-blocker in this group of patients This study provides more evidence that beta blockers may be inferior to other agents in patients with diabetes when managing hypertension also see ASCOT below
The Anglo-Scandinavian Cardiac Outcomes Trial-Blood pressure Lowering Arm
The ASCOT-BPLA was a trial investigating whether newer agents such as calcium-channel blockers and an ACE inhibitor were more effective than therapy based on diuretics and beta-blockers in preventing cardiovascular events10 Hypertensive patients with at least three other cardiovascular risk factors were assigned to either amlodipine 510 mg, adding perindopril 48 mg as required amlodipine-based regimen; n9,639, or atenolol 50100 mg, adding bendroflumethiazide 12525 mg and potassium as required atenolol-based regimen; n9,618 The study was stopped early after a mean follow-up of
55 years because of a significant reduction in all-cause mortality seen with the amlodipine-based regimen11 Consequently, the 10 reduction in the primary end point of non-fatal MI and fatal CHD with the amlodipine-based regimen did not reach statistical signifi-
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cance p0105210 However, virtually all of the secondary end points, except fatal and non-fatal heart failure, were significantly reduced with the amlodipine-based regimen table 110 These results from ASCOT suggest that beta-blockers should no longer be used as first-line antihypertensives in patients with diabetes unless there is concomitant angina or post-MI ASCOT supports the concept that the first-line combination for treatment of hypertension should be with an inhibitor of the RAAS ACE inhibitor or ARB together with a thiazide diuretic or calciumchannel blocker Commonly, all three agents will be required to get to target In addition, it should be emphasised that any one of these drugs can be used as first-line therapy, including a thiazide diuretic see ALLHAT12
The
Hypertension Optimal Treatment trial
The HOT study was a randomised trial that investigated the association between major cardiovascular events and the diastolic blood pressure achieved during treatment; and the potential benefit of a low-dose acetylsalicylic acid in patients with hypertension The study demonstrated that aspirin therapy 75 mg daily significantly reduced major cardiovascular events by 15 p003 and MI by 36 p0002 compared with placebo13 The relative benefit of aspirin on these two end points was similar in the groups of patients with diabetes mellitus as in the whole HOT population Furthermore, these benefits were not associated with an increased risk of cerebral bleeding13
The IRbesartan in patients with type 2 diabetes and MicroAlbuminuria trial
Diabetic nephropathy has become the leading cause of ESRD in many countries including Europe and the United States Microalbuminuria, an albumin excretion rate of 20200 g per minute and hypertension are risk factors for diabetic nephropathy and CVD Patients with type 2 diabetes are therefore at an increased risk of developing renal disease and consequently, renal protection in these patients is imperative IRMA2 compared the
renoprotective effects of irbesartan 150 mg daily, irbesartan 300 mg daily and placebo in hypertensive patients with type 2 diabetes and microalbuminuria14 During the two-year follow-up, irbesartan was associated with a reduc-
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Figure 3 Incidence of diabetic nephropathy with irbesartan in the IRMA2 Study
Figure 4 Kaplan-Meier plot for any diabetes-related end point with metformin treatment in UKPDS 34
15
Any diabetes-related end point
20 Incidence of diabetic nephropathy
Placebo Irbesartan 150 mg Irbesartan 300 mg
60
Lifestyle SU or insulin Metformin
40
10
20
5
0 0 3 6 12 Months of follow-up 18 22 24
0 0 3 6 9 12 16 Years from randomisation
tion in the primary end point of time to onset of diabetic nephropathy compared with placebo figure 314 This study used other antihypertensive agents to achieve similar blood pressures between the groups p0004 for the comparison of systolic blood pressure between the placebo group and the combined irbesartan groups It can therefore be concluded that irbesartan is renoprotective, independent of an
irbesartan-induced reduction in blood pressure in patients with type 2 diabetes and microalbuminuria The higher dose of irbesartan was more effective in reducing the risk of diabetic nephropathy than the lower dose figure 314 The evidence-based dose 300 mg/day of irbesartan should therefore be prescribed by physicians in order to provide the optimal treatment for the patient This study has emphasised that preventing or delaying the development of diabetic nephropathy should be a major treatment goal, and guidelines suggest that routine screening for microalbuminuria is necessary in patients with diabetes This should help to identify high-risk patients early in the course of the disease, so that treatment can be initiated
The Irbesartan in Diabetic Nephropathy Trial
Another ARB trial, IDNT, investigated whether the ARB irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes It also aimed to establish if any reduction in progression was independent of reductions in blood pressure Hypertensive patients with nephropathy due to type 2 diabetes were assigned to irbesartan 300 mg daily, amlodipine 10 mg daily or
placebo15 The primary end point was a composite of a doubling of the baseline serum creatinine concentration, the development of ESRD, or death from any cause At a mean follow-up of 26 years, treatment with losartan was associated with a 20 reduction in the primary end point compared with placebo p002 and a 23 reduction compared with amlodipine p0006 Irbesartan was also associated with a 23 reduction in progression from overt nephropathy to ESRD, compared with placebo and amlodipine
