A Clinical Review and Emerging Perspectives in Cardiac Practice

Introduction

Major cardiovascular outcome trials of SodiumGlucose Cotransport-2 (SGLT2) inhibitors have turned out to be game-changers in cardiac practice. SGLT2 inhibitors, a relatively new class of drugs are beneficial in patients with Type 2 diabetes mellitus (T2DM). All of them have been shown to significantly reduce the risks of hospitalisation due to heart failure, and as well as the progression of renal dysfunction and cardio vascular mortality, both collectively and individually.¹ These molecules have been proved to work in patients without diabetes raising the possibility of broadening their usage in clinical practice.² Clinical practice guidelines of many cardiac, and other societies have positioned these molecules favorably in managing the of patients with or without diabetes, heart failure and chronic kidney disease.^3-5 This article provides an overarching brief clinical review and emerging trends in the usage of SGLT2 inhibitors in cardiac practice. 

SGLT2 inhibitors: What are they, and what do they do?

French chemists isolated Phlorizin from the root bark of the apple tree in 1835, and it was used to target SodiumGlucose Cotransport (SGLT). Phlorizin has been used to study glucosuria for over 150 years.⁶ However, because of its rapid degradation in the gastrointestinal tract, its further development was given up despite its ability to increase renal excretion of glucose in dogs.⁷ Later, Phlorizin was discovered to be a non-specific inhibitor of sodium-glucose cotransporter (SGLT) proteins, and since then, several other types of SGLT proteins have been revealed. In humans, so-far six different isoforms of the SGLT family have been described.⁸ Their actions are independent of insulin. Inhibiting these proteins resulted in changes that improved carbohydrate metabolism, making it an appealing concept for diabetes treatment.^9,10,11 Two isoforms of these receptors are clinically relevant at present, SGLT1 and SGLT2. SGLT proteins are overexpressed in the small intestine and the kidney’s proximal tubule.^12,13 Presently, SGLT-1 and SGLT-2 have been well studied owing to their important role in sodium and glucose transport across the brush borders of the gut and renal cells through an ATPasedependent electrochemical gradient.¹⁴

SGLT2 inhibitors: Mechanisms of benefits

Understanding the mechanistic underpinnings of benefits produced by these molecules has been a subject of investigation and debate. It is not without reason, as the decrease in plasma volume is only temporary. An increase in haematocrit, however, was more durable. This was shown with canagliflozin.¹⁵ This, indeed, was also supported by the secondary analysis of EMPAREG. When compared to placebo, changes in hematocrit and haemoglobin were found to account for nearly half of the risk of cardiovascular death for empagliflozin.¹⁶ Biomarkers like urine albumin/creatinine ratio, serum uric acid, fasting plasma glucose, and HbA1C levels were shown to mediate the benefits not only with empagliflozin but also with canagliflozin in reducing the first hospitalization of heart failure events.^17,12 The EMPA-HEART Cardiolink-6 investigators, in a shortterm placebo-controlled trial of empagliflozin recruiting 97 patients of T2DM and coronary artery disease by using magnetic resonance imaging showed a significant reduction in left ventricular mass indexed to body surface area. This beneficial effect could have been due to a reduction of blood pressure. It may, however, be due to several yet to be identified mechanisms.¹⁸ Given the rapid reduction observed in cardiovascular mortality, an antiatherosclerotic effect is regarded as unlikely. Hemodynamic effects, such as decrease in intravascular volume and blood pressure caused by osmotic diuresis, could provide a more reasonable theory. Benefits may also be attributed to metabolic effects such as cardiac fuel energetics and hormonal effects (increased glucagon release).¹⁹ Other potential pathways include favorable alterations in lipid metabolism, inflammation, and endothelial function. However, further investigations are needed especially in large human clinical trials with mechanistic endpoints, to understand them better and importantly, for their optimum use in therapies.²⁰

In a patient, the presence of heart failure carries a poorer prognosis. The patient’s natural history is marked by the repeated need for hospitalizations, urgent visits to the hospitals, increased number of visits to the clinics, poor quality of life, increased expenditure, and DALY (diasbility adjusted life years). Also, it results in increased risks of cardiovascular mortality with progressive heart failure. SGLT2 inhibitors have now emerged as a pillar in the management of heart failure, alongside Renin angiotensin aldosterone system (RAAS) modulators such as angiotensin receptor neprilysin inhibitor (ARNI), beta-blockers, and mineralocorticoid receptor antagonists (MRA).

