Can the glucose-lowering drugs insulin secretagogues prevent or delay type 2 diabetes mellitus and its associated complications in persons at increased risk of this disease?

Review question

Can the group of glucose-lowering drugs called insulin secretagogues prevent or delay the development of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus?

Background

Insulin secretagogues are widely used to treat people with type 2 diabetes mellitus. The insulin secretagogues can be divided into two main classes of glucose-lowering drugs, namely sulphonylureas (e.g. glibenclamide/glyburide, glipizide and gliclazide) and meglitinide analogues (nateglinide and repaglinide). Insulin secretagogues lower blood glucose by stimulating the secretion of insulin in the body, thereby increasing insulin levels in the blood. People with moderately elevated glucose levels are often said to be at an increased risk for developing type 2 diabetes (often called 'prediabetes'). Therefore, people with moderately elevated glucose levels are frequently recommended to increase exercise and lower calorie intake (behaviour changing or 'lifestyle' interventions) in order to prevent the development of type 2 diabetes. It is currently not known whether insulin secretagogues should be prescribed for people with raised blood glucose levels who do not meet the diagnostic criteria for having type 2 diabetes mellitus. We wanted to find out whether insulin secretagogues could prevent or delay the development of type 2 diabetes mellitus in people with moderately elevated glucose levels. Furthermore, we wanted to analyse the effects of insulin secretagogues on patient-important outcomes such as complications of diabetes (for example kidney and eye disease, heart attacks, strokes), death from any cause, health-related quality of life and side effects of the medications.

Study characteristics

We searched the medical literature and registers of ongoing trials for randomised controlled trials of at least 12 weeks' duration comparing insulin secretagogues with another glucose-lowering drug, placebo or no intervention. Randomised controlled trials are clinical studies in which people are randomly allocated to one of two or more groups so that the effects of different interventions can be compared directly. Participants included in the studies had to have glucose levels higher than considered normal, but below the glucose levels that are used to diagnose type 2 diabetes mellitus. We combined the findings of several studies to answer our review question. We found six randomised controlled trials. A total of 10,018 participants were included. The duration of the interventions varied from six months to five years.

This evidence is up to date as of April 2016.

Key results

Few participants died following treatment with sulphonylureas. Sulphonylureas (most of the evidence was available for glimepiride) did not reduce the risk of developing type 2 diabetes mellitus compared with placebo. No study with sulphonylureas reported on serious side effects, non-fatal heart attacks, non-fatal stroke, heart failure, health-related quality of life or socioeconomic effects.

Only one study reported data on a meglitinide analogue (nateglinide). This large study contributed 95% of all participants of our review. We could not establish firm evidence on the outcomes death from any cause, risk of developing type 2 diabetes mellitus or serious side effects. This study did not report on health-related quality of life or socioeconomic effects.

Future studies should investigate patient-important outcomes and, especially, the side effects of the medications, because we do not know for sure whether 'prediabetes' is just a condition arbitrarily defined by a laboratory measurement or is in fact a real risk factor for type 2 diabetes mellitus, which might be treatable.

Quality of the evidence

All included trials had deficiencies in the way they were conducted or how key items were reported. For the individual comparisons the number of participants was small, resulting in a high risk of random errors (play of chance).

Authors' conclusions: 

There is insufficient evidence to demonstrate whether insulin secretagogues compared mainly with placebo reduce the risk of developing T2DM and its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

Read the full abstract...
Background: 

The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether insulin secretagogues (sulphonylureas and meglitinide analogues) are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown.

Objectives: 

To assess the effects of insulin secretagogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was April 2016.

Selection criteria: 

We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing insulin secretagogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these.

Data collection and analysis: 

Two review authors read all abstracts and full-text articles/records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We carried out trial sequential analyses (TSAs) for all outcomes that could be meta-analysed. We assessed the overall quality of the evidence by using the GRADE instrument.

Main results: 

We included six RCTs with 10,018 participants; 4791 participants with data on allocation to intervention groups were randomised to a second- or third-generation sulphonylurea or a meglitinide analogue as monotherapy and 29 participants were randomised to a second-generation sulphonylurea plus metformin. Three trials investigated a second-generation sulphonylurea, two trials investigated a third-generation sulphonylurea and one trial a meglitinide analogue. A total of 4873 participants with data on allocation to control groups were randomised to a comparator group; 4820 participants were randomised to placebo, 23 to diet and exercise, and 30 participants to metformin monotherapy. One RCT of nateglinide contributed 95% of all participants. The duration of the intervention varied from six months to five years. We judged none of the included trials as at low risk of bias for all 'Risk of bias' domains.

All-cause and cardiovascular mortality following sulphonylurea (glimepiride) treatment were rarely observed (very low-quality evidence). The RR for incidence of T2DM comparing glimepiride monotherapy with placebo was 0.75; 95% CI 0.54 to 1.04; P = 0.08; 2 trials; 307 participants; very low-quality evidence. One of the trials reporting on the incidence of T2DM did not define the diagnostic criteria used. The other trial diagnosed T2DM as two consecutive fasting blood glucose values ≥ 6.1 mmol/L. TSA showed that only 4.5% of the diversity-adjusted required information size was accrued so far. No trial reported data on serious adverse events, non-fatal myocardial infarction (MI), non-fatal stroke, congestive heart failure (HF), health-related quality of life or socioeconomic effects.

One trial with a follow-up of five years compared a meglitinide analogue (nateglinide) with placebo. A total of 310/4645 (6.7%) participants allocated to nateglinide died compared with 312/4661 (6.7%) participants allocated to placebo (hazard ratio (HR) 1.00; 95% CI 0.85 to 1.17; P = 0.98; moderate-quality evidence). The two main criteria for diagnosing T2DM were a fasting plasma glucose level ≥ 7.0 mmol/L or a 2-hour post challenge glucose ≥ 11.1 mmol/L. T2DM developed in 1674/4645 (36.0%) participants in the nateglinide group and in 1580/4661 (33.9%) in the placebo group (HR 1.07; 95% CI 1.00 to 1.15; P = 0.05; moderate-quality evidence). One or more serious adverse event was reported in 2066/4602 (44.9%) participants allocated to nateglinide compared with 2089/4599 (45.6%) participants allocated to placebo. A total of 126/4645 (2.7%) participants allocated to nateglinide died because of cardiovascular disease compared with 118/4661 (2.5%) participants allocated to placebo (HR 1.07; 95% CI 0.83 to 1.38; P = 0.60; moderate-quality evidence). Comparing participants receiving nateglinide with those receiving placebo for the outcomes MI, non-fatal stroke and HF gave the following event rates: MI 116/4645 (2.5%) versus 122/4661 (2.6%), stroke 100/4645 (2.2%) versus 110/4661 (2.4%) and numbers hospitalised for HF 85/4645 (1.8%) versus 100/4661 (2.1%) - (HR 0.85; 95% CI 0.64 to 1.14; P = 0.27). The quality of the evidence was moderate for all these outcomes. Health-related quality of life or socioeconomic effects were not reported.

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