The results of these trials indicate that for this 47-year-old man, a GLP-1 agonist would be a better choice to replace pioglitazone, primarily because the A1C reduction of ≥1.0% that can be achieved with this class of drug, and which is needed in this case, is greater than the reduction that can be expected with a DPP-4 inhibitor. Other issues such as weight loss and low individual incidence of hypoglycemia, which also need to be considered, are discussed in the next article.
FIGURE 3 Comparison of glucose-lowering effects of liraglutide and exenatide37
A, Change in glycosylated hemoglobin (A1C) level from baseline to Week 26 with liraglutide 1.8 mg once a day or exenatide 10 μg twice a day.
B, Efficacy of treatment with liraglutide 1.8 mg once a day vs exenatide 10 μg twice a day: 7-point self-measured plasma glucose profiles from baseline to Week 26.
Reprinted with permission from: Lancet. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). 2009;374:39-47. Copyright Elsevier, 2009.
Case 3
This 68-year-old woman was diagnosed with T2DM 5 years ago. She has experienced disease progression with a rising A1C level despite dual oral therapy. Her current A1C is 7.4%. She also has peripheral arterial disease and osteoporosis, both of which are being treated. For a patient who has failed dual oral therapy with metformin and another agent, the AACE/ACE guidelines suggest the addition of a DPP-4 inhibitor, GLP-1 agonist, or thiazolidinedione (FIGURE 2).4,5 If a DPP-4 inhibitor or GLP-1 agonist is added, the dose of the sulfonylurea should be decreased by 50% due to the increased risk of hypoglycemia.5 Her mild renal insufficiency is also a consideration.
GLP-1 agonists and DPP-4 inhibitors in combination with metformin and other oral agents
Many clinical trials have been conducted with a GLP-1 agonist or DPP-4 inhibitor in combination with lifestyle intervention, metformin, and 1 or 2 other agents. As shown in TABLE 3,41-48 the reductions in A1C observed when a GLP-1 agonist or DPP-4 inhibitor is added to dual therapy are generally similar to those observed with GLP-1 agonist or DPP-4 inhibitor monotherapy, although reductions of up to 1.5% have been observed with the addition of liraglutide.46,47 Similarly, reductions in FPG with combination therapy—7 to 74 mg/dL with GLP-1 agonists and 14 to 29 mg/dL with DPP-4 inhibitors—have been comparable to those observed with monotherapy. These results provide evidence of the effectiveness of GLP-1 agonists and DPP-4 inhibitors in further lowering blood glucose levels when added to dual therapy in patients with advanced disease.
TABLE 3
Selected clinical trials of incretin-based therapies added to combination therapy41-48
| Agent/clinical trial | Combination/duration (wk) | A1C (%) | % Patients achieving A1C <7% | FPG (mg/dL) | ||
|---|---|---|---|---|---|---|
| Baseline | Change | Baseline | Change | |||
| Exenatide (E) | ||||||
| Kendall, 200541 | Met + SU/30 | |||||
| E, 5 μg BID | 8.5 | -0.6 | 27 | 182 | -9 | |
| E, 10 μg BID | 8.5 | -0.6 | 34 | 178 | -11 | |
| Placebo | 8.5 | +0.2 | 9 | 180 | +14 | |
| Blonde, 200642 | Met + SU/52 | |||||
| E, 5 μg BID | 8.3 | -1.1 | 48 | 173 | -16 | |
| E, 10 μg BID | 8.3 | -1.1 | 48 | 173 | -16 | |
| Nauck, 200743 | Met + SU/52 | |||||
| E, 10 μg BID | 8.6 | -1.0 | 32 | 198 | -32 | |
| Aspart 70/30 BID | 8.6 | -0.9 | 24 | 203 | -31 | |
| Heine, 200544 | Met + SU/26 | |||||
| E, 10 μg BID | 8.2 | -1.1 | 46 | 182 | -26 | |
| Glargine OD | 8.3 | -1.1 | 48 | 187 | -52 | |
| Zinman, 200745 | TZD±Met/16 | |||||
| E, 10 μg BID | 7.9 | -0.9 | 62 | 164 | -29 | |
| Placebo | 7.9 | +0.1 | 16 | 159 | +2 | |
| Liraglutide (L) | ||||||
| Russell-Jones, 200946 | Met + Glim/26 | |||||
| L, 1.8 mg OD | 8.3 | -1.3 | NR | 164 | -28 | |
| Glargine | 8.2 | -1.1 | NR | 164 | -32 | |
| Placebo | 8.3 | -0.2 | NR | 169 | +10 | |
| Zinman, 200947 | Met + Rosi/26 | |||||
| L, 1.2 mg OD | 8.5 | -1.5 | 58 | 182 | -43 | |
| L, 1.8 mg OD | 8.6 | -1.5 | 54 | 185 | -48 | |
| Placebo | 8.4 | -0.5 | 28 | 180 | -9 | |
| Sitagliptin (Si) | ||||||
| Hermansen, 200748 | Glim±Met/24 | |||||
| Si, 100 mg OD | 8.3 | -0.5 | 17 | 181 | -4 | |
| Placebo | 8.3 | +0.3 | 5 | 182 | +16 | |
| A1C, glycosylated hemoglobin; BID, twice daily; FPG, fasting plasma glucose; Glim, glimepiride; Met, metformin; NR, not reported; OD, once daily; Rosi, rosiglitazone; SU, sulfonylurea; TZD, thiazolidinedione. | ||||||
GLP-1 agonist and DPP-4 inhibitor trials compared with insulin
While sitagliptin is the only one of the 4 incretin-based therapies approved for use in combination with insulin (TABLE 1),15-19 several studies have compared the efficacy of adding exenatide, liraglutide, or sitagliptin with adding insulin glargine to other glucose-lowering therapy.32,43,44,46 These trials have generally shown a GLP-1 agonist to provide glucose-lowering ability comparable to that with insulin glargine. For example, separate 26-week trials compared exenatide and liraglutide with insulin glargine in patients suboptimally controlled with metformin and a sulfonylurea. In the first (N=551), both exenatide and insulin glargine decreased the mean A1C level 1.1%.44 The FPG level decreased 26 mg/dL in the exenatide group and 52 mg/dL in the insulin glargine group (P<.001). On the other hand, exenatide reduced PPG excursions compared with insulin glargine. In the second trial (N=576), the A1C level decreased 1.3% in the liraglutide group vs 1.1% in the insulin glargine group (P=.0015) and 0.2% in the placebo group (both, P<.0001 vs placebo).46 The FPG level decreased 28 and 32 mg/dL, respectively, in the liraglutide and insulin glargine groups and increased 10 mg/dL in the placebo group. Postprandial glucose decreased 33 and 29 mg/dL, respectively, in the liraglutide and glargine groups but did not change in the placebo group (P<.0001 liraglutide vs placebo). These trials showed that addition of exenatide or liraglutide to metformin and a sulfonylurea provides comparable glucose reduction to addition of insulin glargine.