2.2.2.1

Sodium-Glucose Co-transporter 2 inhibitors in type 2 diabetes mellitus

Results from the seminal EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose) demonstrated reductions in a composite cardiovascular outcomes (myocardial infarction, stroke, and cardiovascular death), cardiovascular death, all-cause death, renal outcomes, and heart failure hospitalizations in patients with type 2 diabetes mellitus and known atherosclerotic cardiovascular disease (ASCVD). Additional SGLT2i clinical trials confirmed the cardiovascular benefits in patients with diabetes. [ , ] A meta-analysis of these large cardiovascular outcome trials evaluated the effects of empagliflozin, canagliflozin, and dapagliflozin in over 34,000 patients with type 2 diabetes and demonstrated a 23% reduction in the composite outcome of cardiovascular death or hospitalization for heart failure (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.71–0.84; p < 0.0001), and a 31% reduction in hospitalization for heart failure (HR 0.69; 95% CI 0.61–0.79; p < 0.0001). These robust benefits were seen regardless of the presence or absence of cardiovascular disease or history of heart failure, but with baseline renal function conferring the strongest predictor of cardiovascular benefit. [ , ] The cardiovascular effects of the fourth SGLT2i, ertugliflozin, appear to be less impressive compared to the rest of the class. The results of subgroup analyses suggest possibly enhanced reductions in hospitalization for heart failure with or without cardiovascular death among patients with more advanced renal disease. [ , ]

2.2.2.2

Sodium-Glucose co-transporter 2 inhibitors in heart failure

The magnitude and consistency of heart failure benefit seen in patients with type 2 diabetes mellitus led to investigations of SGLT2i therapy in patients with HFrEF, regardless of the presence or absence of diabetes. The first heart failure trial, the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), was a phase III placebo-controlled trial conducted in 4744 patients with New York Heart Association (NYHA) class II, III, or IV HFrEF and elevated pro-B-type natriuretic peptide (NT-proBNP) who were randomized to dapagliflozin 10 mg daily or placebo added to background GDMT. The second heart failure trial, EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction), studied a similar population of 3370 patients who were randomized to empagliflozin 10 mg daily or placebo. Though there were modest differences between patient characteristics in the DAPA-HF and EMPEROR-Reduced trials – left ventricular ejection fraction (27% vs 31%), NT-proBNP (1428 pg/mL vs 1887 pg/mL), and ARNI use (11% vs 20%), both trials demonstrated significantly reduced heart failure hospitalizations and improved quality of life measures, with an acceptable safety profile. In addition, the DAPA-HF trial demonstrated reductions in cardiovascular death and the EMPEROR-Reduced trial showed improved renal outcomes. A meta-analysis of data from the DAPA-HF and EMPEROR-Reduced trials demonstrated consistently favorable outcomes and safety across a broad spectrum of HFrEF severity. Pooled results from these two trials demonstrated significant reductions in cardiovascular death or first hospitalization for heart failure: 26% relative risk reduction (RRR), (HR 0.74; 95% CI 0.68–0.82; p < 0.0001), cardiovascular death: 14% RRR, (HR 0.86; 95% CI 0.76–0.98; p = 0.027), first hospitalization for heart failure: 31% RRR, (HR 0.69; 95% CI 0.62–0.78), all-cause mortality: 13% RRR, (HR 0.87; 95%CI 0.77–0.98; p = 0.018), and a composite renal outcome (chronic dialysis, renal transplantation, or a ≥ 50% sustained reduction of eGFR): 38% RRR, (HR 0.62; 95% CI 0.43–0.90). Additionally, SGLT2i use produced significant increases in quality of life measures. [ , ] It is important to note that these cardio-renal benefits occurred despite high utilization rates of standard GDMT (~92% treated with ACEI/ARB/ARNI, ~95% with a β-blocker, and ~71% with a MRA), and were maintained regardless of background HFrEF GDMT (including ARNI use) or achieved GDMT target doses (≥50% or <50%). Finally, reductions in adverse clinical outcomes were discernible within weeks of SGLT2i initiation, which is very relevant for clinical care as patients with HFrEF have a high risk for 30-day readmissions and short survival once diagnosed.

