10 Years of SGLT2 Inhibitors: A Decade of Redefining Cardiometabolic Care

On March 29, thousands of patients across the world, with and without type 2 diabetes, will take SGLT2 inhibitors as part of their management of one or more cardiometabolic diseases. However, just 10 years ago, few could have imagined this reality.

On March 29, 2013, the United States was introduced to SGLT2 inhibitors with the US Food and Drug Administration’s approval of canagliflozin (Invokana).¹ Immediately following approval, the agent found itself as an ugly duckling of sorts, with a modest effect on glycemic control relative to the agents already featured in treatment armamentarium, such as GLP-1 receptor agonists and DPP-4 inhibitors.

Approved with an indication as an adjunct to diet and exercise for improving glycemic control in people with type 2 diabetes,¹ the class was burdened by provider concerns related to amputations and risk of diabetic ketoacidosis.² At the time, few, if any, could have imagined the manner in which this class would revolutionize management of cardiometabolic disease.

“We didn't really know what its place would be. On top of that, the higher price tag was higher compared to generic drugs like metformin, sulfonylureas, and the pioglitazone,” explained Diana Isaacs, PharmD, endocrine clinical pharmacist at the Cleveland Clinic. “So, we were not exactly sure, I think in our minds, DPP-4 inhibitors were comparable to that, but we weren't sure about the safety profile. So, we really didn't know what its place in therapy would be at that time.”

Fast-forward a decade, the class has a prominent role in both the of management and clinical guideline recommendations for patient populations both with and without type 2 diabetes, including heart failure and chronic kidney disease (CKD).^3,4 What makes this ascent to stardom in the world of cardiometabolic health even more remarkable, is the unconventionality of its journey to centerpiece in treatment algorithms.

“In the beginning, it was a diabetes drug. Now it's a kidney drug and it's a cardiac drug. We’re even using it in the hospital, and we don't use brand names in in the hospital,” explained Natalie Bellini, DNP, a nurse practitioner and director of the Diabetes Technology Program at University Hospitals Diabetes and Metabolic Care Center, in an interview. “If you think about that jump, from 2013-2023, it is just staggering, right? I think that is the best way to think about it."

A Silver Lining for Cardiometabolic Health

Years preceding the approval of canagliflozin, a quiet storm had been brewing in type 2 diabetes. Unbeknownst to patients and care providers at the time, some of the cornerstones of therapy for type 2 diabetes at the time, namely thiazolidinediones, may have been increasing the risk of cardiovascular disease events, despite the apparent benefits on glucose control.

One study examining this phenomenon was an article published in the New England Journal of Medicine by Steve Nissen, MD, and Kathy Wolski, MPH, in 2007, which detailed the results of a search of multiple data sources outlining the effect of rosiglitazone on risk of myocardial infarction and cardiovascular death.⁵ In this study, which included studies with a duration of more than 24 weeks and a randomized control group, Nissen and Wolski reported odds ratios of 1.43 (95% CI, 1.03-1.98; P=.03) for myocardial infarction and 1.64 (95% CI, 0.98-2.74; P=.06) for cardiovascular mortality with use of rosiglitazone.⁵

As a result of this data and other studies purporting potential for increased risk, the FDA issued industry-wide guidance requiring new antidiabetic therapies to demonstrate use was not associated with an unacceptable increase in cardiovascular risk and the recommendations in the guidance were applied to all new drug products intended to treat type 2 diabetes.⁶

A silver lining for cardiometabolic health providers from this new FDA were the revelations that would come forth from some of these cardiovascular outcomes trials, including EMPA-REG Outcome, which would alter the landscape of cardiometabolic risk reduction from that point forward.

EMPA-REG Outcome

Not long after the approval of canagliflozin in 2013, the FDA approved empagliflozin (Jardiance) as an adjunct to diet and exercise for improving glycemic control in adults with type 2 diabetes.⁷ With the FDA’s 2008 guidance in place, Eli Lilly and Company launched the phase 3 EMPA-REG Outcome trial in July 2010 with the intent of examining the cardiovascular safety of the agent against placebo therapy.⁸

Published in November 2015 in the New England Journal of Medicine, results of the study demonstrated use of empagliflozin was associated with a 14% (HR, 0.86 [95.02% CI, 0.74-0.99]; P=.04) relative risk reduction for the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.⁹

In the analysis of secondary outcomes within the trial, results provided what would become the tipping point for the class’s deep dive into cardiometabolic health. Despite finding no significant between-group differences in rates of myocardial infarction or stroke, the empagliflozin group had a significantly lower rates of cardiovascular death (HR, 0.62 [95% CI, 0.49-0.77]; P <.001) and hospitalization for heart failure (HR, 0.65 [95% CI, 0.50-0.85]; P=.002).⁹

“I think that trial, you know, forever changed the field of cardiorenal metabolic medicine, specifically heart failure, because it not only was it positive for the primary endpoint of atherosclerotic cardiovascular disease prevention. But it also showed in a secondary endpoint, primary prevention of heart failure,” said Steve Greene, MD, associate professor of medicine and heart failure specialist at the Duke Clinical Research Institute, in an interview with HCPLive. “So as a heart failure specialist it got my attention. I said, 'Wow, this is actually preventing new onset heart failure’.”

