Weight control among benefits of diabetes Rx

Evidence Mounts for Benefits Of SGLT2 Inhibitors and GLP-1 RAs

By Gina Shaw

Recent evidence shows that not only do sodiumglucose cotransporter-2(SGLT2) inhibitors and long-acting glucagon-like peptide-1 receptor agonists (GLP-1 RAs) help control blood sugar in people with type 2 diabetes, but some of them also have additional health benefits, including weight loss and improved kidney and cardiac outcomes.

“The novel thing about these two classes is that the FDA, in 2008, mandated that all new type 2 diabetes drugs coming to market must prove cardiovascular safety before their approval,” said Heather Whitley, PharmD, a clinical professor at Auburn University’s Harrison College of Pharmacy, in Alabama, and a certified diabetes educator (CDE). “In these large-scale cardiovascular outcome trials, we found that all of the SGLT2s and many of the GLP-1 RAs not only are safe, but also have unique cardiovascular benefits.”

What are the current options within these classes of drugs, and how can pharmacists help ensure optimal medication management using these agents?

SGLT2 Inhibitors

For patients who have type 2 diabetes with cardiovascular disease and/or kidney disease, SGLT2 inhibitors have revolutionized treatment. Currently available agents include canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca/Bristol Myers Squibb), empagliflozin (Jardiance, Boehringer Ingelheim) and ertugliflozin (Steglatro, Merck).

“These agents originally came to the market to lower blood sugar; they allow the sugar to be eliminated through the urine,” Dr. Whitley said. “While they do achieve that goal, they have an even more profound impact on the heart and kidneys.” These benefits include: • a 33% reduction in risk for cardiovascular death or hospitalization for people with heart failure, according to a January 2022 meta-analysis of 10 highquality randomized clinical trials (JAMA Netw Open 2022;5[1]:e2142078); • a smaller, but still statistically significant, reduction in major adverse cardiovascular events (MACE) (SGLT2 group, 9.82%; placebo group, 10.22%; P=0.03); and • a slowed progression of kidney disease in people with type 2 diabetes and those with chronic kidney disease (CKD) who do not have diabetes. Trials have found that these agents reduce the risk for worsening kidney function, end-stage renal disease and renal death by 30% to 46%, depending on the patient subgroup, with more significant benefits in patients with kidney disease and atherosclerotic cardiovascular disease (Front Med 2021;8:728089).

“What is even more remarkable about these agents is that they work fast. The benefit in terms of heart failure begins within the first week,” Dr. Whitley noted. “They also lower the risk for major adverse cardiovascular events, as noted, but this is a benefit that takes a bit longer—about three months or so. The kidney function benefits, which are unique to this class, take about 18 months to achieve. Nonetheless, in the world of pharmacy, it’s an extremely important benefit. Below a certain level of kidney function, we can’t use certain classes of medications, such as antibiotics, to treat infections.”

The risks associated with these agents often are related to their mechanism of action—that is, allowing blood sugar to be eliminated via the urine. “That means that fluid also follows the sugar out through the urine, so you have a risk of dehydration and orthostatic hypotension, along with an increased risk of general yeast infections,” Dr. Whitley said.

GLP-1 RAs

The FDA approved the first long-acting GLP-1 RA, liraglutide (Victoza, Novo Nordisk) in 2010. It was followed by exenatide (Bydureon, AstraZeneca), dulaglutide (Trulicity, Lilly), semaglutide injection (Ozempic, Novo Nordisk) and oral semaglutide (Rybelsus, Novo Nordisk). Three of the agents—dulaglutide, liraglutide and injectable semaglutide—have demonstrated effectiveness in reducing MACE (Ther Adv Endocrinol Metab 2021;12:2042018821997320).

Each of these five agents is slightly different in terms of its magnitude of benefit and side-effect profile, but the most common side effect with the injectable agents is gastrointestinal disturbances, including nausea, vomiting and diarrhea. Studies suggest that patient satisfaction is highest for dulaglutide, a singleuse, disposable pen device. (Ther Adv Endocrinol Metab 2021;12:2042018821997320).

Both SGLT2 inhibitors and GLP-1 RAs also have been found to result in weight loss, which can improve insulin sensitivity and glucose control as well as reduce cardiovascular risk factors and comorbidities. Clinical trial data indicate that both classes of drugs cause a mean weight loss of 2 to 3 kg, or about 4.5 to 6.5 pounds (Obes Rev 2019;20[6]:816-828). “Both have weight loss benefits, but our experience is that weight loss is more profound in the GLP-1 RA class,” Dr. Whitley said.

Patient Perspective on Treatment Choice

Patient preference—whether based on the aforementioned preference for pen injectors or other factors— “definitely plays a significant role in agent selection,” said Katherine Harte, PharmD, a PGY-2 ambulatory care pharmacy resident at the Rhode Island Hospital, in Providence. “For example, some patients really prefer an oral option, while others prefer an injectable with a longer dosing interval like dulaglutide. Financial considerations are also an important factor. Unfortunately, right now, every single long-acting GLP-1 RA and SLGT2 inhibitor is brand-name only and they are expensive medications. There’s no black-and-white answer as to which is most affordable, because it will differ depending on the patient’s insurance coverage and formulary, and if they qualify for other programs such as manufacturer assistance.”

Dr. Whitley advised using a “STEPS” mnemonic while counseling patients on selecting between these classes and among agents in these classes: Safety, Tolerability, Efficacy, Price and Simplicity.

GLP-1 RAs and SGLT2s cause a mean weight loss of about 4.5 to 6.5 pounds

Source: Obes Rev 2019;20(6):816-828. Dr. Harte reported no relevant financial disclosures. Dr. Whitley reported financial relationships with Abbott Laboratories and Abbott Rapid Diagnostics.

DIABETES

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Lessening the Load on PCPs

It makes sense that pharmacist involvement leads to more usage of these recommended medications, commented Patrick Gregory, PharmD, BCACP, CPP, the coordinator for primary care population health pharmacy services at the Duke Population Health Management Office, Duke Health, in Durham, N.C., and an assistant professor of clinical education at the UNC Eshelman School of Pharmacy, in Chapel Hill.

“It adds a lot more work to primary care providers’ plates to get these new medications on board for patients, because typically they need a prior authorization, and even if you get the prior authorization through, costs can still be a big factor with these particular medications,” Dr. Gregory said. Pharmacists have the knowledge and the time to be more involved with patients, not only prescribing the medications, but ensuring they don’t have any barriers to access, he noted.

In August 2017, Dr. Gregory began working in a Duke Health primary care clinic one half-day per week to help manage patients with diabetes. There was a statistically significant increase in SGLT2 inhibitor and GLP-1 RA prescribing in his clinic versus two others that did not include a pharmacist (J Am Pharm Assoc 2022;62[1]:209-213. e1). The percentage of patients prescribed either medication rose to 15% in his clinic versus 11.6% in the other clinics.

Although Dr. Gregory still works in the clinic a half-day weekly, data he helped collect supported a business plan to hire two full-time pharmacists working across four primary care clinics, he said. Now, with their combined work, the office is recruiting for three additional positions to have five fulltime pharmacists covering 10 clinics and two part-time pharmacists covering two more clinics.

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