Treating prediabetes in the obese: are GLP-1 analogues the answer?

Glucagon-like peptide 1 (GLP-1) analogues are increasingly recognised for their considerable clinical effects on weight loss and diabetes. Increasing evidence has shown their use can improve cardiovascular disease risk, decrease mortality, and provide other metabolic improvements. In the Lancet, Carel le Roux and colleagues examined whether 3·0 mg liraglutide administered daily might, over time, reduce the rate of development of type 2 diabetes in individuals with prediabetes. The authors observed a 4·6 kg placebo-subtracted weight reduction with liraglutide (50% of patients lost >5% weight vs 24% in the placebo group) after 3 years—weight loss that is similar to that reported in previous liraglutide studies. A meta-analysis showed a placebo-subtracted 5·3 kg weight reduction in response to 3·0 mg liraglutide administered daily and that 63% of treated patients lost a median of more than 5% weight during 1 year compared with 23% of patients receiving placebo. Intensive lifestyle modification showed similar weight loss of 5·6 kg in the large Diabetes Prevention Program (DPP) study with an average follow-up of 2·8 years. The major finding of le Roux and colleagues, however, is the prediabetes to normoglycaemia conversion in the liraglutide group (66% vs 36% in the placebo group) at the end of 3 years; additionally, only 3% of individuals in the liraglutide group versus 11% in the placebo group developed diabetes by the end of the trial. Effectively, these results indicate that for every three people treated, one person would be expected to become normoglycaemic owing to liraglutide treatment alone. These results were similar in the short-term, earlier reports of this study. Of patients who were prediabetic at screening, 31% in the 3·0 mg liraglutide group and 67% in the placebo group who had prediabetes at baseline continued to have prediabetes at 56 weeks, suggesting a 69% reduction in prediabetes with 3·0 mg liraglutide and a 33% reduction with placebo. At 56 weeks, 4% of patients on 3·0 mg liraglutide developed diabetes compared with 14% in the placebo group. At 20 weeks, 84% of patients with prediabetes on 3·0 mg liraglutide and 96% on 1·8 mg liraglutide became normoglycaemic versus 3% on placebo. At 2 years they showed a 52–62% return to normoglycaemia for patients with prediabetes on 1·8–3·0 mg liraglutide. Another GLP-1 analogue, exenatide, showed similar effects; 77% of treated patients with prediabetes returned to normoglycaemia versus 56% in the placebo group after 24 weeks. To our knowledge, no studies with other GLP-1 analogues have examined how they might impact prediabetes and diabetes risk. Weight loss is generally effective at reducing the incidence of prediabetes and progression to full diabetes. Intensive lifestyle modifications over 4 years in the DPP study in the USA showed 58% risk reduction for incidence of diabetes versus placebo. At 10 years, the risk reduction was 34% for the DPP lifestyle programme. Similar results have been found in the 4 year Finnish DPP study with 58% risk reduction. Metformin, an inexpensive insulin sensitiser and the first-line therapy recommended for diabetes, was shown to reduce incidence of diabetes by 31% in the DPP study. In a small 1 year study, 85% of patients with prediabetes on metformin had returned to normoglycaemia versus 52% of patients receiving placebo. Treatment with thiazolidinediones has also been shown to return patients with prediabetes to normoglycaemia—51% with rosiglitazone Published Online February 22, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)30315-X