A Role in Heart Failure

“In my career to have a therapy at our disposal like this, it really is the breakthrough in pharmacotherapy of my time as a doctor.” - Steve Greene, MD

EMPA-REG Outcome provided the first clinical trial evidence of the cardiometabolic risk reduction possible with SGLT2 inhibitor use. Publishing of the trial in 2015 was followed by CANVAS in 2017and then DECLARE-TIMI 58 in 2019.^10,11 Together, the 3 trials established the provided substantial evidence of the purported heart failure benefits seen in EMPA-REG outcome were a class effect for SGLT2 inhibitors.

Not ones to rest on their laurels, this information was disseminated among the cardiology community, who responded with the desire to know more about the efficacy and safety of the class, both in and outside of patient populations with type 2 diabetes. It would be dapagliflozin (Farxiga), the third SGLT2 inhibitor to receive approval from the FDA to provide this answer, with the results of the DAPA-HF trial coming less than a year long after the publishing of DECLARE-TIMI 58 in January 2019.¹²

In the phase 3 DAPA-HF trial, 4744 patients with or without type 2 diabetes with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to dapagliflozin or placebo. A 6263-patient trial, which had a primary composite outcome of worsening heart failure or cardiovascular death, results indicated use of dapagliflozin was associated with a 26% (HR, 0.74 [95% CI, 0.65-0.85]; P <.001) relative reduction in risk of the trial’s primary outcome.¹³

Following DAPA-HF and the confirmation of a class effect in EMPEROR-Reduced, the cardiology community, once again, set its sights on toppling the next potential domino: could this agent have a role in treatment of heart failure with preserved ejection fraction (HFpEF)? The answer they sought came in the form of the EMPEROR-Preserved trial, which was published in 2021.¹⁴

In EMPEROR-Preserved, which enrolled a population of patients with 5988 patients with class II, III, or III heart failure and an ejection fraction of more than 40%, results demonstrated use of empagliflozin was associated with a 21% reduction in relative risk of the trial’s primary composite outcome of worsening heart failure or cardiovascular death. In September 2022, the DELIVER trial, which examined dapagliflozin in HFpEF, solidified the idea of the purported benefits as a class effect for the agent after providing evidence of an 18% (HR, 0.82 [95% CI, 0.73-0.82]; P <.001).¹⁴

However, the most significant milestone in the journey of SGLT2 inhibitors as a treatment for heart failure came in April 2022 with the publishing of the latest iteration of national heart failure guidelines in the US, which received endorsement from the American College of Cardiology, American Heart Association, Heart Failure Society of America, and other major organizations.³ In the guideline, the sponsoring organizations expanded guideline-directed medical therapy for HFrEF to now included SLGT2 inhibitors and the class also received a Class 2a recommendation for HFpEF as well as heart failure with mildly reduced ejection fraction.³

“What is so unique about SGLT2 inhibitors, to me, really are one that it's so simple to use and that the safety and tolerability is really remarkable. I think it really sets itself apart from even some of the other pillars in heart failure. When you think about it's one pill once a day, no titration, and it is exceedingly safe,” Greene explained. “So, it really separates itself out. Yes, it's efficacious, just like the guideline-directed therapies, but it's exceedingly simple to use and well-tolerated. Then I think the other sweetener, with the SGLT2 inhibitor class, is that it's good for cardiovascular outcomes, but it's amazing for kidney outcomes as well.”

A Role in CKD

At the 10-year anniversary of approval, the benefits of SGLT2 inhibitors for CKD have been well-documented and publicized. However, at the time of approval from the FDA, there was great concern among practitioners about the potential for renal damage with use of the class.

