PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study

Figures & data

Table 1 Concomitant glucose-lowering medication use during the study

	Pioglitazone			Placebo
	Baseline (% pts)	Final visit (% pts)	Absolute change from baseline	Baseline (% pts)	Final visit (% pts)	Absolute change from baseline
Any glucose-lowering medication	95.8	91.6	−4.2%	96.0	95.5	−0.5%
Any insulin	33.2	35.9	+2.7%	34.0	46.4	+12.4%
Any metformin	61.2	58.1	−3.1%	61.8	63.6	+1.8%
Sulfonylurea	62.3	53.3	−9.0%	61.8	52.2	−9.6%

Abbreviations: pts, patients.

Table 2 Concomitant cardiovascular medication use during the study

	Pioglitazone			Placebo
	Baseline (% pts)	Final visit (% pts)	Absolute change from baseline	Baseline (% pts)	Final visit (% pts)	Absolute change from baseline
Any cardiovascular medication	95.1	96.2	1.1%	94.8	96.5	1.7%
ACE inhibitors	62.6	64.8	2.2%	63.0	66.7	3.7%
β-blockers	54.6	57.9	3.3%	54.5	60.6	6.1%
Angiotensin II antagonists	6.5	9.6	3.1%	7.0	10.9	3.9%
Calcium channel blockers	34.2	35.4	1.2%	36.6	39.5	2.9%
Nitrates	39.1	35.8	−3.3%	39.7	34.8	−4.9%
Thiazide diuretics	15.4	18.5	+3.1%	16.3	20.2	+3.9%
Loop diuretics	14.3	22.0	+7.7%	14.4	19.8	+5.4%
Cardiac glycosides	5.0	4.4	−0.6%	4.8	3.6	−1.2%
Antiplatelet medication	85.3	88.2	+2.9%	82.6	87.7	+5.1%
Aspirin	74.5	76.2	+1.7%	71.7	73.9	+2.2%
Lipid-altering medication	50.7	61.8	11.1%	52.6	62.7	10.1%
Statins	42.5	55.0	+12.5%	43.2	55.5	+12.3%
Fibrates	10.1	8.6	−1.5%	11.2	10.1	−1.1%

Abbreviations: pts, patients.

Figure 1 Main outcome results in PROactive. A. Primary composite endpoint (all-cause mortality, non-fatal MI (including silent MI), stroke, major leg amputation, acute coronary syndrome, cardiac intervention, or leg revascularization); B. Main secondary composite endpoint (all-cause mortality, non-fatal MI, or stroke). Both figures reproduced with permission from Dormandy JA, Charbonnel B, Eckland DJ, et al. 2005. PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet, 366: 1279–89. Copyright © 2005 Elsevier.

Table 3 Effects of pioglitazone and placebo on individual components of the composite endpoints and total events during the study

Endpoint	Primary composite		Secondary composite		Total events
	Pioglitazone	Placebo	Pioglitazone	Placebo	Pioglitazone	Placebo
Any event	514	572	301	358	803	900
Death	110	122	129	142	177	186
Non-fatal (excl silent MI)	85	95	90	116	108	132
Silent MI	20	23	—	—	23	25
Stroke	76	96	82	100	92	119
Major leg amputation	9	15	—	—	28	28
ACS	42	63	—	—	65	78
Coronary revascularization	101	101	—	—	195	240
Leg revascularization	71	57	—	—	115	92

Abbreviations: ACS, acute coronary syndrome; MI, myocardial infarction.

Table 4 Change in metabolic parameters from baseline to final visit

	Pioglitazone	Placebo	p-value
HbA1c (% absolute change)	−0.8 [−1.6, −0.1]	−0.3 [−1.1, 0.4]	<0.001
Triglycerides (% change)	−11.4 [−34.4, 18.3]	1.8 [−23.7, 33.9]	<0.001
LDL-cholesterol (% change)	7.2 [−11.2, 27.6]	4.9 [−13.9, 23.8]	0.0034
HDL-cholesterol (% change)	19.0 [6.6, 33.3]	10.1 [−1.7, 21.4]	<0.001
LDL/HDL (% change)	−9.5 [−27.3, 10.1]	−4.2 [−21.7, 15.8]	<0.001

Data are median [interquartile range].

