A Q&A With Gary Besinque, PharmD
Click here to view video highlights from this interview.
AJMC®: Kaiser Permanente has set up a clinical pathway for the use of SGLT2 [sodium-glucose cotransporter-2] inhibitors for patients with heart failure (HF). Could you describe this pathway?
BESINQUE: We update our HF management guidelines every 2 years. Well before our most recent update in April 2021, we recognized the impact of the various trials the FDA [United States Food and Drug Administration] had asked for that assessed the cardiovascular (CV) safety of SGLT2 inhibitors in patients with type 2 diabetes (T2D).1-4 Thereafter, a good number of studies examining SGLT2 inhibitors in patients with HF and with or without T2D demonstrated impressive results. Given all of this evidence, we began to consider where SGLT2 inhibitors would be placed in HF management.
We did an analogous exploration for the treatment of our patients with kidney failure. So both our kidney failure and HF guidelines were amended last year to include the institution of SGLT2-inhibitor therapies.
For HF, guidance on whether to start SGLT2 inhibitors is based on where a patient is on the continuum of HF disease. We’re happy to recognize that presence or absence of T2D is not material to the decision to start an SGLT2 inhibitor.
AJMC®: When is the initiation of SGLT2-inhibitor therapy recommended?
BESINQUE: Generally, when we're tweaking the HF guidelines, we make incremental moves, and that's what happened when we introduced SGLT2 inhibitors. For early initiation—especially in patients with HF after a heart attack—we still rely heavily on the 3 β-blockers that have demonstrated good safety and efficacy in HF: carvedilol, bisoprolol, and metoprolol tartrate. After these have been initiated, we recommend then initiating ACE [angiotensin-converting enzyme] inhibitors or ARBs [angiotensin receptor blockers].
For patients with HF—especially those with better ejection fraction and better New York Heart Association (NYHA) functional class—we think that SGLT2 inhibitors should be initiated third. We recommend initiating MRAs [mineralocorticoid receptor antagonists] and ARNIs [angiotensin receptor-neprilysin inhibitors] last.
AJMC®: Could you expand upon the evidence base that led to Kaiser’s recommendations for SGLT2 inhibitors in HF therapy?
BESINQUE: Some 15 years ago, the T2D medications thiazolidinedione, pioglitazone, and rosiglitazone got bad marks in some meta-analyses and the FDA-mandated CV safety trials for new T2D medications.5,6 This was the genesis of all of these remarkable trials assessing the CV safety of SGLT2 inhibitors in patients with T2D and trials examining SGLT2 inhibitors in patients with HF regardless of T2D.1-4,7-9
One of the first CV safety trials for SGLT2 inhibitors in patients with T2D left the biggest impression. The EMPA-REG OUTCOME trial [NCT01131676] involved use of empagliflozin in patients with established CV disease [CVD] and T2D.1,10 Remarkably, the 2 trial arms diverged almost immediately after initiation of therapy. At the end of 3 years, the patients in the placebo group demonstrated morbidity in the form of nonfatal MI [myocardial infarction], nonfatal stroke, and CV death. That composite primary outcome was reduced by 38% with the use of the SGLT2 inhibitor empagliflozin.1,10
It was a surprise that simply adding on an antidiabetic agent for patients with established CVD resulted in an improvement in CV status. Everybody sat on the edge of their chairs and said, “What’s going on here?” We’re still trying to figure that out.
Later, of the trials examining SGLT2 inhibitors in patients with or without T2D, EMPEROR-Reduced [NCT03057977] provided some of the most meaningful evidence for our recommendations.8 Most of the patients in that trial had NYHA functional class 2 HF, so our guidelines naturally pointed to these patients as having the most potential for improvement under SGLT2-inhibitor therapy.8
AJMC®: Was there an economic rationale for Kaiser including these agents earlier on in the spectrum of HF failure and earlier in the sequence of HF treatment?
BESINQUE: There’s an apocryphal tale from very early on. I was talking to 1 of the KOLs [key opinion leaders] in care management. This might have been 2016 or 2017. We spoke about the SGLT2 inhibitors, and he joked that maybe we’d replace our statins with SGLT2 inhibitors. I said, “I better look into this.” I don’t think he was being serious, of course, but that really meant a big deal, because we put statin use high on our list of needs. That impressed me greatly.
