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Glucose-lowering effects of incretin-based therapies

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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.


Selected clinical trials of incretin-based therapies added to combination therapy41-48

Agent/clinical trialCombination/duration (wk)A1C (%)% Patients achieving A1C <7%FPG (mg/dL)
Exenatide (E)
Kendall, 200541Met + SU/30
E, 5 μg BID 8.5-0.627182-9
E, 10 μg BID 8.5-0.634178-11
Placebo 8.5+0.29180+14
Blonde, 200642Met + SU/52
E, 5 μg BID 8.3-1.148173-16
E, 10 μg BID 8.3-1.148173-16
Nauck, 200743Met + SU/52
E, 10 μg BID 8.6-1.032198-32
Aspart 70/30 BID 8.6-0.924203-31
Heine, 200544Met + SU/26
E, 10 μg BID 8.2-1.146182-26
Glargine OD 8.3-1.148187-52
Zinman, 200745TZD±Met/16
E, 10 μg BID 7.9-0.962164-29
Placebo 7.9+0.116159+2
Liraglutide (L)
Russell-Jones, 200946Met + Glim/26
L, 1.8 mg OD 8.3-1.3NR164-28
Glargine 8.2-1.1NR164-32
Placebo 8.3-0.2NR169+10
Zinman, 200947Met + Rosi/26
L, 1.2 mg OD 8.5-1.558182-43
L, 1.8 mg OD 8.6-1.554185-48
Placebo 8.4-0.528180-9
Sitagliptin (Si)
Hermansen, 200748Glim±Met/24
Si, 100 mg OD 8.3-0.517181-4
Placebo 8.3+0.35182+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.

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