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Original Article

SGLT2 Inhibitor Use in Patients with Type 2 Diabetes Mellitus and Heart Failure

Sarah Fraser, MD1, Elizabeth Swiggum, MD, FRCPC1, 2*

1Department of Medicine, University of British Columbia, Vancouver, BC;

2Department of Cardiology, Royal Jubilee Hospital, Victoria, BC

Abstract

Type 2 diabetes mellitus and heart failure, both reduced and preserved ejection fraction phenotypes, are individually associated with significant morbidity and mortality and, when co-morbid, compound their risks for poor outcomes. Sodium-glucose co-transporter 2 inhibitors have demonstrated significant risk reduction in important clinical outcomes in both conditions and should be utilized as foundational therapy to simultaneously target these two diseases. This article will explore the evidence for managing heart failure and type 2 diabetes patients and identify opportunities to improve outcomes.

Résumé

Le diabète de type 2 et l’insuffisance cardiaque, qu’il s’agisse d’un phénotype de fraction d’éjection réduite ou préservée, sont associés individuellement à une morbidité et à une mortalité importantes et, en présence d’affections comorbides, exacerbent les risques de mauvais résultats. Les inhibiteurs du cotransporteur sodium-glucose de type 2 montrent une diminution importante des risques relatifs aux résultats cliniques importants dans les deux affections et devraient être utilisés comme traitement de base pour cibler les deux maladies à la fois. Cet article explore les données probantes sur la prise en charge des patients atteints d’insuffisance cardiaque et de diabète de type 2 et cerne des possibilités d’amélioration des résultats.

Key words: SGLT-2 inhibitor, Heart Failure, HFrEF, HFpEF, T2DM

Corresponding Author: Elizabeth Swiggum: elizabeth.swiggum@islandhealth.ca

Submitted: 19 June 2022; Accepted: 17 July 2022; Published: 19 October 2022

DOI: 10.22374/cjgim.v17iSP2.639

All articles published in DPG Open Access journals
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).

Introduction

Historically, chronic diseases such as heart failure (HF) and type 2 diabetes mellitus (T2DM) have been treated as separate conditions with independent guideline recommendations. Clinically, there is significant overlap and patients frequently live with a combination of these complex disease states (Figure 1). T2DM has been associated with a two- to four-fold higher incidence of both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) compared to those without T2DM.1,2 Both phenotypes of HF account for the a high number of hospital stays, on average lasting eight days, and carry poor prognoses with the estimated 1-year mortality after a first HF hospitalization of 35%.3,4

Figure 1. Overlapping comorbidities of heart failure, type 2 diabetes, and chronic kidney disease.

Equally, the prevalence of T2DM in patients with HF is high, estimated at 35% and, when present, HF occurs at an earlier age and is an independent risk factor for all-cause mortality and HF admissions and readmissions.1,57 Additionally, chronic kidney disease (CKD) affects 4.5% of the general population, but up to 50% of patients with HF and 48% of patients with T2DM.8,9 There is a more -pronounced decline of renal function in patients with HF (2–3 mL/min/1.73 m2/year above the age of 50) and even further in those with both T2DM and HF (5 mL/min/1.73 m2/year above the age of 50), again demonstrating the compounding relationship between these disease states.10

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have emerged at the intersection of these chronic conditions as an individual therapy to simultaneously target these diseases. SGLT2is were, at their inception, studied for glycemic control in T2DM due to their inhibition of glucose reabsorption in the proximal convoluted tubule of the kidney, thereby causing glucosuria and reducing serum glucose.11,12 Large trials of different SGLT2is found modest hemoglobin A1c (HbA1c) lowering of 0.5-1% and average weight loss of 2–3kg after initiation.11,12 Studies further documented SGLT2i’s renal protective effects, reducing the progression to the first of dialysis, transplant, or death from renal causes by 33% across patients with estimated glomerular filtration rate (eGFR) >30mL/min/1.73m2, a benefit maintained in both patients with and without T2DM.1,13,14 In the field of HF, a growing collection of evidence has demonstrated benefit of SGLT2i therapy across a broad spectrum of HF presentations.1517 Canagliflozin, Dapagliflozin, and Empagliflozin are the most common drugs of this class available in Canada, financial coverage of which is dictated by individual provinces. In 2021, with the impressive benefits exhibited to date, SGLT2is have been added to the World Health Organization’s List of Essential Medicines.18

Growing evidence of the benefits associated with SGLT2is has become increasingly compelling across the continuum of these chronic diseases, highlighting the importance of these medications as foundational therapies for T2DM, the full spectrum of HF, and any combination of the two. In this article, we aim to present two clinical cases to base a discussion on how to incorporate the latest evidence on SGLT2i therapy into clinical practice.