SGLT2 inhibitors in heart failure with decreased ejection fraction

The SGLT2 inhibitors, as a class, have been demonstrated to reduce the risk of hospitalization for heart failure, CV death, non-fatal myocardial infarction, and non-fatal stroke in randomized controlled clinical trials. Also, they have shown renal benefits. The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose), a randomized trial recruited 7020 patients with T2DM and prior CV events and followed up for a median of 3.1 years to assess the CV safety and efficacy of empagliflozin 10 mg and 25 mg daily compared with placebo added onto standard therapy. Empagliflozin treatment resulted in a 14 percent decrease in the primary endpoint (3-point MACE; a composite of CV death, nonfatal myocardial infarction, and non-fatal stroke) and a 38 percent decrease in CV death. According to actuarial analysis of data from the EMPA-REG OUTCOME trial, empagliflozin increases the rate of survival by 1 - 5 years in patients with T2DM and established CVD.^{21, 22}

In the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial, patients with NYHA class II-IV HF and an LVEF ≤40% were randomized to empagliflozin 10 mg/d or placebo, in addition to standard therapy. Empagliflozin treatment reduced rates of the primary composite outcome of CV death or hospitalization for worsening heart failure (19.4% vs 24.7%; p <0.001).²³ A study trial CANVAS/CANVAS-R (Canagliflozin Cardiovascular Assessment Study) recruited 10,142 patients diagnosed with T2DM and those at high risk of CVD. All the patients were randomly assigned to receive canagliflozin (100-300 mg daily) or standard therapy with a placebo for a median of 3.1 years. The study also found that canagliflozin treatment reduced 3-point Major Adverse Cardiac Events (MACE) by 14%, reduction in hospitalisation due to heart failure by 33%, and renal events by 40% when compared to placebo, indicating that cardiorenal protection is a class effect of SGLT2 inhibitors.²⁴

DAPA HF investigators evaluated the efficacy of Dapagliflozin in a placebo-controlled phase III clinical trial recruiting 4744 patients classified with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less. Dapagliflozin significantly lowered the rate of CV death/Hospitalization for Heart Failure (HHF) versus placebo, but no significant difference was observed in the rate of MACE between groups. Major Adverse Cardiac Events were not lowered to a significant extent with dapagliflozin versus placebo. Lower rate of the composite endpoint of CV death/HF in dapagliflozin receivers contributed to a decreased rate of heart failure hospitalisation with dapagliflozin versus placebo; but nevertheless, the rate of death due to CV was generally comparable. The findings in diabetic patients were similar to those in non-diabetic patients. The incidence of adverse events associated with renal dysfunction, volume depletion, and hypoglycemia was comparable across treatment groups.²⁵

Sotagliflozin is a dual SGLT inhibitor with a 20-fold higher inhibitory activity for SGLT2 than SGLT1. Variations in SGLT2 selectivity versus SGLT1 selectivity of existing agents have been suggested to be related to inconsistency in efficacy and safety characteristics. Recently, two placebo-controlled trials evaluated its efficacy in acute heart failure and chronic renal disease. In SOLOIST-WHF trial, Sotagliflozin was evaluated in a placebo-controlled randomized clinical trial recruiting a total of 1222 patients, and showed the efficacy and safety of initiating the drug before discharge or early after discharge in patients admitted for acute worsening heart failure. In diabetic patients and patients with recent worsening heart failure, Sotagliflozin therapy started before or shortly after discharge resulted in a significantly less number of deaths from cardiovascular causes, hospitalizations, and urgent visits for heart failure than placebo.²⁶ In SCORED trial which focussed on the renal outcomes, Sotagliflozin significantly decreased the primary endpoints of CV deaths, HF hospitalizations, and HF urgent visits. Even in participants with estimated glomerular filtration rates less than 30 mL/min/173m² , there was a decrease in glycated haemoglobin.²⁷

