Currently available hypoglycemic agents are not able to successfully lower the hemoglobin A1c (HbA1c) level to less than 7% in the majority of type 2 diabetics. If not from ineffective usage, the lack of efficacy is majorly due to a decrease in pancreatic beta cell function. Efficacy is also limited by adverse effects such as weight gain, edema, hypoglycemia, or lack of targeting of postprandial hyperglycemia. New treatment options aside from the conventional antidiabetic agents are being considered for nonpregnant adults with type 2 diabetes.
One recent therapeutic approach is to exploit the role of incretins, intestinally derived peptides which are released in the presence of glucose in the gastrointestinal tract and act to stimulate the secretion of insulin. The two major incretins are glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are active in decreasing blood glucose when levels are less than 55 mg/dL but are quickly degraded by the enzyme dipeptidyl peptidase 4 (DPP4). Because the incretin pathway is disrupted in patients with type 2 diabetes, incretin-based therapies have been developed and used clinically to decrease hyperglycemia. Current therapies include the injectable GLP-1 analogue exenatide which is resistant to degradation by DPP4 and sitagliptin, a DPP4 inhibitor used as a single agent or in combination with metformin or thiazolidendione.
The purpose of this study is to evaluate the efficacy and safety of incretin-based therapies using data collected from 29 randomized controlled clinical trials comparing incretin-based strategies with non-incretin-based agents (placebo or other antidiabetic agents). Each of these pharmaceutical industry-sponsored studies were double-blind except those including insulin which were open-label. Data from clinical studies were gathered from MEDLINE, Cochrane Central Register of Controlled Trials, and other relevant websites and included information from unpublished abstracts since results were found to be consistent with published data. Additionally, only trials lasting at least 12 weeks were included in the analysis to ensure the accurate assessment of efficacy.
Glycemic efficacy was determined primarily by noting the changes in HbA1c from baseline between treatment groups. Fasting plasma glucose and postprandial glycemia following a mixed-meal test were secondary indicators of efficacy. Assessment of safety was determined by evaluating changes in body weight, lipid profile, and hypoglycemia. Any information on the levels of circulating antibodies to the incretin analogue was also noted. Importantly, the description of each trial and method of analysis was also evaluated in order to ensure the quality of the study. For all continuous variables, the weighed mean differences were calculated with a 95% confidence interval (CI) for comparisons across treatment groups while for dichotomous variables, the risk ratios and 95% CIs were calculated.
Results of the meta-analysis showed the GLP-1 analogue exenatide were efficacious in decreasing HbA1c from baseline compared to the placebo and was as effective as insulin in open-label studies. In evaluating postprandial glycemia, exenatide reduced this parameter to a greater extent than insulin glargine or biphasic aspart. Significant weight loss was reported with GLP-1 analogues verses non-incretin-based treatments. Data on the effects of GLP-1 analogues on lipid profiles showed that insulin improved HDL over exenatide but exenatide treatment induced a small decrease in LDL compared to placebo. Mild to moderate nausea and vomiting with some instances of diarrhea was the most common adverse effect and was a major reason for trial withdrawal. These gastrointestinal complications were thought to be due the effects of GLP-1 analogues in reducing gastric emptying and only occurred in the initial weeks of the studies. A high incidence of antibodies raised to these analogues was also noted, but this did not specifically lead to any negative outcomes.
The DPP4 inhibitors sitagliptin and vildagliptin were found to similarly lower HbA1c compared to placebo but were less efficacious compared with other hypoglycemic agents. Fasting plasma glucose was also reduced with DPP4 inhibitors over placebo. In terms of adverse events, there was a very low incidence of hypoglycemia similar to other treatment groups, and no significant change in lipid profile. There was no risk of gastrointestinal complications as with GLP-1 analogues. However, an increased risk of infections, such as urinary tract infections and nasopharyngitis, as well as headaches was noted with the DPP4 inhibitors sitagliptin and vildagliptin, respectively.
When considering the clinical use of incretin-based therapy, it is important to note that the efficacy of these agents in lowering the HbA1c is highly dependent on the baseline levels. Though these agents were associated with a low risk of hypoglycemia, other potential adverse effects reported in these studies should be taken into consideration, especially since all trials did not go beyond 30 weeks. Combining these agents with other therapies may also increase unwanted effects. Additionally, the clinical data gathered in this study did not consider differential effects in various ethnic populations and in children. Further investigation into the efficacy and safety of incretin therapy is warranted to accurately determine their benefit over currently available treatments for type 2 diabetes.
References:
Efficacy and Safety of Incretin in Type 2 Diabetes: Systematic Review and Meta-analysis
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