2nd Annual Heart iN Diabetes Medical Conference:

Which Glucose-Lowering Drug Class—SGLT2i or GLP1RA—is Better for People with T2D and CVD?

With Zachary T. Bloomgarden, MD, and  Richard E. Pratley, MD

In individuals with type 2 diabetes (T2D), the risks of cardiovascular disease (CVD) are increased severalfold, including hypertension, obesity, and hyperlipidemia. Yet, multiple presentations during the 2nd annual Heart in Diabetes medical conference drew attention to the numerous complications that affected by these concomitant conditions, management approaches so that you are providing the best care with the fewest drawbacks for patients with type 2 diabetes and CVD.

In managing patients with poorly controlled diabetes, the question arises: What medication should you prescribe when metformin is clearly not sufficient to improve glucose control and a variety of other symptoms—sodium glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1RA)?

Following the debate between Zachary T. Bloomgarden, MD, and  Richard E. Pratley, MD, EndocrineWeb sat down with each of these experts to explore their arguments for choosing SGLT2is or GLP1-RAs after metformin for patients with type 2 diabetes.

Which would you choose? See if you feel the same after reading and/or listening to arguments from both sides.

In Favor of SGLT2 Inhibitors As Preferred Treatment in T2D

Zachary T. Bloomgarden, MD, clinical professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City, argued in favor of SGLT2i as the preferred class to manage patients with diabetes who are also at risk for cardiovascular disease.1

“The story of SGT2s go back more than a decade with basic animal studies showing that despite the side effect of liver toxicity, this class of drugs lead to improvements in both beta cell function and peripheral insulin action,”said Dr. Bloomgarden.

Ongoing research has shown that by normalizing blood glucose through a renal effect, the SGLTti class increases glucose loss in the urine, the result has been a reversal in the pathophysiologic abnormalities the commonly arise in patients type 2 diabetes.3

In making his case,1 Dr. Bloomgarden told EndcorineWeb that there are three compelling reasons to make the SGLT2i the preferred class for secondary prevention in people with type 2 diabetes.

Growing Need for Cardiovascular Benefits of SGLT2i

The most significant benefits—dramatic improvements in cardiovascular disease (CVD) composite outcomes, specifically hospitalizations due to heart failure, CVD events, and total mortality—came out of the Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG) trial in 2015,and the Canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS) trial in 2017,5  he said.

Findings from these two large randomized clinical trials demonstrated significant improvement in major atherosclerotic cardiovascular events (MACE), including a reduction in heart failure risk and CVD mortality (P value for SGLT-2i vs other glucose-lowering medications: 0.001).4,5

“Add to that the real world data showing a 51% decline in CVD mortality vs other glucose-lowering agents and decreases heart failure hospitalizations and mortality,6  said Dr. Bloomgarden.

Renal Risk Reduction and Patient Adherence

Reduction in Renal Impairment with SGLT2i

“Second, most individuals with type 2 diabetes have or will develop renal disease,” said Dr. Bloomgarden, "so the SGLT2is Improved renal outcomes (eg, preservation of renal function and reduction in acute kidney injury)."

From the EMPA-REG, renal outcomes (HR 0.61, = 0.001) and eGFR showed benefit for both below 60 and at or above 60 as well as less incident or worsening of nephropathy at both doses (10 mg, 25mg; P = 001).4

EMPA-REG provided signals of a slower decline in renal failure with a net 50% reduction in end-stage renal disease.And CANVAS findings suggesting a 40% reduction in estimated glomerular filtration rate (eGFR), RRT requirement, and reduction in renal death (HR 0.60, 95% CI 0.47-0.77).5

In addition, CANVAS demonstrated a significant reduction in progression of albuminuria with canagliflozin over 338 weeks (HR 0.73)5 and with EMPA-REG a normalization of albuminuria.6

“Blood pressure lowering, which has an otherwise unmet need, affords another benefit in individuals with hypertension or prediabetes renal benefits,” said Dr. Bloomgarden.

Patients Drug Adherence with SGLT2i Offers Critical Advantage 

My third point concerns the 800-pound gorilla in the room, and from a patient perspective, is about adherence, he said. "Let’s face it, all the benefits in the world will not lead to improved outcomes if the patient stops taking their medication."

“While not specific to SGLT2is, for every 100 prescriptions written, only 50-70% are filled, only 25-30% is taken as prescribed and 15-20% are refilled.”7,8 "What we can say is that medication adherence to GLP1s is only 34% over one year based on claims data of 1321 patients with T2D receiving liraglutide,he said, even with the support of a study coordinator.

The SGLT2i glucose-lowering drug class is easy to take so there is better tolerability given their oral administration in comparison to the injectable administration needed for most of the GLP1s. As is typical of medications delivered by injection, we also know that patients complain of injection frequency, pain associated with needle size, injection site reactions.10,11

An equally important consideration is the matter of adverse side effect. “In comparison to the GLP1s, which have an issue of poor tolerance due to the gastrointestinal side effects, the SGLT2i class may cause increased urinary frequency and genital tract infections which are a more manageable annoyance,” said Dr. Bloomgarden.    