Case 1

A 68-year-old man with history of ischemic cardiomyopathy with a left ventricular ejection fraction (LVEF) of 30% is referred for exertional dyspnea in the ambulatory setting. He describes progressive shortness of breath over six months, unable to climb two flights of stairs without symptoms New York Heart Association (NYHA II). He has had two previous hospitalizations for heart failure requiring intravenous diuresis. His past medical history is relevant for an anterior ST-elevation myocardial infarction that required primary percutaneous intervention with two drug eluting stents to the left anterior descending artery. He also has familial hypercholesterolemia and paroxysmal atrial fibrillation. He is retired and does not smoke or use substances. Current medications include apixaban, bisoprolol, clopidogrel, sacubitril-valsartan, spironolactone, furosemide, pantoprazole, and atorvastatin on maximum tolerated doses. His blood pressure in clinic is 111/83 with no orthostatic symptoms. Laboratory investigations reveal normal complete blood count, sodium 142 mmol/L, potassium 5.3 mmol/L, creatinine 108 umol/L, eGFR 67 mL/min/1.73 sqm, and NTproBNP 1700 ng/L. HbA1c was 5.9%. He was started on dapagliflozin 10 mg oral daily.

The Evidence

SGLT2is have become established as a foundational pillar of therapy, amongst renin-angiotensin-aldosterone system (RAAS) inhibitors, beta-blockers, and mineralocorticoid receptor antagonists (MRA), to reduce symptoms, hospitalizations, and mortality.4 In the landmark 2019 trial, Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF), dapagliflozin 10 mg was compared to placebo in 4744 patients with and without diabetes, with LVEF <40% over a median follow-up of 18.2 months. The composite of CV death or HF hospitalization was reduced by a 4.9% ARR in the treatment arm driven by a reduction in HF hospitalization (ARR 3.7%). Dapagliflozin also reduced all-cause mortality (ARR 2.3%), and produced clinically meaningful (defined as greater than five point) improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ) for HF symptoms (ARR 7.6%)15 The beneficial effects of SGLT2is were upheld in the 2020 trial, Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced), which investigated the efficacy and safety of empagliflozin in people with NYHA II to IV HFrEF (LVEF <40%).16 In this study, the incidence of cardiovascular death or hospitalization for HF was significantly lower with empagliflozin (ARR 5.2% largely driven by hospitalization risk reduction) compared with placebo.16

SGLT2is act by reducing glucose reabsorption in the proximal tubule, thereby producing their antihyperglycemic effects. The mechanism for improving outcomes in patients with HF continues to be investigated, currently thought to be secondary to the natriuresis and diuresis effects reducing risk for cardiac decompensation.1,15 Other proposed mechanisms include favourable effects on hemodynamics, endothelial function, inflammation, reduction in weight, improvements in filling pressures and ventricular remodelling, and on slowing the progression of renal disease, a common comorbidity in both HF and T2DM patients with pathogenic effects including hypertension, fluid retention, activation of RAAS, anemia, hyperkalemia, and more. progression of kidney disease.14,15,16

Since patients with established HF are rarely naïve to pharmacologic therapies, questions have arisen regarding adequately prioritizing the most appropriate guideline--directed medical therapy up-titration schedule.10 Our patient exemplifies this, currently on three of the four foundational pillars and furosemide diuretic. The answer from recent guidelines is to deemphasize sequencing of the pillars of foundational heart failure therapy and rather focus on early initiation and combination.4 We now know that the efficacy of an SGLT2i, even as add-on therapy notwithstanding the individual combination of drugs that patients are treated with, is maintained in both DAPA-HF and EMPEROR-Reduced. The clinical benefits are seen independent of doses of other drugs or a variety of combinations of foundational therapies of heart failure.15,17,18

