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GLP-1 Agonist/Basal Insulin Combinations: New Headway for Diabetes Treatment

Jul 16, 2016

With Sanofi’s LixiLan®  filed for FDA approval, GLP-1 agonist/basal insulin combinations may be potential game changers.

Sanofi’s LixiLan combines their insulin glargine Lantus with their GLP-1 Lyxumia (lixisenatide). Combining insulin with a GLP-1 agonist results in lower risk of hypoglycemia and, potentially, better weight control. The FDA decision is expected in August; if approved, LixiLan will enter the U.S. market ahead of competitor combo drug, Novo Nordisk’s Xultophy. Xultophy, which combines the GLP-1 Victoza with long-acting insulin Tresiba, is approved in Europe, but not yet in the U.S.

Lixisenatide combined with glargine works on both the postprandial plasma glucose and fasting plasma glucose respectively, which reduces the HbA1c of type 2 diabetes patients. In previous studies, it was found that patients with elevated HbA1c after initiation of insulin glargine had a tremendous reduction in HbA1c goals. Patients also showed an overall improvement in their postprandial hyperglycemia.

The objective of this study was to evaluate the efficacy and safety of lixisenatide in patients with HbA1c still elevated after initiation of insulin glargine. Eligible participants were adult patients with type 2 diabetes. Using a double blind, parallel group randomized a population of (n=446) with HbA1c 7-10% despite oral therapy. Insulin glargine was periodically titrated during a 12-week run in. Candidates with fasting glucose ≤ 140mg/dl.(7.8 mmol/L) and HbA1c 7-9% were then randomized to lixisenatide 20µg or placebo for 24 weeks while insulin titration continued. Injections were self-administered by participants. The primary outcome of measure that used ANCOVA model had a definite change of HbA1c from baseline to week 24. Secondary efficacy of measure, however, included a change from baseline to week 24 in 2-h PPG and blood glucose excursions during a standardized breakfast meal test; seven – point plasma – calibrated SMPG; FPG; body weight; and average daily insulin glargine dosage. Measurements of body weight, insulin dosage, FPG, and HbA1c were recorded at baseline, at endpoint, and at intervals throughout the trial. Extra categorical secondary efficacy variables included the percentage of participants achieving HbA1c target of < 7% or ≤6.5% at week 24.

With a power of 90%, a difference of 0.4% change of HbA1c was detected from baseline to week 24 between lixisenatide and placebo with the assumption that the common SD was 1.3% and a two-sided test at a 5% significance level. Safety variables were assessed in the safety population.

During the 12-week run-in phase the response to HbA1c decreased from baseline was drastically higher with lixisenatide compared with placebo having adjusted mean square (LS) changes of -0.7 and -0.4% respectively and LS mean difference for lixisenatide versus placebo was -0.3% (P<0.0001). The fasting plasma glucose did not change much, but the standardized meal study the LS mean difference of a 2-hr postprandial value from baseline between lixisenatide and placebo treatment was 57mg/dl.(-3.2 mmol/L) (95% CI, -4.0 to -2.4: P< 0.0001). SMPG had a significant decrease with lixisenatide compared to the placebo (LS mean difference -0.4 mmol/L; P=0.0071). Body weight increased by 0.3kg in the lixisenatide group as compared to 1.2kg in the placebo group. Insulin dose, however, increased in both groups with placebo being slightly higher than lixisenatide. Symptomatic hypoglycemia occurred in 20% of participants as compared to 11.7% in the placebo group. Serious adverse reactions like injection site reaction, MI myeloma pancreatitis, increase in calcitonin occurred in both groups with no report of increase in blood pressure or heart rate.

In summary, for people who still have an HbA1c of 7.0% or higher even after the initiation of insulin glargine, the addition of lixisenatide to treatment regimen decreased their HbA1c and PPG drastically. However, future studies like examining the tolerability and effectiveness of lixisenatide relative to other therapies especially DPP-4 inhibitors, GLP-IRA agents inhibitors when added to basal insulin would be fascinating. This study, however, had a number of weaknesses, the first being that Sanofi the manufacturer of lixisenatide funded it so there might be some bias. Other weaknesses included the study not addressing pertinent clinical questions like what additional measures might improve 40% of the participants randomized to lixisenatide that did not attain the 7.0% HbA1c goal. Also the 12-week initiation and optimization of insulin glargine was too short. Finally, lixisenatide was assessed versus placebo rather than an active comparator.

LixiLan has also looked promising in phase 2 trials: in one recent study, the drug led to an average A1c reduction of 1.8% (slightly greater than the 1.6% seen with Lantus alone) along with reductions in post-meal blood sugars, no increase in hypoglycemia, and low rates of gastrointestinal side effects.

Practice Pearls:     

  • The effect of lixisenatide treatment was most apparent after the morning meal.
  • Adding lixisenatide prevented weight gain with limited increase in hypoglycemia and reduced A1c 1.8%.
  • This treatment regimen should be a good alternative to patients not reaching their HbA1c goals with a recent initiation of basal insulin.


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Raccah D, Bretzel RG, Owens D, Riddle M.”When Insulin Therapy in Type 2 Diabetes Mellitus is not enough- What next.” Diabetes Metab Rev. 2007; 23(4): 257-64. Web 4 June 2016.

Riddle, Mattew C.et al. “Adding Once – Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled With Newly Initiated and Continuously Titrated Basal Insulin Glargine: A 24- week, Randomized, Placebo-Controlled Study (GetGoal Duo 1).” Diabetes Care 36.9 (2013): 2497- 2503. PMC. Web. 4 June 2016.

Tzefos M, Olin JL.”Glucagon –Like Peptide -1 agonist in therapeutic management of adults with type 2 Diabetes Mellitus.” Annals Pharmacotherapy 2010; 44(7-8) June 4 2016.