SGLT2 inhibitors in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction has been a difficult entity to treat as several clinical trials have turned out to be negative. Recently, the results of the EMPEROR-Preserved trial were published. Empagliflozin was used in this double-blind trial. 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% were randomly assigned to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. It happens to be the first Phase III trial to meet its primary outcome.²⁸This may be characterized as a win against a formidable foe given the paucity of positive trials of heart failure with preserved left ventricular functions. Future trials like DELIVER with dapagliflozin may further confirm these results.²⁹ Based on the results of these trials, one may consider using SGLT2 inhibitors in heart failure with preserved left ventricular systolic functions.

SGLT2 inhibitors in chronic kidney disease and cardiovascular outcomes

SGLT2 inhibitors were shown to decrease renal function decline in patients with chronic kidney diseases of various etiologies. This has been demonstrated in patients with and without diabetes. The DAPA-CKD trial (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) demonstrated renal and cardiac protection. Dapagliflozin (10 mg once daily) or placebo was given to 4304 people with an estimated glomerular filtration rate (GFR) of 25 to 75 mL per minute per 1.73 m² of body surface area and a urinary albumin-tocreatinine ratio (albumin measured in milligrams and creatinine measured in grams). The key outcome was a 50 percent drop in estimated GFR over time, end-stage kidney disease, or death from renal or cardiovascular causes. The risk of a composite of a sustained decline in estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes in patients with chronic kidney disease, was significantlyreduced by Dapagliflozin regardless of diabetes status.³⁰ The DIAMOND trial found comparable outcomes in non-diabetic patients with chronic kidney disease.³¹ Likewise, empagliflozin and canagliflozin have been shown to be beneficial.^32,33

SGLT2 inhibitors in HF without diabetes

Clinical trials of SGLT2 inhibitors have clearly shown that the benefits of this class of drugs are beyond reducing blood sugar levels. Indeed, it was shown in DAPA-HF trial that irrespective of the absence or presence of diabetes, dapagliflozin was found to be beneficial.²⁵ Other trials also have shown that the results may not be explained by the reduction of blood sugars. This has paved the way for the use of SGLT2 inhibitors in the syndrome of heart failure even without diabetes.

When to initiate SGLT2 inhibitors?

There is always a concern as to when is the best time to initiate SGLT2 inhibitors therapy in a patient who has been diagnosed with acute decompensated heart failure. Till recently, the clinical trials of SGLT2 inhibitors recruited patients with stable heart failure. Clinical experience suggests that heart failure drugs benefit more when started early in proper doses. Potentially, in a patient with acute decompensated heart failure, one may miss using such a drug during follow-up visits in routine busy office practice. Polypharmacy being generally required to optimize the therapy, the importance of timing could be well appreciated. Typically and traditionally, many patients require weeks to months to reach adequate doses of medicines. Good examples are ARNI, betablockers, and others. Such an important and clinical question has been now answered with SGLT2 inhibitors. In a randomized controlled clinical trial, including 1222 patients, SOLOIST-WHF Trial investigators evaluated the efficacy of Sotagliflozin when initiated before or early after discharge. The study reported that in patients with T2DM and recent worsening heart failure, Sotagliflozin therapy started before or shortly after discharge contributed to a significantly lower total number of deaths from hospitalizations, cardiovascular causes, and urgent visits for heart failure than placebo.²⁶

