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Head to Head Study: Insulin vs. GLP-1 Receptor Agonists

Study focuses on differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs. insulin treatment in patients with type 2 treated with oral glucose-lowering medications (OGLM).

Effects of GLP-1 RA on blood glucose are believed to be mediated primarily through GLP-1 receptors on pancreatic islet cells, the stomach, liver and brain. GLP-1 receptors have also been found in the heart, kidneys and blood vessels, suggesting activation of these receptors may have direct effects on cardiovascular and other functions. Indeed many studies have observed that GLP-1 RA treatment is associated with favorable changes in risk factors or markers for cardiovascular disease such as blood pressure, triglycerides, low density lipoprotein cholesterol (LDL-C), C-reactive protein and adiponectin, as reviewed.

Treatment algorithms for type 2 diabetes call for intensification of therapy over time as the disease progresses and glycemic control worsens. If diet, exercise and oral antihyperglycemic medications (OAMs) fail to maintain glycemic control, then basal insulin is added and ultimately prandial insulin may be required. However, such an intensification strategy carries risk of increased hypoglycemia and weight gain, both of which are associated with worse long-term outcomes. An alternative strategy is to intensify therapy by the addition of a short-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) rather than prandial insulin. Short-acting GLP-1 RAs such as exenatide twice daily are particularly effective at reducing postprandial glucose while basal insulin has a greater effect on fasting glucose, providing a physiological rationale for this complementary approach. This review analyzes the latest randomized controlled clinical trials of insulin/GLP-1 RA combination therapy and examines results from ‘real-world’ use of the combinations as reported through observational and clinical practice studies. The most common finding across all types of studies was that combination therapy improved glycemic control without weight gain or an increased risk of hypoglycemia. Many studies reported weight loss and a reduction in insulin use when a GLP-1 RA was added to existing insulin therapy. Overall, the relative degree of benefit to glycemic control and weight was influenced by the insulin titration employed in conjunction with the GLP-1 RA. The greatest glycemic benefits were observed in studies with structured titration of insulin to glycemic targets while the greatest weight benefits were observed in studies with a protocol-specified focus on insulin sparing. The adverse event profile of GLP-1 RAs in the reviewed trials was similar to that reported with GLP-1 RAs as monotherapy or in combination with OAMs with gastrointestinal events being the most commonly reported.

So for this study they did a search in PubMed for randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified.  Differences from baseline values were compared for HbA1c, fasting plasma glucose, body weight, blood pressure, heart rate and lipoproteins. Proportions of patients reporting hypoglycemic episodes were compared.

The results showed that of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively.

Basal insulin was more effective in reducing fasting plasma glucose. GLP-1 RAs reduced body weight more effectively. The proportion of patients experiencing hypoglycemic episodes was 34% lower with GLP-1 RAs, with a similar trend for severe hypoglycemia. Systolic blood pressure was lower and the heart rate higher with GLP-1 RAs. Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting ones in reducing HbA1c and fasting glucose, but similar regarding body weight.

From the results it was concluded that slightly better glycemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding body weight, hypoglycemia, blood pressure and lipoproteins. These differences are in contrast to insulin being prescribed far more often than GLP-1 RAs.

Practice Pearls:

  • Results showed that adding GLP-1 RAs to other orals achieved better glycemic control.
  • Results also showed an improvement in triglycerides and LDL.
  • There was also less weight gain compared to insulin and even showed some weight loss.
  • But if only looking at fasting blood sugars, then using basal insulin was more effective in glucose control.

Diabetes, Obesity and Metabolism, October 2016; Volume 18, Issue 10