The combined results from pivotal cardiovascular outcome trials demonstrate a progressive decline in all-cause mortality with the addition of each successive evidence-based pharmacotherapy. The estimated 2 year mortality is reduced from a baseline of 35% to 10% with 4-class GDMT consisting of ANRI, β-blocker, MRA, and SGLT2i ( Fig. 1 ). It is plausible that the addition of SGLT2i to GDMT will reduce disease progression and extend longevity across a broader spectrum of patients with HFrEF in real-world applications. A decision analytic model estimated that of the 3.1 million patients with HFrEF living in the United States, 69% (2.1 million) would be eligible for SGLT2i therapy that may prevent over 34,000 deaths annually, if optimally implemented. Estimates of the lifetime effect of conventional “dual” drug therapy (β-blocker and ACEI or ARB) as compared to comprehensive “quintuple” drug therapy (β-blocker, ARNI [ARB and neprilysin inhibitor], MRA, and SGLT2i) suggest a 62% additional reduction in cardiovascular death or hospitalization for heart failure (HR 0.38; 95% CI 0.30–0.47) and 47% reduction in all-cause mortality (HR 0.53; 95% CI 0.40–0.70) with the latter. This translates into an additional 2.7–8.3 and 1.4–6.3 extra years (depending on age of therapy start) free from cardiovascular death or hospitalization for heart failure and survival, respectively. Thus, a rapidly growing body of evidence strongly supports the addition of SGLT2i to the armamentarium of GDMT, establishing SGLT2i as the 5th pillar of proven HFrEF pharmacotherapies and a key component of the recent suggestion that comprehensive therapy with a combination of β-blocker, ACEi / ARB, neprilysin inhibitor, MRA, and SGLT2i is the new standard of care for patients with HFrEF ( Fig. 2 – Central Illustration ).

Relative risk reduction and sequential reduction in all-cause mortality with evidence-based heart failure pharmacotherapy compared to placebo .

Note. Adapted from Bassi NS, et al. JAMA Cardiol. 2020;5(8):948–951

ARNI, angiotensin receptor–neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose co-transporter 2 inhibitor.

The five pillars of HFrEF Pharmacotherapy .

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker; MRA, mineralocorticoid receptor antagonist; NI, neprilysin inhibitor; SGLT2i, sodium-glucose co-transporter 2 inhibitor.

2.2.2.3

Sodium-Glucose co-transporter 2 inhibitors in kidney disease

Another important clinical finding from clinical trials of SGLT2i therapy, and one that may impart heart failure benefit, is renal protection. This is significant due to the complex interplay between the triad of heart failure, chronic kidney disease (CKD), and type 2 diabetes mellitus. Up to 50% of heart failure patients have type 2 diabetes mellitus and/or CKD, with each condition independently increasing the risk for hospitalization and/or death and predisposing to medication toxicities as the conditions approach end-stage disease. [ , ] A meta-analysis of data from the large cardiovascular outcome trials evaluating empagliflozin, canagliflozin, and dapagliflozin demonstrated a significant 45% reduction in progression of a composite of renal disease outcomes (worsening renal function, end-stage renal disease [ESRD], or renal death), (HR 0.55; 95% CI 0.48–0.64; p < 0.0001). The renal protective effects were further demonstrated in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, which showed a 30% RRR ( p = 0.00001) in the composite outcome of ESRD, doubling of serum creatinine, or death from renal or cardiovascular causes in high risk patients with type 2 diabetes mellitus and advanced CKD. Taking the renal benefits a step further, the results of the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial established dapagliflozin as an efficacious agent in patients with CKD regardless of the presence or absence of diabetes, down to an eGFR of 25 ml/min at enrollment. Dapagliflozin reduced the composite outcome of a sustained decline in eGFR ≥50%, ESRD, or death from renal or cardiovascular causes by 39% (HR 0.61; 95% CI 0.51–0.72; p < 0.001). Both the CREDENCE and DAPA-CKD trials were prematurely stopped for overwhelming benefit, as recommended by the data and safety monitoring committee. Also, in both trials, SGLT2i use was associated with ~30% RRR in the composite endpoint of cardiovascular death or hospitalization for heart failure, despite a low prevalence (<15%) of heart failure at baseline. This indicated that heart failure benefit occurs even among very high risk patients with advanced CKD, a comorbidity commonly associated with HFrEF.

