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

Dormandy, J. A.; Charbonnel, B.; Eckland, D.J.A.; Erdmann, Erland; Massi‐Benedetti, Massimo; Moules, Ian K.; Skene, Allan M.; Tan, Meng H.; Lefèbvre, Pierre; Murray, Gordon D.; Standl, Eberhard; Wilcox, Robert G.; Wilhelmsen, Lars; Betteridge, John; Birkeland, Kåre I.; Golay, Alain; Heine, Robert J.; Korányi, László; Laakso, Markku; Mokáň, Marián; Norkus, Antanas; Pīrāgs, Valdis; Podar, T; Scheen, André; Scherbaum, Werner A.; Schernthaner, Guntram; Schmitz, Ole; Škrha, J; Smith, Ulf; Tatoń, J

doi:10.1016/s0140-6736(05)67528-9

Cited by 3,822 publications

(2,955 citation statements)

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“…The PROactive trial found a non‐significant 10% reduction in the primary outcome associated with a 0.5% reduction in HbA1c achieved with randomization to pioglitazone in a high‐CV‐risk population with type 2 diabetes but without heart failure 1; this outcome is similar to our MACE+ composite. In the PROactive and CREDIT studies, the benefits of good HbA1c values with regard to CV risk were greater for MACE than MACE+ (MACE being driven only by disease status, and MACE+ also including clinical interventions).…”

Section: Discussionsupporting

confidence: 66%

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Relationship of glycaemic control and hypoglycaemic episodes to 4‐year cardiovascular outcomes in people with type 2 diabetes starting insulin

Freemantle

Danchin

Calvi-Gries³

et al. 2015

Diabetes Obesity Metabolism

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AimsTo examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non‐interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study.MethodsData on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV‐specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time‐dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all‐cause mortality was examined.ResultsA total of 147 primary events were accrued during up to 54 months of follow‐up. In all, 60 CV‐specific deaths, 44 non‐fatal MIs and 57 non‐fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12–1.40; p < 0.0001]. CV death [HR 1.31 (95% CI 1.10–1.57); p = 0.0027] and stroke [HR 1.36 (95% CI 1.17–1.59); p < 0.0001] were both strongly associated with HbA1c, while MI was not [HR 1.05 (95% CI 0.83–1.32)]. One or more severe hypoglycaemic episodes affected 175 participants, while 1508 participants experienced one or more symptomatic hypoglycaemic events. We found no relationship between severe/symptomatic hypoglycaemic events and CV‐specific/all‐cause death.ConclusionsOngoing poorer glucose control was associated with CV events; hypoglycaemia was not associated with CV‐specific/all‐cause death.

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Section: Discussionsupporting

confidence: 66%

“…The relationship between glycaemic control and cardiovascular (CV) outcome remains uncertain, with recent randomized trials giving contradictory results 1, 2, 3, 4. Observational studies can provide insights that may be generalized to clinical populations 5.…”

Section: Introductionmentioning

confidence: 99%

Relationship of glycaemic control and hypoglycaemic episodes to 4‐year cardiovascular outcomes in people with type 2 diabetes starting insulin

Freemantle

Danchin

Calvi-Gries³

et al. 2015

Diabetes Obesity Metabolism

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“…This has led to black box warnings for both glitazones. The absolute risk is small, amounting to 0.5% compared to 0.1% for placebo in the DREAM trial of rosiglitazone, 49 6% compared to 4% in the PROactive trial 47 of pioglitazone, and a doubling of relative risk upon meta-analysis. 50 One analysis suggests that even when symptoms occur, they tend to be relatively welltolerated.…”

Section: Adverse Effects Of Glitazonesmentioning

confidence: 92%

“…Unlike rosiglitazone, pioglitazone has not been associated with increased risks of cardiovascular events or mortality. The prospective, placebo-controlled PROactive trial of 5,238 subjects with diabetes and known cardiovascular disease demonstrated no increase in risk 47 nor did a subsequent meta-analysis that included the PROactive data as well as other data. 48 The PROactive trial has been criticized for being too stringent in its endpoints and post-hoc reanalysis specifically for major adverse cardiovascular events suggests that the drug reduces the risk of cardiovascular disease.…”