In brief, we expect that SGLT2 inhibitors will reduce hospitalization and that the savings from that reduction will outstrip the cost of the drug. In the EMPA-REG OUTCOMES trial, the heavy lifting in the outcomes was actually done by a reduction in HF hospitalizations. In HF, everybody has been struggling with 30-day readmission. A reduction in the number of hospitalizations over time would more than make up for the extra cost of instituting SGLT2 inhibitors early.
AJMC®: What were the clinical and economic consequences of this decision to use SGLT2 inhibitors earlier in HF treatment?
BESINQUE: Time will tell. We put in the endorsement of SGLT2-inhibitor use back in April 2021. So it’s been just over a year that we’ve offered the suggestion that SGLT2 inhibitors might be helpful in the management of patients with HF. We have some very capable people in our outcomes group who are watching this SGLT2-inhibitor deployment, and I eagerly anticipate some output from them.
AJMC®: In their April 2022 HF management guideline, the American College of Cardiology, American Heart Association, and Heart Failure Society of America now recommend the use of SGLT2 inhibitors in patients who are at risk for HF.11 What might be the value of bringing SGLT2 inhibitors to this early stage of treatment?
BESINQUE: Some great trials have demonstrated that SGLT2 inhibitors improve CV outcomes in not only HFrEF [HF with reduced ejection fraction], but also HFpEF [HF with preserved ejection fraction]. Indeed, the more myocardium there is to improve, the better. Myocardial energetics come into play. If you have better heart function, you're preserving it longer. But the super fuel elements in SGLT2 inhibitors work at all stages of HF. Ultimately, the payoff of using SGLT2 inhibitors across all stages of HF might come in the form of lower health care utilization, lower morbidity and mortality, and improved quality of life, which are all great goals.
AJMC®: Milton Packer, MD, and John McMurray, MD, recommend that patients with HFrEF should be started on a β-blocker and an SGLT2 inhibitor, and the remaining 2 pillars of HFrEF should be added to the treatment sequence within 4 weeks.12 This sequence is much more rapid than the conventional treatment approach, which takes 6 months or more. From an economic perspective, how compelling is this rapid approach?
BESINQUE: It definitely has merit. We certainly have struggled, especially with HFpEF, and it may be that introducing SGLT2 inhibitors very early in the care of these patients could make a strong impact on the quality of life and other dimensions of health care delivery. Some early adopters in Kaiser are testing this out already on a small cohort of their patients to see if they can discern that.
But you do have to have numbers. We will have to await the arrival of good-sized number of patients who were treated in that way. As I said earlier, we really don't know what SGLT2 inhibitors are doing. Once we do, we can find the people who need help in those areas. There's an awful lot left to be explored in terms of where best to place this particular class of drugs in the treatment of HF.
AJMC®: Earlier this year, results were published from the EMPULSE trial, which demonstrated that beneficial effects of an SGLT2 inhibitor on health status persisted through 90 days in patients who were hospitalized for acute HF.13 From a payer perspective, how relevant are these results?
BESINQUE: EMPULSE trial participants were hospitalized with an HF exacerbation and started out on an SGLT2 inhibitor in-house. From the very beginning, once they were stabilized and off inotropes, for example, and diuretics were stabilized, then investigators started SGLT2 inhibitors and watched patients for 90 days. Payer perspective–wise, we really like to have a very large scale RCT [randomized controlled trial] to base our important guidance on. These results are going to contribute to our thinking, but you'll have to treat a few more folks before we really take notice. This said, EMPULSE teases at the very thorny issue of 30-day hospital readmissions for patients with HF. We’re still wrestling with that issue and holding out hopes that SGLT2 inhibitors will contribute to solving that problem.
Interestingly, in addition to the main trial analyses, EMPULSE investigators also performed a post-hoc analysis of the KCCQ [Kansas City Cardiomyopathy Questionnaire] that was sent to patients.14 It has a 100-point scale, and the questionnaires were sent out every couple of weeks. It turns out that the difference between the SGLT2-inhibitor arm and the non-SGLT2–inhibitor arm averaged about 4 points. In the paper, it was called small, but we saw real improvement in KCCQ score and in the various dimensions. All the different facets of KCCQ showed that improvement.
