- Email: [email protected]
Vascular outcome in type 2 diabetes: an ADVANCE?
Comment
plans must be developed in a way that reflects the needs of their citizens, which means not only more joint working across governments, but also between donors, parliamentarians, non-governmental organisations, and the private sector. In Ethiopia, an ambitious national programme to provide universal primary health care has been backed by several donors. Over 17 000 new salaried female Health Extension Workers, in health posts close to their communities, are now providing preventive services and basic curative care.6 Working in partnership will give us the greatest results. The IHP is not another funding mechanism to add to the myriad already available. Instead it aims to bring together the efforts of all, to produce more than the sum of its parts. I am pleased to have the opportunity to describe the IHP to Lancet readers. If we are to be successful in our efforts to meet the MDGs, particularly on health, we are going to need your support. The
IHP is a statement of intent in response to the global health emergency we face: I believe all of us have a contribution to make. Douglas Alexander Secretary of State for International Development, Department for International Development, London SW1E 5HE, UK [email protected] I declare that I have no conflict of interest. 1
2 3 4
5 6
UN DESA. Millennium Development Goals 2007. Progress Chart. http://www.un.org/millenniumgoals/pdf/mdg2007-progress.pdf (accessed Sept 4, 2007). International Health Partnerships. http://www.dfid.gov.uk/news/files/ ihp/default.asp UN Millennium Development Goals Report 2007. http://www.un.org/ millenniumgoals/pdf/mdg2007.pdf (accessed Sept 4, 2007). WHO/UNAIDS/UNICEF. Towards universal access: scaling up priority HIV/ AIDS interventions in the health sector. 2007. http://www.who.int/hiv/ mediacentre/univeral_access_progress_report_en.pdf (accessed Sept 4, 2007). WHO. World Health Report 2006—working together for health. http://www.who.int/whr/2006/en/ (accessed Sept 4, 2007). Centre for National Health Development in Ethiopia. The Health Extension Program. http://cnhde.ei.columbia.edu/programs/hep/ (accessed Sept 4, 2007).
Vascular outcome in type 2 diabetes: an ADVANCE? Published Online September 2, 2007 DOI:10.1016/S01406736(07)61304-X See Articles page 829
804
In today’s Lancet, the ADVANCE investigators report the results of a large randomised trial of perindopril and indapamide in patients with type 2 diabetes and at least one additional risk factor.1 Eligible patients were assigned the angiotensin-converting enzyme (ACE) inhibitor perindopril with the diuretic indapamide, or placebo. All other drugs already being taken (except for another ACE inhibitor or thiazide diuretic) were continued; other antihypertensive drugs could be added by the physician. Just over 11 000 patients were randomised. In a mean 4·3 years of follow-up, those taking perindopril and indapamide had lower blood pressure (5·6 mm Hg systolic, 2·2 mm Hg diastolic) than did those on placebo, and a 9% reduction in relative risk of major macrovascular or microvascular events (placebo 16·8%; intervention 15·5%; absolute risk reduction 1·3%). The overall relative risk of death was reduced by 14% in the treatment group. The investigators make much of their results, recommending that this fixed-dose combination of perindopril and indapamide be considered for all patients with type 2 diabetes irrespective of their existing blood pressure, stating: “If the benefits seen in ADVANCE were applied to just half the population
with diabetes worldwide, more than a million deaths would be avoided over 5 years.” Before examination of the validity of this claim, the study methods warrant scrutiny. First, the rarity of cough (intervention 3·3%; placebo 1·3%) as a reason for discontinuation seems surprising. However, 43% of participants were already taking an ACE inhibitor before the trial and 1·8% of eligible patients dropped out because of cough in the 6 weeks before randomisation. Therefore, most of the 10–15% of patients who started taking an ACE inhibitor and who would be expected to develop a cough2 were already excluded. Such infrequency of cough would not be seen if ACE inhibitors were started in ACE-inhibitor-naive patients. Second, according to the design, all patients (except for those who dropped out) who were allocated to active treatment should be taking perindopril at the end of follow-up. However, 55% of those assigned to placebo were also taking perindopril at the end of follow-up. The third issue relates to the validity of the claim that better outcomes could be attributed solely to the intake of perindopril and indapamide, which lowered www.thelancet.com Vol 370 September 8, 2007
Comment
Science Photo Library
