Type 2 Diabetes Therapy Intensification: Part I: Insulin vs GLP-1 Agonists

Short-Acting GLP-1RAs

Short-acting GLP-1RAs appear to achieve glucose control primarily through reductions in postprandial gluclose.⁴ Controlling postprandial glucose contributes to overall HbA1 levels.⁵ Lixisenatide is a short-acting GLP-1RA evaluated as intensification of basal insulin in the Get-Goal series of randomized, controlled, phase 3 clinical trials.⁹ Comparators varied between the lixisenatide trials and included placebo, RAI, or another GLP-1RA.^4,9

Data showed once-daily lixisenatide was noninferior to RAI given once daily or three times daily at reducing HbA1c levels. Lixisenatide was superior to RAI add-on therapy at achieving weight reduction.⁹ In a meta-analysis of 5 trials comparing lixisenatide vs RAI, 29% of patients taking lixisenatide achieved the composite end point of an HbA1c <7%, no weight gain, and no incidents of hypoglycemia compared with 15% of patients taking an RAI (P =.0046).⁴

Exenatide was the first FDA-approved GLP-1RA.⁶ Several trials looked at twice-daily exenatide as an add-on to basal insulin in patients with an HbA1c >8%. Similar to lixisenatide in the Get-Goal trials, exenatide was noninferior to a basal-plus regimen and contributed to greater weight loss.⁴ Exenatide was also associated with greater reductions in fasting plasma glucose than the RAI.⁴ Studies have not compared exenatide with lixisenatide in patients using basal insulin, but a head-to-head comparison of both GLP-1RAs in patients taking oral metformin reported similar efficacy outcomes.⁹

Long-Acting GLP-1RAs

Long-acting GLP-1RAs predominantly affect fasting plasma glucose levels.⁴ However, at least 1 study of long-acting liraglutide showed it also reduced postprandial glucose levels from baseline.⁴ A systematic analysis of studies that added liraglutide to basal insulin for patients with an HbA1c >7.5% concluded that once-daily liraglutide reduced the HbA1c more than insulin up-titration or a basal-plus regimen.⁴ The mean decrease in HbA1c across the trials ranged from –0.6% to −1.9%.⁴ Liraglutide was also associated with significantly more weight loss than a basal-plus regimen. Other studies have shown liraglutide to be noninferior to RAI at reducing HbA1c.⁴

Albiglutide is another long-acting GLP-1RA. It was compared with a basal-bolus regimen in people who had suboptimal HbA1c levels despite basal insulin use.¹⁰ Albiglutide was administered once weekly, whereas the RAI was injected 3 times daily.¹⁰ After 26 weeks, albiglutide was noninferior to the RAI at reducing the HbA1c.¹⁰ Albiglutide contributed to weight loss, whereas the RAI caused weight gain. No cases of severe hypoglycemia occurred with albiglutide vs 2 cases in RAI users.

In early 2017, the FDA expanded indications for the GLP-1RA dulaglutide to include coadministration with basal insulin based partly on results from the phase 3 AWARD-9 trial (ClinicalTrials.gov identifier: NCT02152371). AWARD-9 compared weekly dulaglutide vs placebo as intensification for basal insulin.¹¹ At 28 weeks, the dulaglutide group had significantly greater mean reductions in HbA1c and significantly more weight loss, and required significantly smaller increases in basal insulin dose.¹¹ A phase 3 trial that compared dulaglutide with RAI in patients taking basal insulin observed similar decreases in glucose levels with both therapies.¹² Patients taking dulaglutide experienced more stable glucose levels during the 1-year trial.

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References

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