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Glucose-lowering effects of incretin-based therapies

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GLP-1 agonists and DPP-4 inhibitors as monotherapy

Use of GLP-1 agonists and DPP-4 inhibitors as monotherapy in combination with lifestyle intervention has been investigated in several clinical trials.2,3,21-25 Generally, as monotherapy, DPP-4 inhibitors have been shown to reduce A1C by 0.5% to 0.9% and GLP-1 agonists by 0.5% to 1.5%.1-3 Increasing the dose provides additional modest glucose reduction. For our patient in Case 1, therefore, either of the DPP-4 inhibitors, sitagliptin or saxagliptin, would be expected to reduce his A1C from his current level of 7.5% to the target level of <7.0%. The GLP-1 agonists, exenatide or liraglutide, would also be expected to reduce his A1C to the target level.

Results of clinical trials have shown that monotherapy with a DPP-4 inhibitor or GLP-1 agonist reduces FPG levels by 11 to 22 mg/dL and 11 to 61 mg/dL, respectively. Reductions in PPG levels range from 24 to 35 mg/dL for the DPP-4 inhibitors and 21 to 48 mg/dL for the GLP-1 agonists. The substantial reduction in PPG is especially important as the A1C level drops to <8.0%6 and approaches the target level of <7.0%, as is the case with this patient.

The greater reductions in FPG and PPG observed with GLP-1 agonists compared with DPP-4 inhibitors likely stem from the pharmacologic level of GLP-1 activity achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor,26-28 which is in contrast to the indirect action of the DPP-4 inhibitors and the resulting lower physiologic levels of endogenous GLP-1.29

The glucose-lowering ability of DPP-4 inhibitors and GLP-1 agonists appears to be affected by the baseline A1C level and history of previous treatment. A monotherapy trial with sitagliptin showed that patients with a baseline A1C level ≥9.0% experienced a reduction in A1C of 1.5% compared with 0.6% for those with a baseline A1C level <8.0%.30 For the patient in Case 1, the reduction of 0.6% would be sufficient to lower his A1C to <7.0%.

Similarly, limited data suggest that patients previously treated with glucose-lowering therapy achieve a smaller reduction in A1C compared with those managed with diet and exercise alone. In a study by Garber et al,2 patients previously managed with diet and exercise alone achieved a reduction in A1C of 1.2% and 1.6% with liraglutide 1.2 mg and 1.8 mg once daily, respectively, vs 0.5% and 0.7% for those previously treated with glucose-lowering monotherapy.

In summary, data from clinical trials support the efficacy of DPP-4 inhibitors and GLP-1 agonists as monotherapy in combination with lifestyle intervention. In the case of this 53-year-old man with an A1C level of 7.5%, either of the 2 DPP-4 inhibitors or the 2 GLP-1 agonists would provide sufficient glucose-lowering to achieve the target A1C level of <7.0%. Furthermore, although a greater reduction has been observed with GLP-1 agonists (0.5% to 1.5%), the DPP-4 inhibitors also should provide for significant reduction (0.5% to 0.9%) of this patient’s PPG level.

We now turn our attention to the glycemic effects of the GLP-1 agonists and DPP-4 inhibitors in combination with 1 or more pharmacologic agents.

Case 2

This 47-year-old man was diagnosed with T2DM 2.5 years ago. The addition of pioglitazone to the combination of lifestyle intervention and metformin has resulted in significant edema and weight gain. He refuses to take a diuretic because of previous experience and wants to discontinue his pioglitazone. He currently has an A1C of 7.0%. What should replace pioglitazone for this patient, who is no longer achieving glycemic control with lifestyle intervention and metformin?

For a patient with an A1C level of 7.6% to 9.0%, the AACE/ACE 2009 guidelines suggest adding a GLP-1 agonist, DPP-4 inhibitor, or thiazolidinedione (FIGURE 2).4,5 Among these 3 options, GLP-1 agonists and DPP-4 inhibitors are preferred due to both their efficacy data when combined with metformin and their overall safety profiles. The GLP-1 agonists are preferred over the DPP-4 inhibitors due to better reduction of PPG levels and potential for substantial weight loss. Thiazolidinediones would be the third choice because of their risks of weight gain, edema, congestive heart failure, and fractures.4

GLP-1 agonists and DPP-4 inhibitors in combination with metformin

Many clinical trials have been conducted with GLP-1 agonists and DPP-4 inhibitors in combination with lifestyle intervention and metformin (TABLE 2).31-36 These trials generally show similar trends in A1C reduction as with monotherapy, although a somewhat greater reduction has been seen with GLP-1 agonists compared with DPP-4 inhibitors. Increasing the dose may provide additional modest glucose reduction. As is typical with monotherapy, patients with a higher baseline A1C level (ie, ≥9.0%) achieve greater A1C reduction. The same holds true for reductions in FPG and PPG levels. For the patient in Case 2, who had an A1C level of 7.8% prior to addition of pioglitazone, discontinuation of pioglitazone and addition of either exenatide or liraglutide to lifestyle intervention and metformin would be expected to lower his A1C level to the target of <7.0%. Although possible, it is unlikely that addition of sitagliptin or saxagliptin would achieve the target A1C level.

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