so-called Polypill4 becomes available, because that pill contains a generic ACE inhibitor, a diuretic (although in a lower dose than in ADVANCE), a statin, and aspirin. The cost of 30 tablets of trade-name perindopril in Dallas, TX, USA, is US$61; the cost of 30 tablets of generic lisinopril is $4 at many pharmacies. Therefore, giving all patients with diabetes a trial with a generic ACE inhibitor might be logical so that the 10–15% of patients who cough could be excluded from future intake of the Polypill. Thereafter a reconstituted Polypill (without the β blocker but with a calcium antagonist) could be provided to all patients with type 2 diabetes, and to those recommended by Wald and Law—all people older than 55 years and everyone with existing cardiovascular disease.4 The fixed combination of perindopril and indapamide could be the best possible protector against hypertension-related consequences for patients with type 2 diabetes, but I believe that other drugs—if they lower blood pressure as much and do not have metabolic side-effects—would be as protective as this combination treatment. As has been said many times before by many experts: in most circumstances, lowering the blood pressure is what counts, not the way by which it is lowered.5 blood pressure. The physicians who monitored patients were free to adjust antihypertensive and diuretic regimens, and obviously did so. By the end of the trial, more participants assigned to placebo were taking an angiotensin-receptor blocker or a β blocker, a calcium antagonist, a thiazide or other diuretic, or other blood-pressure-lowering drug than were those in the intervention group. That the physicians giving all of these extra drugs did not reduce the blood pressure of patients allocated placebo (not known to the physician) as much as they lowered the blood pressure of those allocated to the intervention in ADVANCE is strange. Perindopril and indapamide are surely not that much stronger than other antihypertensives in view of the almost equal efficacy of all antihypertensive agents in moderate doses.3 Even if issues with the methods can be addressed, do the results warrant the conclusion that a fixed combination of perindopril and indapamide would be of so much value that it should be considered for all patients with type 2 diabetes? Certainly not if the www.thelancet.com Vol 370 September 8, 2007
Norman M Kaplan Department of Internal Medicine, Hypertension Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA [email protected] I declare that I have no conflict of interest. 1
2
3
4 5
ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; published online Sept 2, 2007. DOI:10.1016/S0140-6736(07)61303-8. Kaplan NM. Treatment of hypertension: drug therapy. In: Kaplan’s clinical hypertension, 9th edn. Lippincott Williams and Wilkins: Philadelphia, 2006; 257–58. Kaplan NM. Treatment of hypertension: drug therapy. In: Kaplan’s clinical hypertension, 9th edn. Lippincott Williams and Wilkins: Philadelphia, 2006; 264–65. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419–23. Staessen JA, Wang J-G, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003; 21: 1055–76.
805
plans must be developed in a way that reflects the needs of their citizens, which means not only more joint working across governments, but also between donors, parliamentarians, non-governmental organisations, and the private sector. In Ethiopia, an ambitious national programme to provide universal primary health care has been backed by several donors. Over 17 000 new salaried female Health Extension Workers, in health posts close to their communities, are now providing preventive services and basic curative care.6 Working in partnership will give us the greatest results. The IHP is not another funding mechanism to add to the myriad already available. Instead it aims to bring together the efforts of all, to produce more than the sum of its parts. I am pleased to have the opportunity to describe the IHP to Lancet readers. If we are to be successful in our efforts to meet the MDGs, particularly on health, we are going to need your support. The
IHP is a statement of intent in response to the global health emergency we face: I believe all of us have a contribution to make. Douglas Alexander Secretary of State for International Development, Department for International Development, London SW1E 5HE, UK [email protected] I declare that I have no conflict of interest. 1
2 3 4
5 6
UN DESA. Millennium Development Goals 2007. Progress Chart. http://www.un.org/millenniumgoals/pdf/mdg2007-progress.pdf (accessed Sept 4, 2007). International Health Partnerships. http://www.dfid.gov.uk/news/files/ ihp/default.asp UN Millennium Development Goals Report 2007. http://www.un.org/ millenniumgoals/pdf/mdg2007.pdf (accessed Sept 4, 2007). WHO/UNAIDS/UNICEF. Towards universal access: scaling up priority HIV/ AIDS interventions in the health sector. 2007. http://www.who.int/hiv/ mediacentre/univeral_access_progress_report_en.pdf (accessed Sept 4, 2007). WHO. World Health Report 2006—working together for health. http://www.who.int/whr/2006/en/ (accessed Sept 4, 2007). Centre for National Health Development in Ethiopia. The Health Extension Program. http://cnhde.ei.columbia.edu/programs/hep/ (accessed Sept 4, 2007).