There may also be benefit to early combination therapy in HF with synergistic potential such that one drug may facilitate the use of another. A subgroup analysis of DAPA-HF revealed a reduced risk of hyperkalemia (defined as potassium >6.0 mmol/L) in patients taking an MRA, half as likely with dapagliflozin compared to placebo (HR 0.5, 95% CI 0.29-0.85) although plausible mechanism remains speculative.15 In addition, a recent meta-analysis by Seidu et al., concluded SGLT2is combined with RAAS inhibitors had additive cardiorenal benefit compared to SGLT2 is alone, while no significant safety differences were found.19

Our patient did not have diabetes with his HbA1c of 5.9% however, SGLT2i therapy also holds a potential preventative benefit for him. Data from large, randomized control trials pooled 4003 patients without T2DM showed SGLT2i therapy reduced the incidence of new-onset T2DM (HR 0.67, 95%CI:0.51-0.88, P=0.0040) despite the minimal difference in HbA1c compared to patients who received placebo.20 Notably, DKA and hypoglycemia have not occurred in a patient without T2DM in any of the large SGLT2i trials.14,15,21

Case 2

A 62-year-old woman presented to hospital after several weeks of progressively worsening dyspnea on exertion, orthopnea, and anasarca. At baseline, she had poorly controlled type 2 diabetes (HbA1c 8.5%), atrial fibrillation (diagnosed six months prior requiring cardioversion), chronic kidney disease (baseline eGFR 45 mL/min/1.73 sq m), hypertension, and sleep disordered breathing requiring BIPAP. Her home medications included metoprolol, ramipril, gabapentin, atorvastatin, gliclazide, metformin, and insulin. Admission blood work revealed normal complete blood count, sodium 136 mmol/L, potassium 4.9 mmol/L with bicarbonate 35 mmol/L and albumin 35 g/L. Creatinine was increased from her baseline at 178 umol/L (eGFR 35 mL/min/1.73 sq m). NTproBNP 12,048 ng/L, HbA1c 8.5% and urine albumin creatinine ratio 1.2.

An echocardiogram three years earlier demonstrated preserved LVEF, aortic sclerosis and borderline hypertrophy. While awaiting a contemporary echo, treatment was initiated. With diuresis, her renal function improved to her baseline, and spironolactone was added. After transitioning from intravenous to oral diuresis, empagliflozin was started at 10 mg daily. Echocardiogram was completed on hospitalization day four and confirmed an LVEF of 65% with left ventricular hypertrophy, normal aortic valve hemodynamics, and elevated filling pressures consistent with HFpEF.

The Evidence

Until recently, there has never been such opportunity to positively impact the prognosis of patients with HFpEF with pharmacologic therapy. In 2021, the Empagliflozin in Heart Failure with a Preserved Ejection Fraction (EMPEROR-Preserved) trial, a multicenter, double-blind, parallel-group, placebo-controlled trial randomized 5988 with LVEF >40% and NYHA II-IV to treatment with placebo or empagliflozin 10 mg daily.22 T2DM was present in 49% of each group respectively.22 With a median of 26.2 months of follow-up, EMPEROR-PRESERVED found empagliflozin reduced the risk of HF hospitalizations or CV death in patients in patients with HFpEF (ARR 2.6%), paving the way for the use of SGLT2is in HFpEF.17,22 Additionally, there was a 3.2% absolute risk reduction in risk of a first HF hospitalization.23 Benefits of empagliflozin persisted regardless of diabetic status with HR 0.79 (95%CI 0.67-0.94) in those with T2DM at baseline compared to HR 0.78 (95%CI 0.64-0.95) in patients without diabetes.23 Nassif et al’s 2021 publication, the SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial (PRESERVED-HF), went on to demonstrate significant symptomatic benefit of dapagliflozin in patients with HFpEF finding improvements in both KCCQ symptom scores and distance walked in the six-minute walk test at 12 weeks compared to placebo.24 The recent DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure) trial confirmed the suspected class benefit of SGLT2i.25 This multicenter, double-blind, placebo-controlled trial enrolled 6263 patients with LVEF >40%, randomized to placebo or dapagliflozin 10mg daily and found dapagliflozin reduced the composite risk of HF hospitalizations or CV death in patients with HFpEF (ARR 3.1%).25 Once again, benefits were upheld regardless of diabetic status (45% had T2DM per group) and in the presence or absence of patients who had a recovered ejection fraction (18% of participants had previous LVEF <40% that had improved to >40% prior to the trial).25 While EMPEROR-Preserved results suggested that benefits may have been preferentially seen in patients with mildly reduced LVEF but were attenuated in those with LVEF ≥ 50%, DELIVER’s benefits were consistent across all LVEF categories.23,25

