Sunday , November 19 2017
Home / Conditions / Type 2 Diabetes / Risks and Benefits of GLP-1s

Risks and Benefits of GLP-1s

Systemic review, network meta-analysis found treatment resulted in greatest reductions in HbA1c, fasting blood glucose, and body weight.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is secreted by L cells in the intestine in response to the presence of food. GLP-1 exerts several effects to lower blood glucose levels, including stimulating the pancreatic islets to secrete insulin while suppressing the secretion of glucagon; and at high doses, delaying gastric emptying and inducing satiety (reduction in food intake)  While there are many non-insulin options used to help manage diabetes, glucagon-like peptide 1 receptor agonists (GLP-1RAs or GLP1s) have been a popular topic of discussion due to its once a week convenient dosing and its efficacy. This relatively new option has been the center of numerous studies. Findings from these studies can help both healthcare providers and patients better understand the risk and benefits of these drugs.

GLP-1s help restore insulin secretion while inhibiting the release of glucagon when glucose levels are elevated.  In addition, the drug delays gastric emptying and decreases food intake, which makes it a viable therapy for type 2 diabetes.

In the human body, GLP-1s are produced by the gut in response to food. The release of GLP reduces appetite and the release of insulin. Therefore, in diabetic patients, these functions are impacted. As a result, drugs that mimic the glucagon-like peptide 1 hormone help restore these functions.

There are currently several licensed GLP-1 receptor agonists on the market that have been approved for treatment of type 2 diabetes. Exenatide have been approved to be used in monotherapy. They are 53% identical to regular GLP-1 found in the body, and is recommended to be used twice a day. This class of drug has been shown to decrease A1c by 0.4 to 1.5% when used in combination with another oral antidiabetic medication. The drug has an acute effect on the beta pancreatic cells and impacts how responsive they are to glucose.

Liraglutide is another subtype of GLP-1. They are even more similar (97%) to the native GLP-1s found in the body. This type of GLP-1 allows for once a day dosing. Clinical trials (LEAD) indicate that when used in monotherapy or in combination with other oral antidiabetics, liraglutides show A1c reductions up to 1.5%. Patients with pancreatitis cannot use these drugs. Studies have also shown delayed gastric emptying in patients using these drugs.

Since a notable difference between these two subclasses of GLP-1, one must evaluate the efficacy and tolerability of long-acting versus short-acting options.

A systematic review containing a compilation of 34 trials compared several GLP-1Ras and evaluated their respective impact on HbA1c reduction. The study showed that Dulaglutide 1.5 mg, Exenatide used once weekly and Taspoglutide 20mg had the greatest reductions in HbA1c, fasting blood glucose, and body weight. Furthermore, these drugs all had similar hypoglycemia risks. However, development of Taspoglutide has since been halted due to allergic reactions at the injection sites.

Recent studies has shown that there is some beneficial effect of using liraglutide or exenatide in terms of fasting and post-prandial lipid profiles in type 2 diabetic patients. One of these studies included 533 subjects to Liraglutide or placebo, results showed significant reductions in serum LDL, free fatty acids, and triglycerides in the treatment group compared to placebo group.

In a head-to-head comparison of Liraglutide versus Exenatide, results indicate that Liraglutide had a greater reduction in mean A1c and decrease in plasma glucose compared to Exenatide. Both drugs had similar adverse effect and safety profiles. However, Liraglutide had slightly lower frequency of nausea. When compared to other oral antidiabetic options, GLP-1s had greater reduction in A1c compared to DPP-4 inhibitors such as Sitagliptin.

Emerging data from clinical studies indicate that GLP-1 agonists may have beneficial effects on the cardiovascular system as well as on risk factors for cardiovascular disease. This is not surprising, given that GLP-1 receptors have been detected in cardiomyocytes and coronary and vascular endothelial cells.   Significant reductions in both systolic and diastolic blood pressure from baseline have been observed with twice-daily and once-weekly exenatide treatment, while treatment with liraglutide has resulted in significant reduction in systolic blood pressure, but not diastolic blood pressure. The reduction in systolic blood pressure has been shown to be independent of concomitant antihypertensive medication use as well as additive to the effects of antihypertensive medication. The underlying mechanism of the antihypertensive effect of GLP-1 agonists is unknown, although weight loss may be a contributing factor. However, statistical analyses have shown no correlation between weight loss and reduction in blood pressure. Furthermore, the reduction in systolic blood pressure occurs before significant weight loss. Recent evidence, however, suggests that the GLP-1 agonist, exenatide, may improve arterial stiffness and endothelial function, which may provide a partial explanation for the antihypertensive effect of GLP-1 agonists.

Side effects from long term use of GLP-1s have been an area of concern. Since these drugs are relatively new, there are limited studies to evaluate the claims of GLP-1 induced pancreatitis. While pancreatitis by itself is not a major concern, chronic pancreatitis is linked to an increase in the risk for pancreatic cancer. However, recently, larger studies such as the SAVOR-TIMI and EXAMINE trials have found no difference existed between incretin drug users and non-users in terms of their odds ratio (OR) for pancreatic cancer. In addition, the study showed that the risk of developing pancreatic cancer amongst users of different glucose lowering agents were similar. This suggests that the disease state itself is a risk factor for pancreatic cancer and not necessarily the drug class. Although there are limited studies to thoroughly evaluate these findings, both patients and prescribers should be cautious of long term use of GLP-1s. Use of these drugs should be used in conjunction to exercise and a healthy diet.

Practice Pearls:

  • A meta-analysis of 34 trials found that Dulaglutide 1.5 mg, Exenatide used once weekly and Taspoglutide 20mg had the greatest reductions in HbA1c, fasting blood glucose, and body weight.
  • In a head-to-head comparison of Liraglutide versus Exenatide, results indicate that Liraglutide had a greater reduction in mean A1c and decrease in plasma glucose compared to Exenatide.
  • The study’s results suggest that diabetes is a risk factor for pancreatic cancer and not necessarily the GLP-1 drug class.

European Association for the Study of Diabetes 2015 Meeting. Stockholm, Sweden. Abstract 17, presented September 15, 2015.

Butler, Peter C., Sarah Dry, and Robert Elashoff. “GLP-1–Based Therapy for Diabetes: What You Do Not Know Can Hurt You.” Diabetes Care 33.2 (2010): 453–455. PMC. Web. 12 Dec. 2015.

Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011;34 Suppl 2:S279-84.

Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ. Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis. Ann Intern Med. [Epub ahead of print 8 December 2015] doi:10.7326/M15-1432

McDougall, C., McKay, G. A., and Fisher, M. (2011) Drugs for diabetes: part 6 GLP-1 receptor agonists. British Journal of Cardiology, 18(4), pp. 167-169.