Diabetes is a chronic condition that imposes a significant burden on patients, healthcare, and society. In 2018, 34.2 million US residents, 10.5% of the population, were estimated to have diabetes.¹ The estimated economic burden of diabetes was $327 billion in 2017, including both direct and indirect costs.² The prevalence of diabetes and its associated economic burden are projected to increase in the coming years.³ In 2008, the Food and Drug Administration (FDA) issued guidance which revolutionized non-insulin medication approval⁴ creating a shift from the glucocentric approach of clinical trials to assessing the cardiovascular safety of medications. Subsequently, several medications, including sodium-glucose contransporter-2 inhibitors (SGLT2i), showed surprising cardiometabolic-renal benefits and potential to curtail the pandemic of diabetes-associated complications.

A meta-analysis of six SGLT2i trials supported the evidence that SGLT2i reduces major adverse cardiovascular (CV) events, with the largest benefits in reduction of heart failure (HF) hospitalization and improved kidney outcomes.⁵ Although the mechanisms underlying the effects remain elusive, it is clear that these are unrelated to tighter glycemic control.⁵ Indeed, another meta-analysis of studies assessing dapagliflozin and empagliflozin supported the benefits for HF, renal outcomes, all cause, and cardiovascular death, irrespective of underlying diabetes status.⁶ These benefits were demonstrated in patients with reduced ejection fraction (EF), and it has been theorized that SGLT2i may have similar benefits in HF patients with preserved EF. Applying the CREDENCE (assessing canagliflozin) trial to the US population, a third of US diabetes patients have renal disease that would qualify them for SGLT2i therapy.^7,8

Despite therapeutic potential, uptake of SGLT2i is low, particularly among cardiologists.^9,10 So far, most of the clinical trials included stable HF patients, with macroalbuminuria or eGFR ≥30 mL/min/1.73m². There has been no data to support safety and efficacy of SGLT2i in vulnerable patients with diabetes recovering from acute HF or with broader definition of chronic kidney disease (CKD) including microalbuminuria. Here we review the results of two multicenter trials published at the end of 2020, SOLOIST-WHF and SCORED, that addressed these questions.^11,12 Both trials evaluated sotagliflozin, a novel dual SGLT1 and SGLT2 inhibitor. SGLT2 inhibition increases glucose excretion, while SGLT1i decreases glucose absorption via the digestive tract independent of kidney function.^11-14

SOLOIST-WHF Trial
The SOLOIST-WHF trial was a randomized, placebo-controlled trial that evaluated patients with type-2 diabetes mellitus (T2DM) and acute decompensated HF after attaining clinical stability either before or within 3 days after discharge.¹² Clinical stability was defined as no need for oxygen, intravenous diuretics, or vasodilator, systolic blood pressure of ≥100mg, and transitioning from intravenous to oral diuretic therapy. Exclusion criteria included end-stage HF, recent myocardial infarction (MI)/stroke/ percutaneous coronary intervention (PCI)/ coronary artery bypass graft surgery (CABG), or eGFR <30 mL/min/1.73 m². A total of 1,222 patients (mean age 70 years, 33.7% female) were enrolled and randomized to sotagliflozin (200mg once daily; titrated to 400mg if tolerated) (n=608) or placebo (n=614) with a median follow-up of 9 months. Mean EF was 35%, and background therapy for HF was identical in both arms. Due to the COVID-19 pandemic and loss of funding, the study was stopped prematurely, and the primary endpoint was changed to include composite of deaths from CV causes and hospitalization or urgent care visit for HF.¹²

The results showed a lower rate of primary endpoint events in the sotagliflozin arm (51.0 per 100 patient-years) than the placebo arm (76.3 per 100 patient-years) (Hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.52-0.85, P<0.001).¹² There were significant relative and absolute risk reductions within 28 days after sotagliflozin initiation, with a projected number-needed-to-treat of four over just 1 year of follow-up. These reductions were consistent across multiple pre-specified subgroups, e.g., age, sex, geographical region, renal function, and stratification by EF.¹² For secondary endpoints, the rate of hospitalization and urgent care visits for HF was significantly reduced with sotagliflozin (40.4 per 100 patient-years) versus placebo (63.9 per 100 person-years), but there was no difference in CV mortality.¹² Rate of diarrhea and severe hypoglycemia were higher, and venous thrombotic events were lower with sotagliflozin compared to placebo.¹² No significant differences were noted in volume depletion or acute kidney injury.

