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Am Fam Physician. 2021;104(2):139-140

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Clinical Question

How does pioglitazone (Actos) compare with other pharmacologic glucose-lowering agents and lifestyle interventions in the prevention or delay of type 2 diabetes mellitus in individuals with prediabetes?

Evidence-Based Answer

Pioglitazone prevents or delays the incidence of type 2 diabetes in individuals with prediabetes when compared with placebo (absolute risk reduction [ARR] = 11.3%; 95% CI, 0.9% to 15.6%; number needed to treat [NNT] = 9) or no intervention (ARR = 13.3%; 95% CI, 11.6% to 14.9%; NNT = 7). Compared with metformin, however, pioglitazone does not reduce the incidence of type 2 diabetes in those with prediabetes.1 (Strength of Recommendation: A, based on consistent, good-quality patient-oriented evidence.)

Practice Pointers

Prediabetes is a condition with various definitions describing patients whose average blood glucose levels are higher than normal.1 Approximately 34.5% of the U.S. adult population has prediabetes, with a higher prevalence in men and a similar prevalence among all ethnic groups.2 The authors of this review sought to determine the effect of pioglitazone (a thiazolidinedione) on the prevention or delay of type 2 diabetes and its associated complications in individuals with prediabetes.

This review included 27 randomized controlled trials with 4,186 participants; most trials were conducted in outpatient settings, three of which were in the United States.1 Primary outcomes of this review were all-cause mortality, incidence of type 2 diabetes, and serious adverse events. Most studies identified individuals with prediabetes using the World Health Organization 1999, American Diabetes Association (ADA) 2003, or ADA 2010 diagnostic criteria for impaired fasting glucose or impaired glucose tolerance. A range of 15 to 30 mg of pioglitazone and varied doses of metformin (38 mg, 250 mg, and 750 mg) were typically used. The length of interventions ranged from six to 36 months.

Pioglitazone was compared with metformin, acarbose (Precose), or repaglinide in three studies involving 331 participants. Each comparison group had matching behavior-changing interventions. All-cause mortality was not reported in the included studies, and there were no serious adverse events in the comparison groups. Pioglitazone did not reduce the incidence of type 2 diabetes compared with metformin (low-certainty evidence).

Compared with placebo, pioglitazone reduced or delayed type 2 diabetes (ARR = 11.3%; 95% CI, 0.9% to 15.6%; NNT = 9; six studies; n = 1,395; low-certainty evidence). However, this effect was no longer present in three studies after a washout and extended follow-up period ranging between three weeks and one year after the study period.

Compared with no intervention, pioglitazone performed better in the prevention or delay of type 2 diabetes (ARR = 13.3%; 95% CI, 11.6% to 14.9%; NNT = 7; 16 studies; n = 2,053; moderate-certainty evidence). Analysis of all-cause mortality revealed no harmful effects (three studies; n = 866; very low-certainty evidence) and no serious adverse events with the use of pioglitazone (seven studies; n = 1,211; low-certainty evidence).

Pioglitazone was compared with behavior-changing interventions (diet and exercise) in one study involving 96 participants. There was no significant effect on the incidence of type 2 diabetes or serious adverse events with the use of pioglitazone (downgraded to low-certainty evidence).

Limitations of this review include variations in the diagnostic criteria for prediabetes, exclusion of individuals with comorbidities commonly encountered in primary care settings (except for hypertension), and differences in the dosages of administered medications.

The ADA recommends yearly testing of individuals who have prediabetes given the estimated annual rate of conversion from prediabetes to type 2 diabetes of 3% to 11%.3,4 Current treatment recommendations for those with prediabetes include intensive behavioral lifestyle intervention (modeled after the Diabetes Prevention Program, a goal-based intervention to achieve and maintain 7% loss of initial body weight and increase moderate-intensity physical activity to at least 150 minutes per week), dietary modification, individualized medical nutrition therapy, and consideration of medications such as thiazolidinediones.5 The cost of 30 tablets of 15-mg pioglitazone is about $15, and the cost of 60 tablets of 500-mg metformin is about $14.6 Pioglitazone carries a black box warning for causing or worsening congestive heart failure.

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These are summaries of reviews from the Cochrane Library.

This series is coordinated by Corey D. Fogleman, MD, assistant medical editor.

A collection of Cochrane for Clinicians published in AFP is available at https://www.aafp.org/afp/cochrane.

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