Short-acting exenatide has been available since 2005; it is approved for monotherapy or as part of combination therapy as an adjunct to diet and exercise. Clinical trials showed that exenatide 5 μg to 10 μg injected subcutaneously twice a day lowers HbA
1c by almost a percentage point (0.8%) and at the same time is associated with weight loss of 3 to 6 pounds over 30 weeks. The greatest weight loss was obtained when exenatide was used with metformin.
21 The most potent glucose-lowering effects occurred when exenatide was used in combination with metformin and a thiazolidinedione.
22 Subsequent studies have shown HbA
1c reductions of -1.3% and -1.6% at 9 and 12 months, respectively.
23 In a “real world study,”
24 a progressive reduction of weight (about 10 lb) was also observed. The primary effect of short-acting GLP-1 agonists such as exenatide is the lowering of PPG levels.
25 Exenatide is also being developed as a long-acting (once weekly) product. This formulation is still being investigated, but it shows that a more persistent GLP-1 agonist can result in greater effects on FPG levels, as well as PPG levels, leading to more profound overall HbA
1c reductions.
26 When higher HbA
1c levels (>9%) are involved, fasting plasma glucose levels are of particular importance because they make a substantially greater contribution to HbA
1c. When patients are switched from short-acting to long-acting exenatide, there may be a temporary deterioration in glucose control until blood concentrations of the longer-acting agent are achieved.
Liraglutide is the first of the long-acting GLP-1 agonists to be approved in the United States. This long-acting GLP-1 agonist is administered subcutaneously once a day. It has been studied in more than 65,000 patients internationally. Liraglutide has been studied in combination with metformin,
20,27 sulfonylureas,
28 thiazolidinediones plus metformin,
29 and metformin plus sulfonylureas.
20,30 As a longer-acting agent, more profound reductions in HbA
1c levels have been observed with liraglutide across clinical trials than were observed in the twice-a-day exenatide registration trials, reflecting an effect on both FPG and PPG levels. When compared directly with a long-acting insulin analog, liraglutide resulted in statistically significant better glucose-lowering without the risk of hypo-glycemia or weight gain.
30
Both exenatide and liraglutide are associated with weight loss when used as monotherapy or as part of combination-therapy strategies. Weight loss is more profound in patients with greater starting body mass indices.
31 Glucagon-like peptide-1 agonists also have beneficial effects on blood pressure.
24,28 Lipid effects are more mixed from study to study but are generally beneficial; some (but not all) of these effects may be related to weight loss. Significant improvements in very low-density lipoprotein, free fatty acids, and triglycerides have been observed.
32
Head-to-head comparisons of liraglutide and exenatide show that liraglutide once a day provided statistically significant greater improvements in glycemic control than did exenatide twice a day (when used in combination with oral antidiabetic therapy).
20 In the open-label extension to this trial, patients on exenatide were switched to liraglutide, and further reductions in HbA
1c and weight were observed without an increased risk of hypoglycemia.
33 Further lowering of HbA
1c after switching from exenatide may be explained primarily by reductions in FPG levels by liraglutide.