SCORED Trial
The SCORED trial was a multicenter, double-blind, placebo-controlled trial which randomized 10,584 patients with T2DM, CKD, and additional CV risk factors to receive sotagliflozin (200mg once daily; titrated to 400mg if tolerated) or placebo.¹¹ Mean age was 69 years; 44.9% were women; mean eGFR was 44.5 mL/min/1.73m²; albuminuria (normal 35%, microalbuminuria 33.9%, macroalbuminuria 31%), and mean EF was 60%. Median follow-up was 16 months. Due to the COVID-19 pandemic, the study was stopped early, and the primary endpoint was changed to the composite of CV deaths and hospitalizations or urgent visits for HF. Primary endpoint was 5.6 events per 100 patient-years in the sotagliflozin arm versus 7.5 events per 100 patient-years in the placebo arm, with a relative risk reduction of 26% between sotagliflozin and placebo (HR 0.74; 95% CI 0.63-0.88; P<0.001).¹¹ The difference was mostly driven by a reduction in hospitalization and urgent care visits for HF (HR 0.67, CI 0.55-0.82; P<0.001). The secondary endpoint, i.e., death from CV cause, was similar in both arms.¹¹

A significant reduction in original primary endpoint of death from CV cause, or non-fatal MI, or non-fatal stroke was also noted (HR 0.84 CI, 0.72 to 0.99; P<0.05).¹¹ The effect of sotagliflozin was consistent regardless of whether left ventricular EF was <50% or preserved, across full range of eGFR down to <30 mL/min/1.73m² with micro- or macroalbuminuria and became evident within 3 months. Results also showed significant reduction in HbA1c across eGFR range, weight loss, lower systolic blood pressure with sotagliflozin,¹¹ and improvement in eGFR.¹¹ Rate of diarrhea, volume depletion, genital mycotic infection, and diabetic ketoacidosis were higher in the sotagliflozin arm, while there was no difference in urinary tract infection, severe hypoglycemia, or amputation between both arms.¹¹

What are the strengths and weaknesses of these trials?
Both trials were multicenter, randomized, double-blind, placebo-controlled trials, and SCORED was large with 10,584 number of participants. Participants had multiple CV risk factors and were on similar guideline-directed medical therapy.^11,12 SOLOIST-WHF enrolled a novel patient population (at discharge or within 3 days of discharge from acute HF) of great importance to practicing cardiologists. However, loss of funding and the COVID-19 pandemic limited participant enrollment and thus statistical power to evaluate all endpoints. Primary and secondary endpoints were changed, and this may have biased the results in favor of sotagliflozin.^11,12

What are the clinical implications of both trials?
Based on the SOLOIST-WHF trial, early sotagliflozin initiation was well tolerated in T2DM patients with acute decompensated HF, and this resulted in reduced cardiovascular death and hospitalizations or urgent visits for HF.¹² In the SCORED trial, which enrolled T2DM patients with CKD across the full range of albuminuria,¹¹ there was a reduction in the same endpoints as SOLOIST-WHF. These benefits could be due to class effect and supports the use of SGLT2i in vulnerable patients with diabetes and CKD, or in the management of HF including around hospital discharge.^11,12 Unlike SGLT2i, SGLT1 inhibition by sotagliflozin provided HbA1c reduction even at lower eGFR range,¹¹ and therefore a drug like sotagliflozin may be valuable for better glycemic control even at lower eGFR. The SCORED trial showed a lower rate of stroke, which suggests that sotagliflozin may possibly favorably affect atherosclerotic CV disease. Better HbA1c control and atherosclerotic benefits could be due to SGLT1 effects; this important hypothesis needs to be validated in larger randomized clinical trials and further investigated from a mechanistic point of view.¹¹

How does this novel dual SGLT-1/2 inhibitor fit in to the current SGLT2 paradigm and what is the future direction of SGLT2 and SGLT1 inhibitors?
Prior SGLT2i trials, including the EMPEROR-Reduced trial of empagliflozin, showed efficacy of SGLT2i on CV outcomes with the key endpoints driven by reduction in HF outcomes.^15,16 However, benefits of SGLT2i on HF were seen in stable, chronic-acute, and chronic outpatients^15,16 but were never tested in patients with acute decompensated HF. The SOLOIST-WHF trial showed that high-risk patients with diabetes hospitalized for acute decompensated HF around discharge can be safely started on SGLT-1/2 inhibitors.¹²

The timing of SOLOIST-WHF in the HF continuum cannot be overemphasized in its clinical importance. HF hospitalization is associated with de-escalation/ discontinuation of guideline-directed medical therapy (GDMT) which leads to increased risk of all-cause mortality,¹⁷ but it is also a sentinel event in initiation and titration of GDMT. Using this transition to start SGLT2 inhibitors will likely increase patient adherence and improve physician awareness to up-titrate GDMT.