Safety of SGLT2 inhibitors vis-a-vie other drugs for diabetes

A recent systematic review and network meta-analysis reported that SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes in T2DM patients, with some variations in benefits and harms. Individual risk profiles of patients determine absolute benefits, with clear implications for clinical practise.³⁴ Another network meta-analysis found that SGLT-2 inhibitors and GLP-1RA are more effective than DPP-4 inhibitors at lowering the threat of most cardiorenal outcomes. In terms of lowering the chance of HHF and renal events, SGLT-2 inhibitors outperform GLP-1RA. Also, GLP-1RA lowered the risk of nonfatal stroke only. The authors concluded that both SGLT2 inhibitors and GLP-1RA should be the favoured treatment for T2DM and cardiorenal diseases.35 Remogliflozin Etabonate is yet another selective SGLT2 inhibitor that has been approved in India. A recent Phase III trial demonstrated it to be efficacious, safe, and noninferior to other currently available SGLT2 inhibitors.³⁶

Risks and concerns

Weight loss caused by SGLT2 inhibitors may higher the risk of development of sarcopenia in elderly patients.³⁷ There have been reports of diabetic ketoacidosis after starting SGLT2 inhibitors. Ketoacidosis can occur in the absence of hyperglycemia, resulting in euglycemic diabetic ketoacidosis. Patients with T2DM and insulin deficiency should be closely monitored for the development of ketoacidosis.³⁸ In the CANVAS/CANVAS-R trial,³⁹ high risk of lower-extremity amputation and bone fracture was noted in the canagliflozin group, although no significant difference was observed in the degree of amputation or fracture in the CREDENCE trial.⁴⁰ In a recent large systematic review and network metaanalysis, it is reported that there was no difference in the odds of serious hypoglycaemia in a comparison of SGLT-2 inhibitor or GLP-1 receptor agonist treatment with placebo. SGLT-2 inhibitor treatment probably did not increase diabetic ketoacidosis when compared with placebo or each other.³⁴

Risk of urinary infection (UTI)

UTI and symptomatic vulvovaginal adverse events have been reported with all gliflozins, as a class effect. Female patients are more likely to develop genital infection. Cases of Fournier′s gangrene in men have also been linked with the usage of SGLT2 inhibitors.⁴¹ In the recently published meta-analysis, SGLT-2 inhibitors increased genital infection compared with placebo and GLP-1 receptor agonists; though, the effects of treatments on Fournier gangrene were uncertain.³⁴ Nevertheless, the patients have to be counseled regarding hygiene to prevent urogenital infections when a patient is started on these drugs. This approach may help in reducing the risks of infection.

As of now, clinical trials of SGLT2 inhibitors have not been designed to definitively answer the question of which individual patient should be treated with which one of these agents. Six SGLT2 inhibitors with demonstrated cardiovascular benefits, including, empagliflozin, canagliflozin, dapagliflozin, and remogliflozin are available. Sotagliflozin and Ertugliflozin are not available in India as yet. Indeed, for the clinician caring for patients with type 2 diabetes with increased cardiovascular risk, heart failure, or chronic kidney disease, treatment options have become an embarrassment of riches.⁴² The challenge ahead will be to guide the clinicians to the appropriate usage of these agents based on their patient’s individual cardiovascular and kidney risks. Further, a close collaboration between several medical specialties is likely to result in better usage of SGLT2 inhibitors. Awareness of the safety profile of this class of drugs should also result in better selection and counseling of a patient by all who are involved in prescribing these drugs. Indeed, too many good choices and consistent results in reported cardiovascular outcomes trials may suggest a distinct possibility of a class effect of the SGLT2 inhibitors. Studies of longer duration using SGLT2 inhibitors when reported should be watched for, hoping that the consistency that has been shown so far in their short and intermediate studies will continue to remain.

Summary

Treatment with SGLT2 inhibitors benefits patients with cardiac failure with reduced as well as preserved ejection fraction, with or without diabetes. These treatments have been reported to reduce hospitalizations in conditions such as heart failure, cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, progression of renal disease, and total mortality. Conducted as mandated, the cardiovascular outcome studies of this class of drugs have been quite a revelation. More interesting and serendipitously revelaed finding is that they are useful even in patients who do not have diabetes.

Funding

No funding received

Conflicts of interest

None