Patients living with chronic, ambulatory HF have clearly benefited from early initiation of SGLT2is and more recently, data is suggesting similar benefit and safety with initiation in the acute inpatient setting. The 2021 trial, Sotagliflozin in patients with diabetes and recent worsening heart failure (SOLOIST-WHF) from the New England Journal of Medicine, demonstrated that benefits of therapy (SGLT1/2i) endured when initiated as an inpatient or within 72 hours of discharge, consistent with earlier EMPA-RESPONSE-AHF 2020 data showing reduced rehospitalizations and mortality.26,27 The 2022 EMPULSE (Empagliflozin in patients hospitalized for acute heart failure) trial, a double-blind trial randomized 530 patients with acute de novo or decompensated chronic HF, to empagliflozin 10mg daily or placebo once clinically stable (median third day of admission) and found those who received empagliflozin were 26% more likely to experience a clinical benefit compared to patients on placebo regardless of LVEF.28 Clinical benefit in this case was defined as a composite of all cause death, number of heart failure events, time to heart failure events, or a five point improvement on the KCCQ at 90 days. Importantly, this trial found that adverse events were reported in 32.3% and 43.6% of empagliflozin- and placebo-treated patients respectively indicating that initiation of empagliflozin in hospitalized patients is both effective and safe to initiate as an inpatient.29 Effects of early empagliflozin initiation on diuresis and kidney function in patients with acute decompensated heart failure (EMPAG-HF) published in 2022, provides further evidence that adding SGLT2i therapy within 12 hours of hospital presentation, in addition to standard treatment, is safe and increases diuresis by 25% without affecting kidney function.29

Renal function is an important factor when initiating these medications and specific eGFR limits are dictated by their indication and respective landmark trials. Current thresholds for Canagliflozin are eGFR >30 mL/min/ 1.73 sqm, for Dapagliflozin eGFR >25 mL/min/1.73 sqm, and for Empagliflozin, >20 mL/min/1.73 sqm. Based on the evidence from CREDENCE and DAPA-CKD trials, once the SGLT2i therapy is initiated at the recommended level of eGFR, it can be continued until the patient initiates dialysis therapy.14,30

After an individual has been hospitalized for HF, the risk of re-admission is significant (25% at 30 days, and 43.9% at 1-year), with each admission associated with an increased risk of mortality.4,31 Rapid initiation and subsequent uptitration of SGLT2i therapy has the potential to impact outcomes for a vulnerable population. DAPA-HF and EMPEROR-Reduced have shown clinical benefits within one month and EMPEROR-Preserved demonstrated benefit by day 18 of initiation.15,19,23 SGLT2i therapy can be initiated at the lowest recommended, once daily dose (10 mg empagliflozin, 10 mg dapagliflozin) which is also the dose used in the majority of trials suggesting no dose titration is required for maximal cardiorenal benefits in HF.1416,23,32

Safety Profile

SGLT-2is are well-tolerated medications with important clinical benefits and in the absence of hemodynamic instability, SGTL2 is do not appear to increase the risk of AKI. In fact, a recent meta-analysis by Donnan et al., analyzed 109 articles and found an overall reduction in AKI has been observed with SGLT2i use (RR 0.59; 95% CI 0.39-0.89), possibly via reduced transglomerular pressure previously described in RAAS blocking agents.22 Assessment of patients’ fluid status will help determine the need for adjustment of concomitant diuretics when initiating SGLT2 inhibitors. The blood pressure-lowering and natriuretic effect of SGLT2 is modest, resulting in a reduction of systolic blood pressure of approximately 3–5 mmHg. Similar to ACE inhibitors, SGLT2i therapy can cause an acute drop in eGFR initially likely due to reduction in intraglomerular pressure; however, the decline in eGFR is subsequently attenuated with continuation of SGLT2i therapy.14,33 For that reason, although periodic monitoring is recommended in people with CKD, guidelines do not recommend routine additional assessment of renal function following prescription of SGLT2 is so as to avoid potential inappropriate discontinuation.8 In the outpatient setting, clinicians should remain mindful to add SGLT-2 inhibitors to their patient’s sick-day medication list.34