Published in June 2019, the CREDENCE trial examined the effects of canagliflozin among a cohort of patients with type 2 diabetes and provided the first definitive signal of evidence as a means of managing CKD in people with type 2 diabetes.¹⁵ Results of the study, which included individuals with an estimated glomerular filtration rate (eGFR) of 30-90 ml/min/1.73m2 and UACR of 300-5000 mg/g, demonstrated use was associated with a 30% relative risk reduction in the trial’s primary composite outcome of end-stage kidney disease, a doubling of the serum creatinine level, or death from renal or cardiovascular causes.¹⁵

As with the phase 3 heart failure programs, the interest of the nephrology community shifted to further examining the class in populations with or without type 2 diabetes. Launched in 2017, the DAPA-CKD trial would provide the community the information they sought upon presentation at the European Society of Cardiology Congress 2020. A phase 3 trial of patients with of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a UACR of 200-5000 mg/g, the DAPA-CKD trial was stopped early by the independent data monitoring committee based on its demonstration of efficacy.¹⁶ In 2022, EMPA-KIDNEY would provide further insight into the effects in people with CKD, with results suggesting the benefit seen with SGLT2 inhibitors was consistent regardless of the presence of albuminuria.¹⁷

“We just had so few drugs come down the pipeline in recent years that are beneficial for the kidney,” explained Jane Davis, DNP, CRNP, of the nephrology division of the University of Alabama at Birmingham. “We just basically stuck with our saying, tried and true, that it was just really exciting to have something that was going to work for the kidney, and the diabetes and the heart of a patient. I mean, it was like, really winning the Triple Crown.”

The Next Frontier

A million-dollar, potentially billion-dollar, question for pharmaceutical companies and researchers alike when it comes to the SGLT2 inhibitor class is: What’s next?

With endorsements form major organizations across a multitude of patient populations, the class has solidified its role in management of cardiometabolic health. However, instead of accepting the class as disease-altering for those with type 2 diabetes, CKD, and heart failure, many purport the community has just scratched the surface when it comes to the true potential of the class.

For Greene, the future included examining effects for heart failure prevention in more specific patient subgroups, such as those undergoing or have undergone cancer treatments including agents known to be associated with cardiotoxicity. For Isaacs and Bellini, the next frontier includes examining the potential benefit of the agent in populations with type 1 diabetes. For Davis and Kim Zuber, PA-C, executive director of the American Academy of Nephrology Physician Assistants, the next steps were not exploring potential in a new therapy but expanding education and implementation efforts to improve uptake of the class as a whole.

“I think we have very good research, but nobody knows about it, I think education. You know, I can talk to a group of 500 or 600 but, for general education, when it is in guidelines then it's a huge deal,” Zuber remarked. “So, one of the quality indicators for patients with diabetes is to do a UACR and to test for kidney disease, however, not only is it not in the 2023 hypertension guidelines, but it's not in any of their quality indicators. So, I think that we're doing, we're getting halfway there. But I think that if we don't put it in guidelines, people won't do it. We can do all the research we want.”

Greene echoed similar sentiments, citing a lack of uptake post-inclusion in the 2022 iteration of national heart failure guidelines.

“There is a culture issue that I think is at play that we need to crack to get really breakthrough get these drugs to our patients. Again, costs will certainly be a challenge for some patients, but it should not be a reason to give up,” Greene explained. “I'm hopeful that the unique features of SGLT2 inhibitors including the simplicity, the safety, and the tolerability. If there is a drug that can break through and actually have a rapid, more rapid early adoption, I think SGLT2 inhibitors have a lot of those characteristics that set it up for success.”

For more on the subject, check out this clip from a special edition episode of Diabetes Dialogue: Technology, Therapeutics, and Real-World Perspectives highlighting the 10-year anniversary of the SGLT2 inhibitor class.

References

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2. Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015;100(8):2849-2852. doi:10.1210/jc.2015-1884
3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2022 May 3;145(18):e1033] [published correction appears in Circulation. 2022 Sep 27;146(13):e185]. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
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7. FDA approves Jardiance® (Empagliflozin) tablets for adults with type 2 diabetes. Eli Lilly and Company. https://investor.lilly.com/news-releases/news-release-details/fda-approves-jardiancer-empagliflozin-tablets-adults-type-2. Published August 1, 2014. Accessed March 29, 2023.
8. Bi 10773 (Empagliflozin) cardiovascular outcome event trial in type 2 diabetes mellitus patients (EMPA-reg outcome). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01131676. Published May 27, 2010. Accessed March 29, 2023.
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12. US FDA approves Farxiga™ Tablets for the treatment of adult patients with type 2 diabetes. AstraZeneca. https://www.astrazeneca.com/media-centre/press-releases/2014/us-fda-approved-farxiga-treatment-type-2-diabetes-patients-13012014.html. Published June 13, 2014. Accessed March 29, 2023.
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