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Glucose-lowering effects of incretin-based therapies

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Selected clinical trials of incretin-based therapies as add-on therapy to metformin31-36

Agent/clinical trialDuration (wk)A1C (%)% Patients achieving A1C < 7%FPG (mg/dL)PPG (mg/dL)
Exenatide (E)
DeFronzo, 20053130
E, 5 μg BID 8.3–0.432176–7NRNR
E, 10 μg BID 8.2–0.846168–10NRNR
Placebo 8.2+0.113170+14NRNR
Barnett, 20073232
E, 5 μg BID x 4 wk, then 10 μg BID 9.0-1.438NR–52NRNR
Glargine 9.0-1.440NR–74NRNR
Liraglutide (L)
Nauck, 20093326
L, 0.6 mg OD 8.4–0.728184–20NR–31
L, 1.2 mg OD 8.3–1.035178–29NR–41
L, 1.8 mg OD 8.4–1.042182–31NR–47
Glim, 4 mg OD 8.4–1.036180–23NR–45
Placebo 8.4+0.111180+7NR+11
Sitagliptin (Si)
Charbonnel, 20063424
Si, 100 mg OD 8.0–0.747169–16NRNR
Placebo 8.0018173+9NRNR
Raz, 20083518a/30
Si, 100 mg OD 9.3–1.022202–29NR–68a
Placebo 9.103198–4NR–14a
Saxagliptin (Sa)
DeFronzo, 20093624
Sa, 2.5 mg OD 8.1–0.637174–14NR–62
Sa, 5 mg OD 8.1–0.744180–22NR–58
Sa, 10 mg OD 8.0–0.644176–21NR–50
Placebo 8.1+0.117174+1NR–18
A1C, glycosylated hemoglobin; BID, twice daily; FPG, fasting plasma glucose; Glim, glimepiride; NR, not reported; OD, once daily; PPG, postprandial glucose.
aMeasured at 18 weeks.

Choosing among incretin-based therapies

The choice of 1 GLP-1 agonist or DPP-4 inhibitor over another can be difficult, but recent data from 3 clinical trials provide some guidance in terms of efficacy and safety. Each of these trials has been a direct comparison of add-on therapy with 2 incretin-based therapies. The first, by Buse et al, was an open-label comparison of exenatide 10 μg twice daily with liraglutide 1.8 mg once daily for 26 weeks.37 Patients with inadequately controlled T2DM on maximally tolerated doses of metformin, sulfonylurea, or both participated in the study (N=464). The mean change in A1C level from baseline to Week 26 was significantly greater with liraglutide than with exenatide (+1.1% vs +0.8%, respectively; P<.0001) (FIGURE 3A).37 The difference between the 2 groups was greatest for patients with a baseline A1C ≥10% (liraglutide, –2.4%; exenatide, –1.2%). Furthermore, more patients in the liraglutide group than in the exenatide group achieved an A1C level <7% (54% vs 43%; P=.0015). This may have been a result of a significantly greater reduction in FPG with liraglutide than with exenatide (29 vs 11 mg/dL; P<.0001). The reduction in PPG after breakfast and after dinner (but not after lunch) from baseline to Week 26, however, was significantly greater with exenatide than with liraglutide (FIGURE 3B).37 Liraglutide increased mean fasting insulin secretion (+12.4 pmol/L), whereas there was a small reduction with exenatide (–1.4 pmol/L; P=.0355). Fasting glucagon secretion was reduced in both the liraglutide and exenatide groups, but the difference was not significant (–19.4 vs –12.3 ng/L; P=.1436). A 14-week extension of this study showed that patients who were switched from exenatide to liraglutide experienced a significant further reduction in A1C (–0.3%), FPG (–16 mg/dL), and body weight (–0.9 kg) (P<.0001 for all mean values).38 In those who continued liraglutide, A1C (–0.1%) and FPG (–4 mg/dL) levels remained relatively stable, while body weight was further reduced (–0.4 kg) (P<.009).

The second study was a crossover trial by DeFronzo et al that compared exenatide with sitagliptin in patients inadequately controlled with metformin (N=95).39 In addition to maintaining a stable dose of metformin, patients received either exenatide 5 μg twice daily for 1 week followed by 10 μg twice daily for 1 week, or sitagliptin 100 mg every morning for 2 weeks. Patients were then crossed over to the other treatment. While the mean change from baseline FPG (178 mg/dL) was similar in the exenatide and sitagliptin groups (–15 vs –19 mg/dL; P=.3234), the change from baseline 2-hour PPG (245 mg/dL) was –112 mg/dL for exenatide vs –37 mg/dL for sitagliptin (P<.0001). Following crossover, the patients who were switched from exenatide to sitagliptin experienced an increase in PPG of approximately 73 mg/dL (from 133 to 205 mg/dL), whereas those switched from sitagliptin to exenatide experienced a further reduction of –76 mg/dL (from 209 to 133 mg/dL). Consistent with these observations, exenatide was more effective than sitagliptin in augmenting postprandial insulin secretion and suppressing postprandial glucagon secretion. Exenatide, but not sitagliptin, significantly slowed gastric emptying (P<.0001).

In the third trial, Pratley et al compared the addition of liraglutide 1.2 mg or 1.8 mg and sitagliptin 100 mg once daily in patients inadequately controlled with metformin 1500 mg daily or more (N=665).40 From a mean A1C level of 8.5% at baseline, reductions in A1C after 26 weeks were 1.2% for liraglutide 1.2 mg and 1.5% for liraglutide 1.8 mg vs 0.9% for sitagliptin (P<.0001 for both liraglutide doses). Mean reductions in FPG were 34 mg/dL for liraglutide 1.2 mg and 39 mg/dL for liraglutide 1.8 mg vs 15 mg/dL for sitagliptin. Weight decreased in all 3 groups but by significantly more with liraglutide: 2.9 kg with liraglutide 1.2 mg and 3.4 kg with liraglutide 1.8 mg vs 1.0 kg with sitagliptin (P<.0001 for both liraglutide doses). Both liraglutide doses resulted in significant improvements from baseline in homeostasis model assessment of β-cell function (HOMA-B): 27.23% with liraglutide 1.2 mg and 28.70% with liraglutide 1.8 mg vs 4.18% with sitagliptin (P<.0001 for both liraglutide doses), whereas no treatment differences were observed for HOMA–insulin resistance or fasting insulin concentration.

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