Efficacy and Safety of Incretin Therapy in Type 2 Diabetes: Systematic Review and Meta-analysis

Amori RE, Lau J, Pittas AG. JAMA. 2007;298:194-206

Fewer than half of US adults with type 2 diabetes reach an A1C of less than 7% despite numerous available therapies. Two incretin-based therapies, exenatide, a glucagon-like peptide 1 (GLP-1) receptor analogue, and sitagliptin, a selective dipeptidyl peptidase 4 (DPP-4) inhibitor (the first oral incretin enhancer), were approved by the FDA within the last 2 years. Exenatide is approved for use in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione. Sitagliptin is approved for use either as monotherapy or in combination with metformin or thiazolidinedione in nonpregnant adults with type 2 diabetes. Additionally, several other incretin-based therapies are in late-stage clinical development. The role of these pharmacotherapies in the management of type 2 diabetes is not well defined, but there is a need for therapies targeting the decline in pancreatic β-cell function without causing weight gain. Accordingly, a meta-analysis was performed to assess the efficacy and safety of incretin-based therapies (GLP-1 analogs and DPP-4 inhibitors) based on published and unpublished randomized controlled trials of both approved agents and agents in late-stage development.

A total of 29 randomized controlled trials (3 of which had a duration of longer than 30 weeks) containing original data of 11,942 patients with type 2 diabetes (ranging in age from 19-78 years) were selected from 355 potentially relevant articles following a search of MEDLINE (1966-May 20, 2007), the Cochrane Central Register of Controlled Trials (second quarter, 2007), prescribing information documents of approved medications, Web sites, personal reference lists and citation sections of recovered articles, and ADA and EASD abstracts for 2005-2006. Studies of less than 12 weeks“ duration were excluded. The following search terms were used: diabetes, blood glucose, hyperglycemia, glucose, glycohemoglobin, hemoglobin A1C, incretin, glucagon-like peptide, enteroglucagon, GLP-1, GIP, exenatide, liraglutide, dipeptidyl peptidase, DPP, LAF237, MK 0431, sitagliptin, vildagliptin, saxagliptin, human, and clinical trial. All selected studies included A1C outcomes for an incretin-based vs a non-incretin-based comparator group (placebo or hypoglycemic agent); studies involving insulin were open-label. Participant withdrawal was approximately 19% in the GLP-1 analog studies (19% with exenatide and 12% with liraglutide), and 18% in the DPP-4 inhibitor studies (20% with sitagliptin and 16% with vildagliptin).

Compared with placebo, there were modest but statistically significant declines in A1C from baseline obtained with GLP-1 analogs and DPP-4 inhibitors (weighted mean differences − 0.97%; 95% CI, − 1.13% to − 0.81% and − 0.74%; 95% CI, − 0.85% to − 0.62%, respectively). There was no difference in A1C in open-label noninferiority studies between exenatide and insulin glargine or biphasic insulin aspart, whereas DPP-4 inhibitors were slightly less effective compared with other hypoglycemic agents (weighted mean difference, 0.21%; 95% CI, 0.02%-0.39%); noninferiority was established when sitagliptin was compared with glipizide and vildagliptin with thiazolidinedione, but noninferiority was not shown when vildagliptin was compared with metformin. Patients receiving exenatide or DPP-4 inhibitors were more likely to achieve an A1C of less than 7% compared with patients receiving placebo (45% vs 10%, risk ratio, 4.2; 95% CI, 3.2-5.5 and 43% vs 17%, risk ratio, 2.5%; 95% CI, 2.1-2.8, respectively), but there was no difference between exenatide and insulin in this respect in noninferiority trials (39% vs 35%, respectively; risk ratio, 1.1; 95% CI, 0.8-1.5). Incretin therapy decreased both fasting and postprandial glycemia; however, improvements in postprandial glycemic excursions were larger, based on mixed-meal tolerance testing. DPP-4 inhibitors and GLP-1 analogs each reduced fasting plasma glucose compared with placebo injection (weighted mean differences, − 18 mg/dL; 95% CI, − 22 to − 14 mg/dL and − 27 mg/dL; 95% CI, − 33 to − 21 mg/dL, respectively). Postprandial glycemia was reduced more with exenatide in the open-label studies comparing exenatide vs insulin glargine or biphasic aspart, whereas there was no difference in fasting plasma glucose (weighted mean difference, 13 mg/dL; 95% CI, − 16 to 41 mg/dL). Exenatide produced a dose-dependent decrease in postprandial glucose excursions up to 87% at the highest dose compared with baseline and statistically significant postprandial decreases in glycemia with sitagliptin measured at 2 hours postprandially and with vildagliptin measured at 2 hours or 4 hours postprandially. In terms of weight, DPP-4 inhibitors caused a small increase compared with placebo (weighted mean difference, 0.5 kg; 95% CI, 0.3-0.7 kg) whereas GLP-1 analogs were associated with a statistically significant weight loss vs comparator groups (weighted mean difference, -2.37 kg; 95% CI, – 3.95, – 0.78). Moreover, when compared with insulin, weight loss associated with exenatide was more pronounced and tended to be progressive, dose dependent, and without apparent plateau by Week 30. Based on 3 trials, lipid profiles did not change either with GLP-1 analogs or with DPP-4 inhibitors, although in the latter case there seemed to be some improvements in triglycerides. The most common adverse events observed with GLP-1 analogs, seen with exenatide, were gastrointestinal (nausea and vomiting), whereas an increased risk of infection, including urinary tract infection and nasopharyngitis, which was not evident from individual studies, was the most significant adverse event revealed in this meta-analysis of DPP-4 inhibitors. Headache was also reported more commonly with DPP-4 inhibitors, especially with vildagliptin. No risk of gastrointestinal adverse effects (nausea, vomiting, diarrhea, and abdominal pain) compared with placebo were reported in studies of DPP-4 inhibitors.

Incretin therapy with modest efficacy and a favorable weight change profile offers an alternative option to currently available hypoglycemic agents for adults with type 2 diabetes. However, since this meta-analysis included trials that, for the most part, lasted less than 30 weeks, the ability to properly assess both long-term efficacy and safety is limited. Differential effects of incretin-based therapy by race or ethnicity or applicability to children could also not be assessed, since most study participants were white and no children were included. Furthermore, since DPP-4 is a ubiquitous cell-membrane protein and is found in lymphocytes, there is cause for concern that DPP-4 inhibitors may have long-term effects on immune function. DPP-4 inhibitors may therefore be contraindicated in patients with a history of either recurrent urinary tract infections or chronic headache, at least until more safety data are available (it can be argued that although the risk of infection may be small, since there are more than 20 million patients with diabetes in the United States, DPP-4 inhibitors may significantly increase the number of urinary tract infections possibly by 1 million new cases per year). In view of these various factors, further evaluation of these new classes of hypoglycemic agents in clinical practice and in long-term efficacy and safety controlled trials is needed in order to clarify their role among well-established therapies for type 2 diabetes.