SGLT2 Inhibitors Play Significant, Growing Role in Glycemic Control

In an interview with Pharmacy Times, Stormi Gale, PharmD, BCCP, a cardiology pharmacy specialist at Novant Health, discussed the important role of SGLT2 inhibitors in glycemic control, as well as the potential cardiovascular and renal benefits. Gale discussed this topic during a session at the American Society of Health-System Pharmacists (ASHP) 2023 Summer Meeting.

Q: Can you give a baseline of information about what SGLT2 inhibitors are and why they’re so effective?

Stormi Gale, PharmD, BCCP: Yeah, definitely. So, SGLT2 inhibitors are a class of medications, you might know them as the “flozins,” as their generic names end in “flozin.” But what's really interesting about these agents is that they were originally developed for diabetes and their mechanism of action in diabetes is primarily to increase urinary excretion of glucose through SGLT2 inhibition in the renal tubules. However, in the early 2000s, there were some concerns about increased cardiovascular risk with some of the anti-hyperglycemics, particularly rosiglitazone. And so, in 2008, the FDA mandated that all of these drugs undergo cardiovascular outcome trials to determine if there was an increase in cardiovascular risk. However, although they were testing for increased cardiovascular risks, some of the trials actually demonstrated benefits in both cardiovascular and renal disease, and SGLT2 inhibitors were one of the classes that demonstrated this. So, there's a couple of different mechanisms that have been proposed for these benefits. By restoring proximal tubule flow and reducing glomerular hypertension, SGLT2 inhibitors can exhibit natural protective effects. The mechanism of benefit in cardiovascular disease is really less well understood, but may include things like improvements in cardiac energy, metabolism, and prevention of adverse remodeling, among some other benefits.

Q: What role do SGLT2 inhibitors play in treatment for patients with diabetes?

Stormi Gale, PharmD, BCCP: Yes, so for many, many years, metformin was recommended as the sole first line agent for diabetes. All the other agents were sort of recommended as an add-on therapy or second line, third line therapies. However, recently SGLT2 inhibitors have become recommended by the [American Diabetes Association] as a first line option for patients who have diabetes and established atherosclerotic cardiovascular disease or those who are at high risk for ASCVD, as well as patients with established kidney disease or heart failure. And that recommendation is really independent of baseline A1C or whether or not they're at their A1C target.

Q: What cardiovascular benefits can SGLT2 inhibitors have, and hwo do these vary for patients with or without diabetes?

Stormi Gale, PharmD, BCCP: Sure, so in select cardiovascular outcomes trials, which again, were designed to ensure that there was no increased cardiovascular risk with these agents, SGLT2 inhibitors were shown to decrease the risk of MACE, or major adverse cardiac events, which is essentially a composite of cardiovascular death, myocardial infarction, or stroke. But another important finding of these cardiovascular outcome trials was this reduction in heart failure, which prompted further studies in patients who have heart failure independent of whether or not they had diabetes. And so, these studies demonstrated really impressive outcomes, things like decreases in mortality and hospitalizations, and even improvements in symptoms when you use SGLT2 inhibitors in patients who had heart failure.

Now, importantly, I'll point out that these benefits have been shown independent of whether or not the patients did have diabetes in those studies and have been shown across all spectrums of ejection fraction. So, this class of agents did receive a Class 1 recommendation for heart failure with reduced ejection fraction as part of the 4 pillars of heart failure therapy and they're also recommended in the guidelines for patients with heart failure and ejection fractions above 40%.

Q: What renal benefits can SGLT2 inhibitors have, and how do these vary for patients with or without diabetes?

Stormi Gale, PharmD, BCCP: Yeah, so similar to what we saw with those cardiovascular benefits, the early detection of renal benefits were really seen in those studies that included only patients with diabetes. But since that time, there have been a couple of studies in patients who have CKD, independent of their diabetes status. And the studies have really found remarkable benefits, including things like decreased progression of kidney disease, and that includes things like slower reduction in EGFR, a longer time for patients not requiring dialysis, decreased onset of renal failure, and even decreased death from cardiovascular or renal causes. And again, the benefits we're seeing are really independent of whether or not the patients had diabetes. And so, these have been endorsed by both the ADA and the [Kidney Disease Improving Global Outcomes] guidelines as first line agents for patients with diabetes and CKD.

Q: With such a wide array of potential benefits, how do you identify the best patients to initiate treatment with SGLT2 inhibitors?

Stormi Gale, PharmD, BCCP: Yeah, so in my practice in general, I am identifying patients by their indication and then really considering if there are any contraindications. So, for example, I practice primarily in heart failure, although many of my patients also have concomitant diabetes and/or CKD. My practice really is to start SGLT2 inhibitors in all of my patients unless I have a really compelling reason not to. So, for example, if they have type 1 diabetes and end-stage renal disease‚ so an EGFR <20, or an inability to access medications due to affordability or financial barriers. Overall, when you look at studies, these agents tend to be really safe. And so, my opinion is that the benefits are going to outweigh the risks in most patients who have chronic diseases like heart failure or CKD.

Q: What role do pharmacists play in treatment with SGLT2 inhibitors?

Stormi Gale, PharmD, BCCP: That's a great question. I cannot overemphasize the importance of the role of the pharmacist in both initiating and managing SGLT2 inhibitors. To start, because the non-diabetic indications are more recently approved, there can be a general lack of familiarity amongst our prescribers, including our cardiologists or nephrologists, and even our primary care physicians for how we utilize these agents. And so, we can have a general lack of prescribing because of that decreased comfort with the class. So, pharmacists can be really pivotal in educating providers about the benefits of the agents as well as their contraindications to help improve that familiarity and, you know, ultimately improve optimization of SGLT2 inhibitors.

Another important role, especially in the United States, is facilitating medication access. So, while the coverage of these agents certainly has improved over the past several years, we do definitely have patients who will still require prior authorizations or who have copays that are not feasible for them. So, pharmacists are really well positioned to navigate those barriers, like the prior authorization process, or identify other avenues for access, such as things like copay cards or patient assistance programs.

Q: Is there anything you’d like to add?

Stormi Gale, PharmD, BCCP: You know, the one thing I should emphasize as part of the role for pharmacists is patient education. So, of course, including things like what to expect in terms of side effects, how to handle sick days, but I think maybe even the most important thing is to make sure patients know why they're prescribed an SGLT2 inhibitor. I can't count the number of times I've seen patients admitted to the hospital for heart failure who had stopped taking their SGLT2 inhibitor because they were under the impression it's for diabetes and [they] were like, “I don't have diabetes so I didn't think I should be taking it.” So, taking that time to educate patients about what the medication is for and even [educating] our providers can really improve that adherence and ultimately improve those patient outcomes. Clinical inertia is a really significant issue for the optimization of chronic diseases, and so by educating both patients and providers about those benefits, we can hopefully overcome some of that inertia and improve the care of those patients that have chronic diagnoses like diabetes, heart failure, and renal disease.