2.2.2.4

Mechanisms of cardiorenal benefit from sodium-glucose co-transporter 2 inhibitors

Significant work has previously been published that investigated the mechanisms by which SGLT2i exert heart failure benefit. Though more work is needed to fully elucidate these mechanisms, several salient hypotheses have been proposed that include improvement in conventional cardiovascular risk factors (hyperglycemia, dyslipidemia, hypertension, and elevated body mass index [BMI]), improvement in hemodynamics, natriuretic effects, reduced cardiac and renal remodeling, inhibition of hormone dysregulation, use of more efficient metabolic substrates, ion channel inhibition, anti-inflammatory effects, and anti-oxidant effects.

2.2.2.5

Sodium-Glucose co-transporter 2 inhibitors side effect profile & monitoring parameters

The SGLT2i’s are generally a well-tolerated class of medications but a brief discussion of relevant side effects and monitoring parameters is warranted. In the DAPA-HF trial, there were no discernable differences in side effects between the dapagliflozin and placebo groups. In the EMPEROR-Reduced trial, the only reported difference in side effects was a higher rate of genital tract infection in the empagliflozin group compared to placebo. Infection risk has been the most common side effect reported in large cardiovascular outcome trials, predominantly genital mycotic infections (candida vaginitis in females [< 5–10%] and balanitis in males [< 2–4%]). These are generally mild in nature, resolve quickly, and uncommonly recur. If treatment is required, usually topical antifungals are sufficient, though oral fluconazole may be needed in more severe cases. Proper counseling is paramount and should focus on daily hygienic measures such as rinsing or wiping after voiding and before bed to ensure no urinary glucose is left in contact with the skin or undergarments. For patients with a history of severe or recurrent mycotic infections, SGLT2i may not be the most appropriate treatment option, since these individuals have a higher incidence of mycotic infections during SGLT2i therapy (> 20% in females and > 10% in males). Urinary tract infections have been reported, but have not been shown to occur at a higher rate as compared to placebo within the large cardiovascular outcome trials. Patients who are prone to have frequent UTIs can have severe ascending urinary tract infections. Case reports of a rare, rapidly progressive life-threatening form of necrotizing fasciitis in the perineal area, called Fournier gangrene, lead to an FDA label update for SGLT2i in 2018. The causal association with SGLT2i use is contentious, but given the serious nature of this infection, patients should promptly notify a healthcare professional about any symptoms of tenderness, redness, or swelling in the genital and/or perineal area.

Pertinent to patients with HFrEF are the hemodynamic effects of SGLT2i, which include both blood pressure lowering and volume depletion. These agents can lower systolic and diastolic blood pressure by an average of ~4–6 and ~1–2 mmHg, respectively. There is also a mild diuretic effect associated with SGLT2i use, resulting in 24-hour urine volumes increasing by ~300 mL/day and an initial reduction in eGFR of ~3–5 ml/min, occurring over the first few weeks, but then followed by stabilization and ultimately improvement over time compared to placebo. [ , ] Initially, concern for acute kidney injury (AKI) with SGLT2i use was raised, prompting an FDA warning, but the results of a meta-analysis have reassuringly shown a consistent 25% lower risk of AKI ( p < 0.0001) among SGLT2i users compared to placebo. In addition, SGLT2i use has been shown to be safe and efficacious in individuals with baseline eGFR as low as 25 ml/min.