AJMC®: You mention the rate of unplanned readmission within 30 days of discharge, which the National Committee for Quality Assurance monitors.15 As we consider the results of the EMPULSE trial, how hopeful should we be that the SGLT2 inhibitors might favorably impact this metric?
BESINQUE: We stumbled across the SGLT2 inhibitors serendipitously, simply because the FDA was concerned about the thiazolidinediones. And lo and behold, we came across some very spectacular results: SGLT2 inhibitors were not only not harmful, but actually helpful in improving the health status of patients with established CVD and T2D. Then we found out that it doesn't matter whether patients with HF have T2D or not; you still get those improvements. It’s not the HbA1C [glycated hemoglobin A1C level] that’s doing this, but something else that is creating some remarkable results. We can be hopeful and should continue to explore what exactly the SGLT2 inhibitors can and cannot do.
AJMC®: What might be the approach to incorporating SGLT2 inhibitors into policy decisions?
BESINQUE: That’s definitely the question of the day. We wonder whether SGLT2 inhibitors can do their magic in other clinical arenas. For example, in CKD [chronic kidney disease], we are seeing post-hoc analyses of the original CV safety trials delving into whether renal function is improved. And, indeed, SGLT2 inhibitors do slow the loss of nephrons over time; as you age, your creatinine clearance continues to fall, but not as rapidly under the influence of SGLT2 inhibitors. So our nephrologists are likewise interested in finding that sweet spot in terms of preserving both kidney function and the piggy bank.
The economics are the elephant in the room when you're talking about instituting newer therapies earlier, where earlier means among a much larger cohort. It does make waves in terms of the finance folks; they’re asking whether you can keep the enterprise afloat. Our purchasing and contracting team does a stellar job. Kaiser's a large operation, so they can acquire some very favorable contracting. That was the case for our SGLT2 inhibitors. This has made it easier to explore the benefits and dimensions of SGLT2-inhibitor use in our program.
Dr Besinque is pharmacist evidence analyst and strategist (retired) at Kaiser Permanente Health Care Plan.
1. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323-334. doi:10.1056/NEJMoa1515920
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389
4. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435. doi:10.1056/NEJMoa2004967
5. Kaul S, Bolger AF, Herrington D, Giugliano RP, Eckel RH. Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College of Cardiology Foundation. Circulation. 2010;121(16):1868-1877. doi:10.1161/CIR.0b013e3181d34114
6. Type 2 diabetes mellitus: evaluating the safety of new drugs for improving glycemic control: guidance for industry. United States Food and Drug Administration. March 2020. Accessed July 7, 2022. https://www.fda.gov/media/135936/download
7. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303
8. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424. doi:10.1056/NEJMoa2022190
9. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038
10. BI 10773 (empagliflozin) cardiovascular outcome event trial in type 2 diabetes mellitus patients (EMPA-REG OUTCOME). ClinicalTrials.gov. Updated May 16, 2016. Accessed July 7, 2022. https://clinicaltrials.gov/ct2/show/NCT01131676
11. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Card Fail. 2022;28(5):e1-e167. doi:10.1016/j.cardfail.2022.02.010
12. Packer M, McMurray JJV. Rapid evidence-based sequencing of foundational drugs for heart failure and a reduced ejection fraction. Eur J Heart Fail. 2021;23(6):882-894. doi:10.1002/ejhf.2149
13. Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-574. doi:10.1038/s41591-021-01659-1
14. Kosiborod MN, Angermann CE, Collins SP, et al. Effects of empagliflozin on symptoms, physical limitations and quality of life in patients hospitalized for acute heart failure - results from the EMPULSE Trial. Circulation. Published online April 4, 2022. doi:10.1161/CIRCULATIONAHA.122.059725
15. Plan all-cause readmissions (PCR). The National Committee For Quality Assurance. Accessed July 11, 2022. https://www.ncqa.org/hedis/measures/plan-all-cause-readmissions/
For other articles and videos in this AJMC® Perspectives publication, please visit “Implementing the 2022 ACC/AHA/HFSA Guideline for the Management of Heart Failure: SGLT2 Inhibitors, Treatment Sequencing, and Value Statements.”