 “On balance, in clinical practice, my approach is to first use the SGLT2is for patients with diabetes, especially for liraglutide, and the once-weekly infection of exenatide but I find that having the GLP1s to be important and useful given their evidence of cardiovascular benefits,” he told Endocrineweb.

Therefore, SGLT2is are a class of drugs that over and above a very important glucose lowering effect, also has quite significant direct benefits especially with regard to reducing the rate of heart failure as well as providing renal protection, he said.

Arguing for GLP-1 RAs as the Best Add-On Therapy for Type 2 Diabetes.

Richard E. Pratley, MD, Diabetes Research Chair at Florida Hospital Diabetes Institute, told EndocrineWeb, “the benefits of glucagon-like peptide-1 receptor agonists (GLP1s) are more tangible against the more modest effects gained by the SGLT2is”

“Today, I argued that GLP1-RAs should be first-line treatment when adding on to metformin in patients with type 2 diabetes, beginning with the fact that this class of glucose-lowering agents addresses multiple metabolic abnormalities present in patients with established type 2 diabetes,”12 said Dr. Pratley. 

 

“Today, I argued that GLP1-RAs should be first-line treatment when adding on to metformin in patients with type 2 diabetes, beginning with the fact that this class of glucose-lowering agents addresses multiple metabolic abnormalities present in patients with established type 2 diabetes,”12 said Dr. Pratley.

The action of GLP1-RAs is effective given the function to enhance insulin secretion and suppress glucagon production, as well as to demonstrate superior efficacy in its hemoglobin A1c (HbA1c) lowering action,13,14  he said.

“Moreover, GLP1-RAs decrease rapid gastric emptying common in poorly controlled diabetes, presenting a favorable effect on central appetite centers that induces a greater sense of satiety, leading to desirable weight loss,”2 Dr. Pratley said.

“While there are few head-to-head trials, results from the DURATION-8 trial demonstrated that semaglutide resulted in a weight loss of 4-6 kg as compared to -1.56 +/- 0.29 kg for exenatide and -2.22 +/- 0.28 kg for dapagliflozin,13 a much larger effect than that seen by any of the SGLTs,” said Dr. Pratley.

GLP-1RAs: Established Cardiovascular Protection

“We've known that the GLP1-RAs have a favorable CVD profile, by which this class delivers significant improvements in cardiovascular risk, which is especially true for liraglutide and semaglutide based on findings from the LEADER trial.14 Another reason: GLP1s have a more favorable lipid-lowering effect with regard to triglycerides,” he said.

 Whereas the SGLT2 inhibitors target glucose uptake in the proximal tubule, there are significant renal side effects nor known renal impairment limiting use of GLP1s, based on eGFR,14 according to Dr. Pratley, and “the GLP1s also reduce serum glucose by increasing peripheral glucose clearance and reducing hepatic glucose production, as well as renoprotective effects,15 as supported by findings of the two randomized control trials, SUSTAIN-616 and ACCORD.17

In fact, with regard to chronic kidney disease, SGLT-2 inhibitors are not recommended in patients with eGFRs less than 45-60 ml/min/1.73 m2

“Admittedly, adherence has been mixed. However for patients who do well, they stay on the GLP1, so it’s a matter of selecting the right patients such as those who are overweight or have a substantially elevated A1c,” he told EndocrineWeb, “and with the introduction of a once-weekly injection, the issue of adherence is likely to become a problem of the past.”

“A final and important advantage is the beneficial use of this class of glucose-lowering agents in special populations—specifically in patients with chronic kidney disease and in the elderly, where SGLT2s do not have the efficacy,” said Dr. Pratley. “GLP-1 RAs may also be preferred in older patients who are susceptible to the hypotensive side effects of SGLT-2 inhibitors and in women who experience frequent urinary tract infections.”

These features, plus their demonstrated cardiovascular benefits make GLP-1 receptor agonists the preferred add-on therapy to metformin in patients with T2DM. In those over 75 years of age, there was a greater reduction (31%) in MACE, notably for all-cause mortality, he said, that and there’s no amputation risk.2

“If there is a barrier to use with the GLP1-RAs, it is cost-related,” Dr. Pratley said, “Overall, the evidence suggests that GLP1s are a great therapeutic option to improve cardiovascular outcomes for patients with T2D,” he said. “That being said, there is a role for SGLT2, for example in patients with risk of heart failure, for which that class has a decided advantage.”

 


 

AND THE DEBATE WINNER IS......

Did you change your vote?  Among the 400 attendees, the debate was won in favor of GLP1-RA: 59% versus 41% for the SGLT2i.

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