The hemodynamic effects of SGLT2i may be more pronounced in patients who are elderly, have more severe hyperglycemia, are taking higher doses of SGLT2i, are treated with loop diuretics, or have more severe renal impairment. Among HFrEF patients on GDMT consisting of multiple antihypertensives and diuretics, particularly in the setting of low blood pressure with fluctuating renal function, vigilant monitoring for signs and symptoms of hypotension and volume depletion is required. In some cases, to pre-emptively avoid adverse effects related to hypotension and volume depletion, initiating SGLT2i at a lower dose (i.e. dapagliflozin 5 mg daily instead of 10 mg daily) or instituting dose reductions of loop diuretics and other antihypertensive medications may be advisable. Counseling patients to record daily weights and blood pressures, maintain appropriate hydration, and undergo periodic assessment of renal function is also advised.

Although SGLT2i do not directly induce hypoglycemia, due to their insulin-independent mechanism of action with reduced glucosuria with lower blood glucose levels (ceasing somewhere ~40–80 mg/dL), the risk of hypoglycemia is increased primarily in combination with insulin or insulin secretagogues. However, dose adjustments for insulin or insulin secretagogues are not routinely recommended when initiating SGLT2i owing to the increased risk for diabetic ketoacidosis (DKA). Among patients with well controlled HgbA1c levels at baseline, or known history of frequent hypoglycemic events, a dose reduction or discontinuation of insulin or insulin secretagogues is prudent. DKA in patients taking SGLT2i typically occurs at normal or modest blood glucose elevation and is exceedingly rare, possibly restricted to patients with occult type 1 diabetes or maturity onset diabetes of the young (MODY). The risk of DKA is heightened in patients with type 1 diabetes mellitus, substantially reduced endogenous insulin secretion, a history of DKA, excessive alcohol use, illicit drug use, or in those hospitalized, acutely ill, or with reduced food/water intake. Patients should be counseled to monitor for early symptoms and signs of ketoacidosis and to discontinue SGLT2i use and seek immediate medical attention should these occur. [ , ] Prevention of DKA entails avoiding the risk factors noted above, as well as discontinuing SGLT2i at least 3 days before intentional fasting or a planned surgery.

Lower limb amputations are rare side effects that were seen only with canagliflozin use in the CANVAS trial, prompting an FDA black box warning in 2017 that was later rescinded in August 2020. Though the causality of the association between SGLT2i and amputation remains ambiguous, caution is suggested in those who may be at increased risk due to a history of prior amputation, peripheral vascular disease, severe peripheral neuropathy, and those with diabetic foot ulcers or infections. In addition, preventive foot care with patient daily self-examinations and provider assessment (visual and monofilament) should be routinely practiced.

Although additional investigation is required to fully elucidate the mechanisms mediating SGLT2i benefits and adverse effects, early evidence indicates several off-target effects, including inhibition of the sodium-hydrogen exchanger (NHE), as plausible explanations for the wide-range of effects exhibited among this drug class.

2.2.2.6

Sodium-Glucose co-transporter 2 inhibitors regulatory & guideline updates

Three of the four SGLT2i medications currently on the market (empagliflozin, canagliflozin, and dapagliflozin) have FDA-labeled indications to reduce the risk of cardiovascular complications but only one (dapagliflozin) is approved to reduce cardiovascular death and hospitalization for heart failure in patients with HFrEF. However, it is expected that empagliflozin will also receive an FDA indication for HFrEF following the results from the recently published EMPEROR-Reduced trial. In addition, guidelines from several major professional societies recommend the use of SGLT2i to reduce the risk for heart failure complications in patients with type 2 diabetes, [ , , ] as well as in nondiabetic patients with HFrEF.

