Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus

Review question

Are the glucose-lowering medicines, DPP-4 inhibitors (e.g. linagliptin or vildagliptin) and GLP-1 analogues (e.g. exenatide or liraglutide) able to prevent or delay the development of type 2 diabetes and its associated complications in people at risk for the development of type 2 diabetes?

Background

DPP-4 inhibitors and GLP-1 analogues are widely used to treat people with type 2 diabetes. People with moderately elevated blood glucose are said to be at an increased risk for developing type 2 diabetes (often referred to as 'prediabetes'). It is currently not known whether DPP-4 inhibitors or GLP-1 analogues should be prescribed for people with raised blood glucose levels who do not have type 2 diabetes. We wanted to find out whether these medicines could prevent or delay type 2 diabetes in people at increased risk. We also wanted to know the effects on patient-important outcomes such as complications of diabetes (e.g. kidney and eye disease, heart attacks, strokes), death from any cause, health-related quality of life (a measure of a person's satisfaction with their life and health) and side effects of the medicines.

Study characteristics

Participants had to have blood glucose levels higher than considered normal, but below the glucose levels that are used to diagnose type 2 diabetes mellitus. We found seven randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) with 2702 participants. The duration of the treatments varied from 12 weeks to 160 weeks. One study investigating liraglutide dominated the evidence (2285/2702 participants). The participants in this study were overweight or obese.

This evidence is up to date as of January 2017.

Key results

DPP-4 inhibitors did not reduce the risk of developing type 2 diabetes compared with placebo (a dummy medicine). In the big study investigating the GLP-1-analogue liraglutide, given in a dose used for obese people (3.0 mg), the development of type 2 diabetes was delayed: 26/1472 (1.8%) participants randomised to liraglutide compared with 46/738 (6.2%) participants randomised to placebo developed type 2 diabetes after 160 weeks. On the other side, 970/1472 (66%) participants randomised to liraglutide compared with 268/738 (36%) participants randomised to placebo switched back to normal glucose levels. This study was extended for another 12 weeks without treatment and five additional participants developed diabetes in the liraglutide group, compared with one participant in the placebo group. After the 12 weeks without treatment, 740/1472 (50%) participants in the liraglutide group compared with 263/738 (36%) participants in the placebo group had glucose levels considered as normal. This means that to keep chances high to prevent type 2 diabetes in people at risk one probably needs to continuously take this drug. Of note, serious adverse events (e.g. defined as hospitalisation or a hazard putting the participant at risk, such as an interaction with another medicine) happened more often following liraglutide treatment (230/1524 (15%) participants in the liraglutide group and 96/755 (13%) participants in the placebo group) and it is unclear whether taking this drug is safe in the long term.

We detected neither an advantage nor a disadvantage of DPP-4 inhibitors or GLP-1 analogues in relation to non-fatal heart attacks, non-fatal strokes or heart failure. Our included studies did not report on other complications of diabetes such as kidney or eye disease. The effects on health-related quality of life were inconclusive. In the included studies, very few participants died and there was no apparent relation to treatment.

Future studies should investigate more patient-important outcomes like complications of diabetes 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, is in fact a real risk factor for type 2 diabetes mellitus and whether treatment of this condition translates into better patient-important outcomes.

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 no firm evidence that DPP-4 inhibitors or GLP-1 analogues compared mainly with placebo substantially influence the risk of T2DM and especially 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 dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 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 DPP-4 inhibitors and GLP-1 analogues 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 (WHO) 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 January 2017.

Selection criteria: 

We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues 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 and 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 planned to use 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 assessed the overall quality of the evidence using the GRADE instrument.

Main results: 

We included seven completed RCTs; about 98 participants were randomised to a DPP-4 inhibitor as monotherapy and 1620 participants were randomised to a GLP-1 analogue as monotherapy. Two trials investigated a DPP-4 inhibitor and five trials investigated a GLP-1 analogue. A total of 924 participants with data on allocation to control groups were randomised to a comparator group; 889 participants were randomised to placebo and 33 participants to metformin monotherapy. One RCT of liraglutide contributed 85% of all participants. The duration of the intervention varied from 12 weeks to 160 weeks. We judged none of the included trials at low risk of bias for all 'Risk of bias' domains and did not perform meta-analyses because there were not enough trials.

One trial comparing the DPP-4 inhibitor vildagliptin with placebo reported no deaths (very low-quality evidence). The incidence of T2DM by means of WHO diagnostic criteria in this trial was 3/90 participants randomised to vildagliptin versus 1/89 participants randomised to placebo (very low-quality evidence). Also, 1/90 participants on vildagliptin versus 2/89 participants on placebo experienced a serious adverse event (very low-quality evidence). One out of 90 participants experienced congestive heart failure in the vildagliptin group versus none in the placebo group (very low-quality evidence). There were no data on non-fatal myocardial infarction, stroke, health-related quality of life or socioeconomic effects reported.

All-cause and cardiovascular mortality following treatment with GLP-1 analogues were rarely reported; one trial of exenatide reported that no participant died. Another trial of liraglutide 3.0 mg showed that 2/1501 in the liraglutide group versus 2/747 in the placebo group died after 160 weeks of treatment (very low-quality evidence).

The incidence of T2DM following treatment with liraglutide 3.0 mg compared to placebo after 160 weeks was 26/1472 (1.8%) participants randomised to liraglutide versus 46/738 (6.2%) participants randomised to placebo (very low-quality evidence). The trial established the risk for (diagnosis of) T2DM as HbA1c 5.7% to 6.4% (6.5% or greater), fasting plasma glucose 5.6 mmol/L or greater to 6.9 mmol/L or less (7.0 mmol/L or greater) or two-hour post-load plasma glucose 7.8 mmol/L or greater to 11.0 mmol/L (11.1 mmol/L). Altogether, 70/1472 (66%) participants regressed from intermediate hyperglycaemia to normoglycaemia compared with 268/738 (36%) participants in the placebo group. The incidence of T2DM after the 12-week off-treatment extension period (i.e. after 172 weeks) showed that five additional participants were diagnosed T2DM in the liraglutide group, compared with one participant in the placebo group. After 12-week treatment cessation, 740/1472 (50%) participants in the liraglutide group compared with 263/738 (36%) participants in the placebo group had normoglycaemia.

One trial used exenatide and 2/17 participants randomised to exenatide versus 1/16 participants randomised to placebo developed T2DM (very low-quality evidence). This trial did not provide a definition of T2DM. One trial reported serious adverse events in 230/1524 (15.1%) participants in the liraglutide 3.0 mg arm versus 96/755 (12.7%) participants in the placebo arm (very low quality evidence). There were no serious adverse events in the trial using exenatide. Non-fatal myocardial infarction was reported in 1/1524 participants in the liraglutide arm and in 0/55 participants in the placebo arm at 172 weeks (very low-quality evidence). One trial reported congestive heart failure in 1/1524 participants in the liraglutide arm and in 1/755 participants in the placebo arm (very low-quality evidence). Participants receiving liraglutide compared with placebo had a small mean improvement in the physical component of the 36-item Short Form scale showing a difference of 0.87 points (95% CI 0.17 to 1.58; P = 0.02; 1 trial; 1791 participants; very low-quality evidence). No trial evaluating GLP-1-analogues reported data on stroke, microvascular complications or socioeconomic effects.

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