Vascular outcome in type 2 diabetes: an ADVANCE? Published Online September 2, 2007 DOI:10.1016/S01406736(07)61304-X See Articles page 829
804
In today’s Lancet, the ADVANCE investigators report the results of a large randomised trial of perindopril and indapamide in patients with type 2 diabetes and at least one additional risk factor.1 Eligible patients were assigned the angiotensin-converting enzyme (ACE) inhibitor perindopril with the diuretic indapamide, or placebo. All other drugs already being taken (except for another ACE inhibitor or thiazide diuretic) were continued; other antihypertensive drugs could be added by the physician. Just over 11 000 patients were randomised. In a mean 4·3 years of follow-up, those taking perindopril and indapamide had lower blood pressure (5·6 mm Hg systolic, 2·2 mm Hg diastolic) than did those on placebo, and a 9% reduction in relative risk of major macrovascular or microvascular events (placebo 16·8%; intervention 15·5%; absolute risk reduction 1·3%). The overall relative risk of death was reduced by 14% in the treatment group. The investigators make much of their results, recommending that this fixed-dose combination of perindopril and indapamide be considered for all patients with type 2 diabetes irrespective of their existing blood pressure, stating: “If the benefits seen in ADVANCE were applied to just half the population
with diabetes worldwide, more than a million deaths would be avoided over 5 years.” Before examination of the validity of this claim, the study methods warrant scrutiny. First, the rarity of cough (intervention 3·3%; placebo 1·3%) as a reason for discontinuation seems surprising. However, 43% of participants were already taking an ACE inhibitor before the trial and 1·8% of eligible patients dropped out because of cough in the 6 weeks before randomisation. Therefore, most of the 10–15% of patients who started taking an ACE inhibitor and who would be expected to develop a cough2 were already excluded. Such infrequency of cough would not be seen if ACE inhibitors were started in ACE-inhibitor-naive patients. Second, according to the design, all patients (except for those who dropped out) who were allocated to active treatment should be taking perindopril at the end of follow-up. However, 55% of those assigned to placebo were also taking perindopril at the end of follow-up. The third issue relates to the validity of the claim that better outcomes could be attributed solely to the intake of perindopril and indapamide, which lowered www.thelancet.com Vol 370 September 8, 2007
Comment
Science Photo Library
so-called Polypill4 becomes available, because that pill contains a generic ACE inhibitor, a diuretic (although in a lower dose than in ADVANCE), a statin, and aspirin. The cost of 30 tablets of trade-name perindopril in Dallas, TX, USA, is US$61; the cost of 30 tablets of generic lisinopril is $4 at many pharmacies. Therefore, giving all patients with diabetes a trial with a generic ACE inhibitor might be logical so that the 10–15% of patients who cough could be excluded from future intake of the Polypill. Thereafter a reconstituted Polypill (without the β blocker but with a calcium antagonist) could be provided to all patients with type 2 diabetes, and to those recommended by Wald and Law—all people older than 55 years and everyone with existing cardiovascular disease.4 The fixed combination of perindopril and indapamide could be the best possible protector against hypertension-related consequences for patients with type 2 diabetes, but I believe that other drugs—if they lower blood pressure as much and do not have metabolic side-effects—would be as protective as this combination treatment. As has been said many times before by many experts: in most circumstances, lowering the blood pressure is what counts, not the way by which it is lowered.5 blood pressure. The physicians who monitored patients were free to adjust antihypertensive and diuretic regimens, and obviously did so. By the end of the trial, more participants assigned to placebo were taking an angiotensin-receptor blocker or a β blocker, a calcium antagonist, a thiazide or other diuretic, or other blood-pressure-lowering drug than were those in the intervention group. That the physicians giving all of these extra drugs did not reduce the blood pressure of patients allocated placebo (not known to the physician) as much as they lowered the blood pressure of those allocated to the intervention in ADVANCE is strange. Perindopril and indapamide are surely not that much stronger than other antihypertensives in view of the almost equal efficacy of all antihypertensive agents in moderate doses.3 Even if issues with the methods can be addressed, do the results warrant the conclusion that a fixed combination of perindopril and indapamide would be of so much value that it should be considered for all patients with type 2 diabetes? Certainly not if the www.thelancet.com Vol 370 September 8, 2007
Norman M Kaplan Department of Internal Medicine, Hypertension Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA [email protected] I declare that I have no conflict of interest. 1
2
3
4 5
ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007; published online Sept 2, 2007. DOI:10.1016/S0140-6736(07)61303-8. Kaplan NM. Treatment of hypertension: drug therapy. In: Kaplan’s clinical hypertension, 9th edn. Lippincott Williams and Wilkins: Philadelphia, 2006; 257–58. Kaplan NM. Treatment of hypertension: drug therapy. In: Kaplan’s clinical hypertension, 9th edn. Lippincott Williams and Wilkins: Philadelphia, 2006; 264–65. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419–23. Staessen JA, Wang J-G, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003; 21: 1055–76.
805