Figure 2 Outcomes in the subgroup of patients with a previous myocardial infarction (MI). A. Prespecified endpoint of fatal/non-fatal MI (excluding silent MI); B. Exploratory composite cardiac endpoint (cardiac death, non-fatal MI, coronary revascularization, or acute coronary syndrome). Figure 2A reproduced with permission from Erdmann E, Dormandy JA, Charbonnel B, et al; on behalf of the PROactive investigators 2007. The effect of pioglitazone on recurrent myocardial infarction in 2445 patients with type 2 diabetes and previous myocardial infarction – Results from PROactive (PROactive 05). J Am Coll Cardiol, 49: 1772–80. Copyright © 2007 Elsevier.

Table 5 Placebo-controlled outcome trials

Trial	Population	n	Study duration	Intervention	Positives	Negatives
PROactive (Dormandy et al 2005)	Secondary prevention in type 2 diabetes and established macrovascular disease	5238	34.5 months	Pioglitazone	Significant 16% relative risk reduction in the endpoint of all-cause mortality, stroke, and MI Prevention of recurrent stroke and MI Effects were observed on top of guideline-directed background CV and diabetes medication	Primary endpoint did not reach significance Study duration relatively short (3 years) Higher rates of serious heart failure with pioglitazone (but fatal heart failure rates were similar)
UGDP (Meinert et al 1970)	Primary prevention in patients with type 2 diabetes	823	5.5 years	Tolbutamine Insulin	First large-scale intervention study	Failed to show any benefit of glucose control on vascular events in type 2 diabetes Inconclusive findings in the insulin groups in terms of delaying or preventing CV complications Increased relative risk of cardiac events with tolbutamine No significant difference in incidence of overall mortality in all of the groups Small patient number and poor patient follow-up
UKPDS (UKPDS 34 1998)	Primary prevention in newly diagnosed drug-naïve with type 2 diabetes	342 (out of 5102)	10.7 years	Metformin	Metformin significantly reduced MI (by 39%) and any diabetes-related endpoint (by 32%) relative to lifestyle management	The number of patients allocated to metformin was less than 10% of the total patient population in the UKPDS and effects were only assessed in a population of obese people The reduction in micro-vascular events was not statistically significant (unlike the results seen in the main study)
CARDS (Colhoun et al 2004)	Primary prevention in patients with type 2 diabetes and CV risk	2838	3.9 years	Atorvastatin	Trial terminated 2 years earlier as the prespecified early stopping rule for efficacy had been met 37% decrease in CV events and 48% decrease in stroke with atorvastatin relative to placebo	Most participants had long-standing diabetes with multiple additional risk factors that were substantially undertreated
FIELD (Keech et al 2005)	Primary and secondary prevention in patients with type 2 diabetes and varying levels of dyslipidemia	9795	5 years	Fenofibrate	Largest intervention study in diabetes to date Significant relative reduction in non-fatal MI (by 24%) Significant 11% relative risk reduction in main secondary outcome (composite of MI, stroke, CVD death, and coronary and carotid revascularization)	Primary endpoint (non-fatal MI or CHD death did not reach significance There was a 19% relative increase in CHD mortality with fenofibrate therapy Statin use during the study was a confounding factor Fenofibrate appeared to confer benefit only in the primary prevention of CVD and increased relative risk in patients with prior CVD Fenofibrate only reduced CVD events in patients <65 years
HOPE (HOPE study investigators 2000)	Secondary prevention in high-CV risk patients (subgroup analysis in patients with type 2 diabetes)	3577 (out of 9541)	4.5 years	Ramipril	Significant 25% relative risk reduction with ramipril in the primary composite endpoint of CV death, MI or stroke Significant relative risk reduction with ramipril in MI, stroke, total mortality and CV death	The analysis in patients with diabetes, but without overt CVD did not reach statistical significance There was a high discontinuation rate due to side effects
HOT (Hansson et al 1998)	Secondary prevention (subgroup analysis in patients with type 2 diabetes)	1501 (out of 18,790)	3.8 years	Aspirin (+ others)	There was a 66% relative risk reduction in mortality and a 51% relative risk reduction in major CV events with aspirin	No effect on stroke prevention Non-fatal major bleeds were twice as common in the aspirin group
CARE (Goldberg et al 1998)	Secondary prevention in patients with previous MI (diabetes subgroup)	586 (out of 4159)	5 years	Pravastatin	22% relative risk reduction in CV events	At the 3-year point, pravastatin produced no benefit
PROSPER (Shepherd et al 2002)	Secondary prevention in elderly patients with a history of/risk for CVD (diabetes subgroup)	623 (out of 5804)	3.2 years	Pravastatin		Non-significant 27% increase in the relative risk of CV death, stroke, or MI with pravastatin Number of patients with diabetes too small to permit accurate interpretation of any treatment effect Patient population ≥70 years
HPS (HPS Collaborative Group 2003)	Primary and secondary prevention in patients with CVD (diabetes subgroup)	2912 (out of 20,536)	5 years	Simvastatin	33% relative risk reduction in CV events	10% had type 1 diabetes
4S (Pyörälä et al 1997)	Secondary prevention in patients with CHD (diabetes subgroup)	483 (out of 4398)	5.4 years	Simvastatin	42% relative risk reduction in CHD events	The event rate was very high (45%) in the placebo group
LIPID (LIPID Study Group 1998)	Secondary prevention in patients with known heart disease (diabetes subgroup)	782 (out of 9014)	6.1 years	Pravastatin		Non-significant 16% relative risk reduction in CV events with pravastatin

Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease.

Figure 3 A. Major cardiac outcomes in the PROactive subgroup with previous myocardial infarction (MI) compared with outcomes in the CARE study. All patients in CARE had diabetes and a previous MI (from data of Goldberg 1998); B. Major vascular outcomes (major coronary events, stroke, and revascularization in patients with diabetes) in the HPS study (from data of Heart Protection Study Collaborative Group 2003). Figure 3A reproduced with permission from Goldberg RB, Mellies MJ, Sacks FM, et al. 1998 for the Care Investigators. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analyses in the cholesterol and recurrent events (CARE) trial. Circulation, 98: 2513–9. Copyright © 1998 Lippincott Williams and Wilkins. Figure 3B reproduced with permission from Heart Protection Study Collaborative Group. 2003. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet, 361:2005–16. Copyright © 2003 Elsevier.

DormandyJACharbonnelBEcklandDJPROactive investigatorsSecondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trialLancet200536612798916214598

 PubMed Web of Science ®Google Scholar

ErdmannEDormandyJACharbonnelBon behalf of the PROactive investigatorsThe effect of pioglitazone on recurrent myocardial infarction in 2445 patients with type 2 diabetes and previous myocardial infarction – Results from PROactive (PROactive 05)J Am Coll Cardiol20074917728017466227

 PubMed Web of Science ®Google Scholar

DormandyJon behalf of the PROactive Writing CommitteePROactive study [letter]Lancet2006367267

 Google Scholar

MeinertCLKnatterudGLProutTEA study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality resultsDiabetes197019Suppl7898304926376

 PubMedGoogle Scholar

UK Prospective Diabetes Study (UKPDS) GroupEffect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)Lancet1998352854659742977

 PubMed Web of Science ®Google Scholar

ColhounHMBetteridgeDJDurringtonPNCARDS investigatorsPrimary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trialLancet20043646859615325833

 PubMed Web of Science ®Google Scholar

KeechASimesRJBarterPFIELD study investigatorsEffects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trialLancet200536618496116310551

 PubMed Web of Science ®Google Scholar

Heart Outcomes Prevention Evaluation (HOPE) Study InvestigatorsEffects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudyLancet2000355253910675071

 PubMed Web of Science ®Google Scholar

HanssonLZanchettiACarruthersSGfor the HOT Study GroupEffects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study GroupLancet19983511755629635947

 PubMed Web of Science ®Google Scholar

GoldbergRBMelliesMJSacksFMfor the Care InvestigatorsCardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels. Subgroup analyses in the cholesterol and recurrent events (CARE) trialCirculation199898251399843456

 PubMed Web of Science ®Google Scholar

ShepherdJBlauwGJMurphyMBPROSPER study groupPROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trialLancet200236016233012457784

 PubMed Web of Science ®Google Scholar

Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trialLancet200336120051612814710

 PubMed Web of Science ®Google Scholar

PyöräläKPedersenTRKjekshusJfor the Scandinavian Simvastatin Survival Study (4S) GroupCholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S)Diabetes Care199720614209096989

 PubMed Web of Science ®Google Scholar

The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study GroupPrevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levelsN Engl J Med19983391349579841303

 PubMed Web of Science ®Google Scholar