My Experience With GLP-1 Receptor Agonists in Patients With Type 2 Diabetes

My Experience With GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Posted By:

When considering the benefits of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) for our patients with type 2 diabetes (T2D), it is important to consider their mechanism of action. They stimulate glucose-dependent insulin release from the pancreatic islets, slow (normalize) gastric emptying, inhibit inappropriate post-meal glucagon release, and reduce food intake. I tell my patients that GLP-1 RAs are like a thermostat. They “kick in when needed to help get insulin out and shut off when not needed.”  They work on the Gut, Liver and Pancreas (GLP), with the bonus of helping you feel full. GLP-1 RAs address many of the metabolic defects seen with diabetes, including reduction in cardiovascular risk, slowing the decrease in glomerular filtration rate, reduction of albuminuria, and finally, weight loss. Therefore, when we use them, we realize that this will be a much broader approach to treating T2D than just glycemic control.

The weight loss benefit has been the most surprising to many of us. We are often seeing our patients with T2D who may be a bit overweight lose 10-14 pounds of weight and a have an A1C reduction of 2% to 3%. A newer glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA tirzepatide, which was approved in summer of 2022, shows even stronger results with regard to weight loss—up to 25 pounds or more of weight loss with the higher doses. This is similar to the weight loss seen with bariatric surgery. While this benefit has a profound effect on our treatment of T2D (and potentially prediabetes), it will also have an impact on the treatment of other conditions such as nonalcoholic steatohepatitis.

Another bonus is that risk of hypoglycemia is very low with these drugs—with semaglutide, severe hypoglycemia with monotherapy was 0%; as an add-on to insulin or metformin it was 3.8%.

GLP-1 RAs and Cardiovascular Risk
The American Diabetes Association (ADA) Standards of Care in Diabetes-2023, which were issued in December 2022 have indicated that persons with T2D and risk of cardiovascular disease should be on a GLP-1 RA with an indication for reduction of cardiovascular risk as first-line care. The US Food and Drug Administration has granted this indication to semaglutide SC, dulaglutide, and liraglutide, based on very large, powerful trials looking at major adverse cardiovascular event endpoints. Tirzepatide and semaglutide oral are also being studied for cardiovascular benefit and we are awaiting those results.

The GLP-1 RAs are not the only class of medications that were originally approved for T2D to get secondary indications for treatment of other conditions. For instance, canagliflozin, empagliflozin, and dapagliflozin, which are sodium-glucose cotransporter 2 (SGLT2) inhibitors, have secondary indications to reduce cardiovascular risk in patients with T2D. Empagliflozin and dapagliflozin have additional approval from the FDA for treating heart failure, and canagliflozin and dapagliflozin are approved to reduce renal complications. Many in the field are now viewing SGLT2 inhibitors as cardiovascular and renal drugs in their own right. In the same way, manufacturers of several of the GLP-1 RAs are supporting trials in patients without T2D to acquire data to support independent recommendations or approvals for cardiovascular or renal benefits.

In addition to the 3 GLP-1 RAs with proven cardiovascular benefit, data indicate no increased cardiovascular risk occurs with the other agents. Given that all patients with T2D have some degree of cardiovascular risk, the update to the ADA guidelines recommending a GLP-1 RA for patients with T2D at risk of cardiovascular disease provides strong support for approval of prior authorizations. The powerful data and the updates to the ADA guidelines are helping clinicians acquire these medications for the patients who can most benefit from them.

Recommendations for Primary Care Providers
My final thought about the use of these agents is that clinicians who treat people with T2D—especially primary care providers—can and should initiate these classes of drugs. They can be used together. SGLT2 inhibitors may be viewed as easier because they are oral medications; GLP-1 RAs, while mostly weekly injections, are straightforward and simple for patients to administer. These drugs have no associated renal or hepatic adverse events and can be used in patients with diminished renal function. They should lead the armamentarium for primary care of patients with T2D.



Filed under: Cardiometabolic , NPs & PAs

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