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Reference - JAMA Intern Med 2016 Jun 6 early online (level 3 [lacking direct] evidence)
- Management of patients with type 2 diabetes who have inadequate glycemic control despite treatment regimens including high-dose insulin therapy is a difficult clinical challenge.
- The addition of liraglutide, a glucagon-like peptide 1 receptor agonist, to high dose insulin regimens reduced HbA1c levels by a mean of 0.9% in 74 patients with inadequately controlled type 2 diabetes.
- Patients given liraglitude should have close monitoring of insulin levels and adjustment during medication initiation due to an increased risk of hypoglycemia.
In many patients with type 2 diabetes treated with insulin, insulin resistance and weight gain associated with insulin use can make it harder to maintain adequate glycemic control over time, leading to even higher insulin doses. Some patients remain poorly controlled even on high insulin doses and the best approach to management of these patients is uncertain. To determine if liraglutide, a GLP-1 receptor agonist, could improve glycemic control in patients on high-dose insulin, 74 patients (mean age 54, 63% female) with inadequately controlled type 2 diabetes were randomized to liraglutide 1.8 mg/day vs. placebo subcutaneously for 6 months. Patients had a mean HbA1c of 8.9% and required insulin > 1.5 units/kg/day (mean total daily dose 247 units). The median duration of diabetes was 17 years and median duration of insulin use was 8 years. All patients were on a maximum tolerated dose of metformin at baseline, but 20% with liraglutide vs. 39% with placebo had complete metformin intolerance (no p value reported).
Ninety-three percent of patients completed all trial visits and were included in the 6-month analysis. Comparing liraglutide vs. placebo, the mean decrease in HbA1c was 0.9% vs. 0% (p = 0.002) and HbA1c levels < 7% was achieved in 22% vs. 3% (p = 0.02, NNT 6). Liraglutide was also associated with a small improvement in weight (-2 kg vs. +0.4 kg, p = 0.02) and a greater decrease in total daily insulin doses (37 units vs. 10 units, p = 0.06). The baseline insulin dose remained unchanged throughout the trial except when titration was required for safety reasons such as hypoglycemia. With this protocol the researchers were unable to determine the effect liraglutide may have on reducing insulin doses and the true risk of hypoglycemia that would be expected when dosing is more freely adjusted. There were no significant differences between groups in the number of adverse events. The results of this trial suggest that addition of liraglutide may improve glycemic control in this hard-to-treat population. It is worth keeping in mind however, that this trial was relatively small and lacked clinical outcomes.
Trials of drugs to treat diabetes are especially challenging from an evidence-based medicine perspective. The most commonly reported outcome is a change in HbA1c, which is a good marker of glucose control and of the risks for microvascular complications such as retinopathy and neuropathy. However, it is not as well correlated with risks for macrovascular complications, such as coronary artery disease, and trials using very low HbA1c targets (< 6%) have found increased risks for hypoglycemia and death (N Engl J Med 2008 Jun 12;358(24):2545, N Engl J Med 2008 Jun 12;358(24):2560). Another recently completed trial further adds to the evidence suggesting liraglutide is safe and effective for patients with type 2 diabetes (N Engl J Med 2016 Jun 13). The LEADER trial found that liraglutide did not increase long-term adverse cardiovascular events and might in fact even decrease the risk for cardiovascular morbidity. It is important to note that the population in the LEADER trial was primarily more typical patients with type 2 diabetes, with less than half of them using any form of insulin. However, its results indirectly suggest that patients achieving improved glycemic control with the addition of liraglutide to regimens including high-dose insulin may not be at increased cardiovascular risk and might even attain some cardiovascular benefits. Overall, the results described here provide the best available evidence for additional management of patients with difficult-to-control diabetes on high doses of insulin.
For more information, see the Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists topic in DynaMed Plus. DynaMed users click here.