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p007 for both comparisons15 It can therefore be concluded that irbesartan is effective in protecting against the progression of nephropathy in patients with type 2 diabetes, independent of a reduction in blood pressure It has been shown from other studies that to provide effective renal benefit, the patient must be identified and treated early on in the disease and that this treatment should include an inhibitor of the RAAS14,16
Oral glucose-lowering agents The UK Prospective Diabetes Study
UKPDS 33 demonstrated that intensive blood-glucose control with either a
sulphonylurea or insulin in patients with type 2 diabetes is associated with a substantial decrease in the risk of microvascular complications17 UKPDS 34 investigated whether intensive blood-glucose control with metformin has any specific advantage or disadvantage in overweight patients with newly diagnosed type 2 diabetes Participants received conventional treatment primarily with diet alone, a sulphonylurea, insulin or metformin The metformin group had a 32 risk reduction in developing any diabetes-related end point compared with patients receiving conventional blood-glucose control p00023 and a significantly greater risk reduction than those assigned to either a sulphonylurea or insulin p00034 figure 418 Treatment with metformin was also associated with a 42 reduction in the risk of diabetes-related death compared with the conventional group; however, no significant difference was observed between those treated with metformin and those treated with either a sulphonylurea or insulin A 36 reduction in all-cause mortality was observed in the metformin group compared with the conventional group p0011, and there was also a greater risk reduction with metformin treatment compared with
either a sulphonylurea or insulin p002118 Although, overall, the UKPDS did not show any significant cardiovascular benefit with intensive glucose control, there appears to be particular cardiovascular benefit with metformin in obese patients
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Key messages
People with type 2 diabetes are at an increased risk of CVD Physicians need to use the wealth of evidence available to provide the optimal treatment for reducing cardiovascular risk in patients with type 2 diabetes Clinical practice and treatment guidelines should reflect the most current clinical evidence
Conclusion
Reducing cardiovascular risk in patients with type 2 diabetes is complex and requires a multifactorial approach, including treatment with statins, antihypertensives commonly low-dose aspirin and antidiabetic agents Some of the studies discussed in this review have helped to direct treatment guidelines such as the new GMS, NICE and JBS 2 There is a need to apply the evidencebase in a systematic way that benefits the patient, such as simplifying treatment regimes and
improving compliance A major challenge facing physicians is to reduce the residual cardiovascular risk in patients with type 2 diabetes who are already prescribed the agents recommended in treatment guidelines This highlights the need for treatments tailored to individual needs The views expressed in this manuscript are those of the author and not necessarily supported by Takeda UK or current product licences
References
1 Winer N, Sowers JR Epidemiology of diabetes J Clin Pharmacol 2004;44:397-405 2 Diabetes UK Diabetes in the UK 2004;1-27 3 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study 4S Lancet 1994;344:1383-9
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with type 2 diabetes, suggesting that metformin should be the first-line pharmacological therapy in patients with type 2 diabetes
4 Pyorala K, Pedersen TR, Kjekshus J et al Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease A subgroup analysis of the Scandinavian Simvastatin
Survival Study 4S Diabetes Care 1997;20:614-20 5 Heart Protection Study Collaborative Group MRC/BHF Heart protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial Lancet 2003;361:2005-16 6 Colhoun HM, Betteridge DJ, Durrington PN et al Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study CARDS: multicentre randomised placebo-controlled trial Lancet 2004;364:685-96 7 Keech A, Simes RJ, Barter P et al 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;366:1849-61 8 Heart Outcomes Prevention Evaluation HOPE Study Investigators Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy Lancet 2000;355:253-9 9 Lindholm LH, Ibsen H, Dahlof B et al Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study LIFE: a randomised trial against atenolol Lancet
2002;359:1004-10 10 Dahlof B, Sever PS, Poulter NR et al 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;366:895-906 11 Jackson G Blood pressure lowering - is degree more important than method? Int J Clin Pract 2005;59:995-7 12 Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ALLHAT JAMA 2002;288:2981-97 13 Hansson L, Zanchetti A, Carruthers SG et al Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment HOT randomised trial HOT Study Group Lancet 1998;351:1755-62 14 Parving HH, Lehnert H, Brochner-Mortensen J et al The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes N Engl J Med 2001;345:870-8 15 Lewis EJ,
Hunsicker LG, Clarke WR et al Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes N Engl J Med 2001;345:851-60 16 Barnett AH, Bain SC, Bouter P et al Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy N Engl J Med 2004;351:1952-61 17 UK Prospective Diabetes Study UKPDS Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes UKPDS 33 Lancet 1998;352:837-53 18 UK Prospective Diabetes Study UKPDS Group Effect of intensive bloodglucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS 34 Lancet 1998;352:854-65
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