2018 American Diabetes Association’s Practice Standards Recommend GLP-1 Injectables.

In the thirteen years since GLP (glucagon-like peptide) receptor agonists first appeared, they have gained wide acceptance among clinicians whose T2D patients have had difficulty meeting their A1c targets on metformin monotherapy (Lifestyle Management + Metformin, as the American Diabetes Association Professional Practice Committee defines it). All the drugs in the GLP-1 class are incretin mimetics, meaning they work by responding to glucose in the digestive tract to stimulate sensitivity to, and secretion of, insulin when needed, and secretion of glucagon when glucose levels drop, and to suppress release of glucose and lipids from the liver into the bloodstream. In television spots the maker of one of the products in this class of drugs, Eli Lily, describes its GLP-1 product Trulicity as one that “activates what’s within” the body to control blood glucose, and that’s a pretty handy way to understand it all — that a GLP-1 agonist helps an underperforming pancreas by optimizing beta cell function. GLP-1’s are not indicated as a first-line therapy for T2D, the way that metformin is, as an adjunct to diet and exercise.

With the publication of the ADA’s 2018 Standards of Medical Care in Diabetes came a major addition to the Antihyperglycemic Therapy decision protocol: a GLP-1 as additional agent to reduce risk of death or major adverse cardiovascular complications for patients with established ASCVD, or arteriosclerotic cardiovascular disease. An accompanying recommendation (See Standards §8 p. S75) states that for such patients “therapy should begin with lifestyle management and metformin and subsequently incorporate an agent proven to reduce major cardiovascular events and cardiovascular mortality (currently empagliflozin [an SGLT-2 Inhibitor] and liraglutide [a GLP-1]), after considering drug-specific and patient factors.” The standard also calls for continuation of a metformin regimen, and monitoring of A1c to determine appropriateness of initiating insulin therapy.

For patients exhibiting heart and circulatory risks, adding a GLP-1 is preferable to an SGLT-2, according to the updated practice standard, due to the relatively higher efficacy of a GLP-1 as a cardioprotective drug. Sulfonylureas (new generation formulations such as glipizide, the usual add-on to metformin for mealtime glucose control) are not thought to have a cardioprotective benefit and have been known to lead to weight gain and hypoglycemia. Older generation sulfonylureas, such as glyburide, are known to contribute to dangerous lows and have fallen out of favor, especially for people taking other antidiabetic medications.

The benefits of adding a GLP-1 extend beyond glucose control to protecting cardiovascular health and helping some people lose weight. All manufacturers state in their FDA labels and prescribing information that their products are to be used as an adjunct to diet and exercise for glucose control. None of the manufacturers advertise their products as weight control agents. The sole exception is Novo’s Saxenda, a liraglutide-based formulation administered in a 3.0 mg dose (versus Victoza, at 1.8 mg). Our colleagues at diaTribe reported shortly after Saxenda’s FDA clearance was granted that although FDA did not approve Saxenda as a T2D medication, it did clear it as a chronic weight control agent, and that many people who had participated in Victoza’s trials had also trialled Saxenda. Results of multiple clinical studies to assess the CV benefit of GLP-1’s as an add-on to metformin allowed the FDA to elevate Victoza (Novo Nordisk liraglutide) last year from the safe-for-CV-patients level to the effective-as-CV risk lowering level for its indicated use. More recently, FDA cleared Novo Nordisk’s once weekly GLP-1 formulation (Ozempic semaglutide), expected to be available by March of 2018.

Your doctor is the best resource for navigating the drug-specific and patient-specific factors to consider in arriving at a GLP-1 choice. These include your baseline A1c, whether your metformin strength needs to be adjusted before adding a GLP-1, and whether you fit the profile of a T2D patient who needs to shed some weight and take particular care of your heart and vascular health. We’ll post the prescribing information for all brands mentioned in this article on our Facebook page alongside the article.

The weight control benefit is achieved by a slowing of gastric emptying, leaving one feeling satiated, or full, after a meal. All drugs in the class come with thyroid tumor warnings, some are still being investigated in clinical trials for their CV benefit, and some cause irritation to the digestive system. They have differing strengths and dosing requirements. All are available in pre-filled pens. Many patients prefer the longer acting formulations for convenience and for simplifying their daily care routines, but the longer acting products have been known to cause injection site discomfort.

When you consult your doctor, you can prepare for your visit with this chart to educate yourself and be fully engaged in the treatment discussion:

Available in the U.S., by subclass, brand, manufacturer and FDA clearance date, and dose frequency:

Exenatide:
Bydureon- Astra Zeneca (2012)-Weekly
Byetta- Astra Zeneca (2005)-Daily

Liraglutide:
Victoza, Saxenda- Novo Nordisk (2010)-Daily

Semaglutide:
Ozempic- Novo Nordisk (2017)- Weekly

Dulaglutide:
Trulicity- Eli Lilly (2014)- Weekly

Lixisenatide:
Adlyxin, Lyxumia- Zealand / Sanofi (2016)- Daily

Discontinued 2017:

Albiglutide:
Eperzan, Tanzeum– GlaxoSmithKlein (UK)- Weekly

Our sister publication Insulin Nation published a broader review of the 2018 Standards of Medical Care revisions on December 27. The full text ADA publication is 150 pages long, in three column print. You can download an abridged for primary care physicians version of the Standards and print it for your self-care library shelf.

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