Does pioglitazone prevent or delay type 2 diabetes and its complications in people at risk of developing type 2 diabetes mellitus?

What is type 2 diabetes?

Type 2 diabetes, also known as adult‐onset diabetes, is the most common type of diabetes. It prevents the body from using insulin properly - insulin is a hormone that helps the body to regulate blood sugar levels. People with type 2 diabetes may suffer long-term effects (diabetic complications), such as eye or kidney disease, or develop foot ulcers. People with moderately elevated blood sugar levels (often referred to as 'prediabetes') are said to have an increased risk of developing diabetes. Pioglitazone is a blood sugar-lowering medicine, which is used to treat people with type 2 diabetes.

What did we want to find out?

We wanted to know whether pioglitazone can also be used to prevent or delay type 2 diabetes in people at increased risk of developing the condition. We examined the effects of pioglitazone on important outcomes for patients, such as complications of diabetes, death from any cause, health-related quality of life and unwanted effects of the treatment.

What did we do?

We searched for studies that investigated pioglitazone used to prevent or delay the onset of type 2 diabetes. Participants had to have elevated blood sugar levels, but lower than diagnostic levels for diabetes, and they needed to be free from other diseases. Studies had to apply the intervention (pioglitazone) for at least 24 weeks.

What we found

We found 27 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) with a total of 4186 participants. The studies compared pioglitazone with other antidiabetic drugs, diet and exercise, placebo (a 'sham' treatment), or no intervention. Twenty-three out of 27 studies were conducted in China. The studies lasted between 24 weeks and three years.

This evidence is up to date as of November 2019.

Key results

Five studies compared pioglitazone with other antidiabetic drugs (metformin, acarbose or repaglinide) and one study compared pioglitazone with diet and exercise. There were no clear beneficial or harmful effects on the risk of developing diabetes comparing the drugs.

Six studies compared pioglitazone with placebo. There was a reduction or delay in the development of type 2 diabetes: 188 out of 1000 people treated with placebo developed type 2 diabetes compared with 75 per 1000 people treated with pioglitazone (possible spread: 32 per 1000 to 179 per 1000).

Twenty-three studies compared pioglitazone with no intervention. There was a reduction or delay in the development of type 2 diabetes: 193 out of 1000 people with no intervention developed type 2 diabetes compared with 60 per 1000 treated with pioglitazone (possible spread: 44 per 1000 to 77 per 1000).

Only a few studies reported death from any cause, serious unwanted effects, non-fatal heart-attacks or strokes. We were not able to detect any clear benefits or harms of pioglitazone for these outcomes. None of the included studies reported health-related quality of life or socioeconomic effects (such as costs of the intervention, absence from work, medication consumption).

We found two ongoing studies that we could potentially include in this review. These studies may contribute data from around 2694 participants to future updates of our review.

Future research should focus on whether the effect of pioglitazone is sustained after people stop taking it. Furthermore, research should focus on patient-important outcomes such as unwanted effects and complications of diabetes.

Quality of the evidence

All studies had problems in their methods or the way they reported results. Moreover, many outcomes were reported by no or just a few studies. We are therefore uncertain whether pioglitazone prevents or delays type 2 diabetes in people at risk of developing the condition.

Authors' conclusions: 

Pioglitazone reduced or delayed the development of T2DM in people at increased risk of T2DM compared with placebo (low-certainty evidence) and compared with no intervention (moderate-certainty evidence). It is unclear whether the effect of pioglitazone is sustained once discontinued. Pioglitazone compared with metformin neither showed advantage nor disadvantage regarding the development of T2DM in people at increased risk (low-certainty evidence).

The data and reporting of all-cause mortality, SAEs, micro- and macrovascular complications were generally sparse. None of the included studies reported on QoL or socioeconomic effects.

Read the full abstract...
Background: 

The term prediabetes is used to describe a population with an elevated risk of developing type 2 diabetes mellitus (T2DM). With projections of an increase in the incidence of T2DM, prevention or delay of the disease and its complications is paramount. It is currently unknown whether pioglitazone is beneficial in the treatment of people with increased risk of developing T2DM.

Objectives: 

To assess the effects of pioglitazone for prevention or delay of T2DM and its associated complications in people at risk of developing T2DM.

Search strategy: 

We searched CENTRAL, MEDLINE, Chinese databases, ICTRP Search Portal and ClinicalTrials.gov. We did not apply any language restrictions. Further, we investigated the reference lists of all included studies and reviews. We tried to contact all study authors. The date of the last search of databases was November 2019 (March 2020 for Chinese databases).