Euglycemic DKA was a concern in early trials that remains quite rare. In SOLOIST-WHF, all patients had T2DM and sotagliflozin had DKA in 2 patients (0.33%) vs placebo, 4 (0.65%) patients experienced this adverse event.26 DAPA-HF showed a ketoacidosis rate of 0.13%, EMPEROR-Reduced had no ketoacidosis events, EMPEROR-Preserved had 0.1% (compared to 0.2% in placebo group) and DELIVER had 2 patients (0.1%).15,16,25 The Donnan et al., metanalysis showed no significant difference in risk of DKA versus placebo (18 trials) or active comparison with incretin (8 trials). In patients on insulin, a stepwise dose--reduction strategy of insulin doses is preferred when initiating an SGLT2i, rather than complete discontinuation, to mitigate the risk of DKA (Figure 2).35 Notably, DKA has not occurred in a patient without T2DM in any of the large SGLT2i trials.

Figure 2. Pathway to starting SGLT2 inhibitor therapy.

The risk of hypoglycemia has not been found to increase in patients taking metformin, dipeptidyl peptidase 4 inhibitors, or glucagon-like peptide-1 receptor agonists and therefore no dose adjustment is required when starting SGLT2i therapy.35,36 Insulin and sulfonylureas however have an inherent hypoglycemia risk and in patients with optimal glycemic control or those already experiencing hypoglycemia, would require dose reduction of 50% or discontinuation of the sulfonylurea and/or a reduction by 10–20% of their rapid-acting (bolus) insulin when initiating an SGLT2i.36 Patients only using basal insulin can reduced their dose by 10% to mitigate risk of hypoglycemia.36 If patients are above their glycemic target with no hypoglycemia history, SGLT2i therapy can be started without dose adjustment. It is worth noting that SGLT2is have not been shown to cause hypoglycemia in patients without diabetes.14,15

The increased glucosuria from the SGLT2i has raised concern for urinary tract infection as an adverse effect and Donnan et al’s metanalysis found that urinary tract infections were the most frequently cited adverse effect of SGLT2i therapy, but even this did not occur more frequently than placebo across the drug class, except in the dapagliflozin subgroup (RR 1.21, 95%CI 1.02-1.43).22 This is largely consistent with a results from a 2017 metanalysis by Liu et al., that reviewed 77 randomized control trials (50 820 patients) and found no increased risk of UTIs in patients who used SGLT2i with the exception of dapagliflozin (RR 1.34, 95%CI1.11-1.63).37 Liu et al’s metanalysis did however suggest an increased risk of genital mycotic infections (GMI) with a 6% event rate in SGLT2i users compared to 2% (RR 3.30, 95% CI 2.74 to 3.99).37 The vast majority of the SGLT2i-related GMI are treatable with topical antifungal agents or a single 150 mg oral dose of fluconazole sold over the counter or by prescription, and do not necessitate discontinuation of SGLT2i therapy. Patients can be counselled on how to reduce risk of and monitor for GMI prior to initiating SGLT2i therapy.

Conclusion

SGLT2is have a growing body of high-quality evidence establishing their role as foundational therapy in both T2DM and HF treatment. In particular, there is now evidence for SGLT2i therapy across the broad spectrum of heart failure, including HFrEF, HFpEF, acute decompensated patients, and chronic ambulatory patients. The benefits are significant, including reduced risk of cardiovascular mortality and heart failure hospitalizations, prevention of T2DM, HF, and progressive renal dysfunction, with favourable patient-reported outcomes. SGLT2is are generally safe and well tolerated medication, with the most common adverse effect being a treatable UTI or GMI. T2DM and HF come with significant morbidity, mortality, and cost to the healthcare system. SGLT2i’s provide a substantial opportunity to interrupt the natural history of these important diseases.

Funding

The CJGIM has received a grant from Eli Lilly Inc. to support the publication of a case-based Supplement on SGLT2 Inhibitor Use in General Internal Medicine Practice. The sponsor has relinquished all control over content, authorship or decision-making and will not be involved in any way with the development of content or the peer-review process. The grant is provided without any explicit or implicit understanding to obtain or retain business between Eli Lilly and the CSIM, CJGIM, any institution or professional affiliated with the CSIM, CJGIM, institution or the supplement.

Informed Consent

The authors confirm that consent for submission and publication of this report including images and associated text has been obtained in line with COPE guidance.

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