The CREDENCE kidney trial (canagliflozin) has shown similar benefits of SGLT2i in reduction of CV events and renal failure.⁸ In CREDENCE, SGLT2i reduced HF events in patients with eGFR >30 mL/min/1.73m², but those with eGFR <30 mL/min/1.73m² were not evaluated.⁸ The SCORED trial has not only shown the benefit of sotagliflozin in patients with eGFR <30 mL/min/1.73m² but also better glycemic control at low eGFR,¹¹ which could be due to SGLT1i, as this was not found in SGLT2i trials. Nonetheless, SGLT inhibitors should be part of the standard care of T2DM patients with HF or CKD.

Perhaps most excitingly, the SOLOIST-WHF and SCORED trials showed beneficial effects of sotagliflozin in HF with preserved EF (HFpEF).^11,12 HFpEF remains one of the most challenging therapeutic conundrums, and any hint of positive trial data is eagerly welcome. However, early ending of the trials, small number of patients (20.9% of the SOLOIST-WHF trial), and large CIs limit the generalizability of data. Further studies are ongoing to confirm the effects of SGLT2i on HFpEF.^11,12

Despite several advantages, sotagliflozin was associated with a higher rate of hypoglycemia, diarrhea, and dehydration which could possibly limit therapy in some individuals. Dual SGLT1/2 inhibitors should be compared to single SGLT2 inhibitors to evaluate CV benefits of dual inhibition.

These are exciting times for SGLT inhibitors, opening new possibilities for patients with HF and CKD. Ongoing trials are studying the effect of SGLT2i in stable chronic HF patients with preserved EF, and additional studies are needed to confirm the potentially game-changing effects in acute decompensated HF of the SOLOIST-WHF trial.

References

1. National Diabetes Statistics Report (cdc.gov). 2020. Available at: https://www.cdc.gov/diabetes/data/statistics-report/index.html. Accessed 01/05/2020.
2. American Diabetes Association. Economic costs of diabetes in the U.S. in 2017. Diabetes Care 2018;41:917-28.
3. Lin J, Thompson TJ, Cheng YJ, et al. Projection of the future diabetes burden in the United States through 2060. Popul Health Metr 2018;16:9.
4. Endocrinologic and metabolic drugs advisory committee meeting (fda.gov). 2018. Available at: www.fda.gov/media/121272/download. Accessed 01/05/2020.
5. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 2020;Oct 7:[Epub ahead of print].
6. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819-29.
7. Aggarwal R, Lu K, Chiu N, Bakris GL, Bhatt DL. U.S. prevalence of individuals with diabetes and chronic kidney disease indicated for SGLT-2 inhibitor therapy. J Am Coll Cardiol 2020;76:2907-10.
8. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-306.
9. Arnold SV, de Lemos JA, Rosenson RS, et al. Use of guideline-recommended risk reduction strategies among patients with diabetes and atherosclerotic cardiovascular disease. Circulation 2019;140:618-20.
10. Vardeny O, Vaduganathan M. Practical guide to prescribing sodium-glucose cotransporter 2 inhibitors for cardiologists. JACC Heart Fail 2019;7:169-72.
11. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129-39.
12. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021:384:117-28.
13. Powell DR, Zambrowicz B, Morrow L, et al. Sotagliflozin decreases postprandial glucose and insulin concentrations by delaying intestinal glucose absorption. J Clin Endocrinol Metab 2020;105:e1235-49.
14. Sands AT, Zambrowicz BP, Rosenstock J, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care 2015;38:1181-88.
15. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.
16. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
17. Srivastava PK, DeVore AD, Hellkamp AS, et al. Heart failure hospitalization and guideline-directed prescribing patterns among heart failure with reduced ejection fraction patients. JACC Heart Fail 2021;9:28-38.

Clinical Topics: Cardiac Surgery, COVID-19 Hub, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery, Cardiac Surgery and Heart Failure, Lipid Metabolism, Acute Heart Failure

Keywords: Diabetes Mellitus, Diabetes Mellitus, Type 2, Metabolic Syndrome, Sodium-Glucose Transporter 2, Albuminuria, Diuretics, Blood Pressure, Pharmaceutical Preparations, Double-Blind Method, Glucose, Patient Discharge, Vasodilator Agents, Numbers Needed To Treat, United States Food and Drug Administration, Confidence Intervals, Pandemics, COVID-19, Cost of Illness, Follow-Up Studies, Percutaneous Coronary Intervention, Stroke Volume, Hypoglycemia, Kidney, Heart Failure, Acute Kidney Injury, Renal Insufficiency, Chronic, Stroke, Myocardial Infarction, Ambulatory Care, Risk Factors, Delivery of Health Care, Gastrointestinal Tract, Coronary Artery Bypass, Reference Standards

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