Selection criteria: 

We included randomised controlled trials (RCTs) with a minimum duration of 24 weeks, and participants diagnosed with intermediate hyperglycaemia with no concomitant diseases, comparing pioglitazone as monotherapy or part of dual therapy with other glucose-lowering drugs, behaviour-changing interventions, placebo or no intervention.

Data collection and analysis: 

Two review authors independently screened abstracts, read full-text articles and records, assessed risk of bias and extracted data. We performed meta-analyses with a random-effects model and calculated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, with 95% confidence intervals (CIs) for effect estimates. We evaluated the certainty of the evidence with the GRADE.

Main results: 

We included 27 studies with a total of 4186 randomised participants. The size of individual studies ranged between 43 and 605 participants and the duration varied between 6 and 36 months. We judged none of the included studies as having low risk of bias across all 'Risk of bias' domains. Most studies identified people at increased risk of T2DM by impaired fasting glucose or impaired glucose tolerance (IGT), or both.

Our main outcome measures were all-cause mortality, incidence of T2DM, serious adverse events (SAEs), cardiovascular mortality, nonfatal myocardial infarction or stroke (NMI/S), health-related quality of life (QoL) and socioeconomic effects. The following comparisons mostly reported only a fraction of our main outcome set.

Three studies compared pioglitazone with metformin. They did not report all-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects. Incidence of T2DM was 9/168 participants in the pioglitazone groups versus 9/163 participants in the metformin groups (RR 0.98, 95% CI 0.40 to 2.38; P = 0.96; 3 studies, 331 participants; low-certainty evidence). No SAEs were reported in two studies (201 participants; low-certainty evidence). One study compared pioglitazone with acarbose. Incidence of T2DM was 1/50 participants in the pioglitazone group versus 2/46 participants in the acarbose group (very low-certainty evidence). No participant experienced a SAE (very low-certainty evidence).One study compared pioglitazone with repaglinide. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 1/48 participants in the repaglinide group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence).

One study compared pioglitazone with a personalised diet and exercise consultation. All-cause and cardiovascular mortality, NMI/S, QoL or socioeconomic effects were not reported. Incidence of T2DM was 2/48 participants in the pioglitazone group versus 5/48 participants in the diet and exercise consultation group (low-certainty evidence). No participant experienced a SAE (low-certainty evidence).

Six studies compared pioglitazone with placebo. No study reported on QoL or socioeconomic effects. All-cause mortality was 5/577 participants the in the pioglitazone groups versus 2/579 participants in the placebo groups (Peto odds ratio 2.38, 95% CI 0.54 to 10.50; P = 0.25; 4 studies, 1156 participants; very low-certainty evidence). Incidence of T2DM was 80/700 participants in the pioglitazone groups versus 131/695 participants in the placebo groups (RR 0.40, 95% CI 0.17 to 0.95; P = 0.04; 6 studies, 1395 participants; low-certainty evidence). There were 3/93 participants with SAEs in the pioglitazone groups versus 1/94 participants in the placebo groups (RR 3.00, 95% CI 0.32 to 28.22; P = 0.34; 2 studies, 187 participants; very low-certainty evidence). However, the largest study for this comparison did not distinguish between serious and non-serious adverse events. This study reported that 121/303 (39.9%) participants in the pioglitazone group versus 151/299 (50.5%) participants in the placebo group experienced an adverse event (P = 0.03). One study observed cardiovascular mortality in 2/181 participants in the pioglitazone group versus 0/186 participants in the placebo group (RR 5.14, 95% CI 0.25 to 106.28; P = 0.29; very low-certainty evidence). One study observed NMI in 2/303 participants in the pioglitazone group versus 1/299 participants in the placebo group (RR 1.97: 95% CI 0.18 to 21.65; P = 0.58; very low-certainty evidence).

Twenty-one studies compared pioglitazone with no intervention. No study reported on cardiovascular mortality, NMI/S, QoL or socioeconomic effects. All-cause mortality was 11/441 participants in the pioglitazone groups versus 12/425 participants in the no-intervention groups (RR 0.85, 95% CI 0.38 to 1.91; P = 0.70; 3 studies, 866 participants; very low-certainty evidence). Incidence of T2DM was 60/1034 participants in the pioglitazone groups versus 197/1019 participants in the no-intervention groups (RR 0.31, 95% CI 0.23 to 0.40; P < 0.001; 16 studies, 2053 participants; moderate-certainty evidence). Studies reported SAEs in 16/610 participants in the pioglitazone groups versus 21/601 participants in the no-intervention groups (RR 0.71, 95% CI 0.38 to 1.32; P = 0.28; 7 studies, 1211 participants; low-certainty evidence).

We identified two ongoing studies, comparing pioglitazone with placebo and with other glucose-lowering drugs. These studies, with 2694 participants. may contribute evidence to future updates of this review.

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