2.2.2.7

Place in therapy for sodium-glucose co-transporter 2 inhibitors

Based on the totality of the evidence, SGLT2i are highly recommended therapies in patients who are at high risk of or with established cardiovascular disease. Within the diabetes treatment paradigm, metformin is still the preferred initial therapy, with SGLT2i or glucagon-like peptide-1 receptor agonists (GLP-1 RA) recommended as next add-on therapies in patients with ASCVD, high risk of ASCVD, heart failure, or established kidney disease, independent of HgbA1C level. [ , ] Specifically for patients with heart failure or risk of heart failure, SGLT2i represent one of the most efficacious treatments for prevention of disease development. Among patients with concurrent HFrEF and diabetes, SGLT2i are the only agents documented to reduce heart failure-related outcomes. As a result, SGLT2i use should be preferentially utilized to reduce the burden of heart failure and its associated complications.

Among patient with HFrEF, SGLT2i therapy is recommended in symptomatic patients established on maximally tolerated doses of, or with documented intolerances to, GDMT consisting of ACEI or ARB, or ARNI and β-blocker, and MRA. Though SGLT2i therapy is a welcome addition to GDMT, several lingering clinical questions exist.

Do patients need to be on target doses of guideline-directed medical therapy prior to initiating sodium-glucose co-transporter 2 inhibitors?

To garner the full benefit of HFrEF based-therapies, every effort should be made to achieve target doses, but in the real-world setting this is not always feasible due to dose-related side effects. Thus, achievement of maximally tolerated doses of background GDMT is not a prerequisite prior to the addition of SGLT2i given data to suggest cardiovascular benefit regardless of achievement of GDMT target doses.

Should mineralocorticoid receptor antagonists be added prior to use of sodium-glucose co-transporter 2 inhibitors?

Baseline use of MRA in the DAPA-HF and EMPEROR-Reduced trials was >70% due to inclusion criteria requiring or encouraging use of MRA. A recent subanalysis of the EMPEROR-Reduced trials demonstrated use of MRA did not influence heart failure or renal outcomes. However, the trial did suggest that the addition SGLT2i promoted improved MRA adherence, an important finding in the high risk heart failure population and another proposed benefit of SGLT2i initiation. Since MRA are associated with significant reductions in clinical endpoints (comparable to or greater than results from SGLT2i), as well as high clinician familiarity, good patient tolerability, and low cost, it seems prudent to recommend use of MRA in patients with heart failure prior to use of SGLT2i, when clinically feasible. However, if intolerances preclude MRA use, SGLT2i are an acceptable alternative. Scenarios most likely to favor SGLT2i use in lieu of MRA include adverse events such as hyperkalemia or gynecomastia. Additionally, MRA lack the renal benefit displayed by SGLT2i, thus if the clinician identifies a patient at high risk for renal complications, SGLT2i may be a more appropriate agent.

Should angiotensin receptor–neprilysin inhibitor be added prior to use of sodium-glucose co-transporter 2 inhibitors?

Baseline use of ARNI in the DAPA-HF and EMPEROR-Reduced trials were <20% with inclusion criteria requiring some form of inhibitor of the renin-angiotensin system (ACEI, ARB, or ARNI) but not ARNI specifically. As ARNI and SGLT2i are associated with similar improvements in heart failure, mortality and quality of life outcomes, and are both expensive branded medications, clinician choice and patient preference (side effect profile, once daily versus twice daily dosing) may play a larger role in therapy delineation between these two agents. Another factor to consider is renal function. Though both agents display an attenuation in renal deterioration, SGLT2i appear to display a more pronounced effect and significantly reduce hard renal endpoints such as progression to ESRD and renal death. If the decision is made to circumvent MRA and/or ARNI for SGLT2i therapy, it is reassuring that the cardio-renal benefits from SGLT2i were achieved regardless of background HFrEF GDMT. Additionally, both therapies have been shown to be cost-effective in patients with HFrEF and display comparable value to one another. [ , ]