Section: Adverse Effects Of Glitazonesmentioning

confidence: 99%

“…Glitazones induce weight gain in some but not all patients, typically in the range of 10 pounds. 21,28,47,52,53 This seemingly paradoxical effect for a class of drugs that improves IS is due to increased peripheral rather than visceral fat and thus should not confer the metabolic and inflammatory abnormalities associated with intraabdominal fat. 54 Pioglitazone treatment for 16 weeks caused a 4% increase in body mass index, an 11% increase in total fat mass, a 14% increase in subcutaneous fat mass, but a 9% decrease in intraabdominal fat and improved hepatic and peripheral IS.…”

Section: Adverse Effects Of Glitazonesmentioning

confidence: 99%

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Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

2010

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Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials. (HEPATOLOGY 2010;52:2206-2215 N onalcoholic steatohepatitis (NASH) is emerging as the next big therapeutic challenge in hepatology. 1 Currently the top cause of newly identified chronic liver diseases, NASH has potential for fibrosis, cirrhosis decompensation, and hepatocellular carcinoma. Not all individuals with metabolic risk factors will experience these adverse outcomes and identifying those at risk is critical. Prognostic markers for progression have mostly been derived from histological studies. Compared to steatosis alone or to steatosis and minimal inflammation, the coexistence of inflammation, cell injury (ballooning), and steatosis, a pathological aggregate labeled steatohepatitis, is associated with a significant increase in overall mortality and in liver-related mortality. The degree of inflammation is the best predictor of fibrosis progression, 2 a widely accepted surrogate for hard endpoints such as cirrhosis, endstage liver disease, and possibly hepatocellular carcinoma.Insulin resistance (IR) is consistently found in patients with NASH in both cross-sectional and longitudinal studies. Moreover, there is a stepwise increase in the severity of IR and its phenotypic complications (clustered as elements of the metabolic syndrome) between normal liver, isolated steatosis, and steatohepatitis that has prompted speculation that IR might contribute to liver damage. Logically, most therapeutic trials focused on insulin sensitizers (IS) as candidate therapies.The aim of this report is to critically review the results of trials of metformin and glitazones for NASH. We highlight methodological challenges for trial design and propose endpoints for future proof of principle, registrational, and postmarketing trials.

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Low-Dose Rosiglitazone in Patients With Insulin-Requiring Type 2 Diabetes

Hollander

Yu²,

Chou³

2007

Arch Intern Med

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Background: The objective was to compare the efficacy and safety of adding low-dose rosiglitazone (2 or 4 mg/d) to insulin therapy vs continued insulin monotherapy in patients with type 2 diabetes mellitus who were unable to achieve glycemic control with insulin therapy alone. Methods: In this 24-week, double-blind study, 630 individuals with type 2 diabetes mellitus that was inadequately controlled with insulin therapy alone were randomized to treatment with rosiglitazone (2 or 4 mg/d) or placebo in combination with ongoing insulin therapy. The dosage of insulin therapy could be adjusted at the investigator's discretion if required for hypoglycemia or additional glycemic control. Results: The addition of rosiglitazone (2 or 4 mg/d) to insulin therapy significantly decreased mean glycated hemoglobin concentrations compared with placebo plus insulin (-0.3% [P = .

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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

Cited by 3,822 publications

References 19 publications

Relationship of glycaemic control and hypoglycaemic episodes to 4‐year cardiovascular outcomes in people with type 2 diabetes starting insulin

Relationship of glycaemic control and hypoglycaemic episodes to 4‐year cardiovascular outcomes in people with type 2 diabetes starting insulin

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

Low-Dose Rosiglitazone in Patients With Insulin-Requiring Type 2 Diabetes

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