A Call for a New Paradigm for Diabetes Care in the Era of Sodium–Glucose Cotransporter 2 Inhibitors (SGLT2i)

Approximately 12% of US adults have type 2 diabetes (T2DM). Persons with T2DM commonly have comorbid conditions and are at high risk for micro- and macrovascular complications. Results from several large clinical trials (Table 1) of patients with T2DM who are treated with sodium–glucose cotransporter 2 inhibitors (SGLT2i) have generated intense interest because this class of medications provides benefits beyond glucose control such as a reduction in cardiovascular events and a slower progression of kidney disease in patients with T2DM [1‐5].

Since 2008, the US Food and Drug Administration (FDA) has mandated that new drugs for T2DM demonstrate cardiovascular safety and noninferiority to placebo treatment. In 2015, the first cardiovascular outcome trial with an SGLT2i, empagliflozin, unexpectedly revealed that treatment with empagliflozin was superior to placebo in the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes-Removing Excess Glucose [1], Table 1). Specifically, patients with T2DM treated with empagliflozin had a 14% decreased risk of major adverse clinical events (MACE) including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death compared to those on placebo [1]. In 2017, patients with T2DM treated with canagliflozin also had a similar 14% reduction in MACE in CANVAS (Canagliflozin Cardiovascular Assessment Study) [2]. Outcome trials of dapagliflozin [5] and ertugliflozin [6] showed noninferiority, though not superiority, in MACE when compared to placebo (Table 1).

While initial trials of SGLT2i were needed to demonstrate cardiovascular safety, two recent SGLT2i trials were conducted to evaluate benefits of SGLT2i in patients with diabetic kidney disease [4] and history of heart failure [3]. The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial was the first study dedicated to the evaluation of kidney outcomes in a population with T2DM and albuminuric diabetic kidney disease (urine albumin-to-creatinine ratio, UACR, > 300 mg/g) [4]. Kidney outcomes included progression to end-stage kidney disease (dialysis, transplantation, or a sustained estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m²), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. The trial was stopped early owing to benefit and showed that treatment with canagliflozin reduced kidney outcomes by 30% compared to placebo. In addition, CREDENCE confirmed cardiovascular benefits seen in CANVAS [2] and showed a 20% reduction in MACE in patients treated with canagliflozin versus placebo [2]. These results are particularly striking when considering that the benefit of canagliflozin was apparent in patients on maximally tolerated dose of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB). On the basis of these results, the FDA approved a new indication for canagliflozin for the treatment of diabetic kidney disease in September 2019, marking the first drug since ACEi and ARBs to demonstrate renoprotective benefits in patients with diabetic kidney disease.

The DAPA-CKD (Dapagliflozin And Prevention of Adverse outcomes in CKD) study is the second trial dedicated to kidney-disease-related outcomes in patients with chronic kidney disease (eGFR 25–75 mL/min/1.73 m² and UACR ≥ 200 mg/g) and in those with and without T2DM [7]. Like CREDENCE [4], the primary outcome includes a composite kidney outcome (≥ 50% sustained decline in eGFR, end-stage kidney disease) or renal or cardiovascular death. The DAPA-CKD trial terminated early in March 2020 for benefits in the dapagliflozin group; however, full results have not been released. The EMPA-KIDNEY (The Study of Heart and Kidney Protection with Empagliflozin) study is ongoing and evaluates the effects of empagliflozin for patients with chronic kidney disease (eGFR 20–45 or 45–90 mL/min/1.73 m² with UACR ≥ 200 mg/g) on composite kidney outcomes (end-stage kidney disease, sustained decline in eGFR < 10 mL/min/1.73 m², sustained decline of ≥ 40% in eGFR from randomization) or renal or cardiovascular death.

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial was the first SGLT2i study to enroll participants with reduced ejection fraction ≤ 40% with and without T2DM [3]. The DAPA-HF cohort included 42% of subjects with baseline T2DM; the results showed that dapagliflozin reduced a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death by 26%. This trial not only demonstrated benefits of SGLT2i for heart failure and cardiovascular death but importantly it showed similar efficacy for individuals with and without T2DM. In addition, SGLT2i showed cardiac benefits for patients who were already on standard therapy for heart failure which included ACEi/ARBs or sacubitril–valsartan, beta-blockers, and mineralocorticoid receptor antagonists. Ongoing trials that are evaluating primary heart failure outcomes include dapagliflozin in patients with preserved ejection fraction (DELIVER) and empagliflozin in patients with reduced (ejection fraction ≤ 40%) and preserved ejection fraction (EMPEROR-Reduced and EMPEROR-Preserved, respectively).

Several mechanisms have been proposed to underlie the cardiovascular and renal benefits of SGLT2i. Foremost, SGLT2i inhibit renal reabsorption of glucose, as well as sodium, in the proximal renal tubules, leading to glycosuria and natriuresis [8]. These direct effects of SGLT2i explain the decrease in serum glucose, weight, and blood pressure in patients who are treated with SGLT2i. In addition, SGLT2i also have indirect hemodynamic and metabolic effects. Inhibition of proximal sodium reabsorption leads to increased delivery of sodium to the macula densa, which stimulates tubulo-glomerular feedback and afferent arterial vasoconstriction, and reduces glomerular hyperfiltration [9]. This cascade is thought to play a major role in the renoprotective effects of SGLT2i. SGLT2i also alter the insulin to glucagon ratio and increase hepatic ketone production which are believed to be efficient fuel sources for cardiomyocytes [10] and may mediate the cardiac benefits of SGLT2i. Lastly, SGLT2i may also inhibit sodium–hydrogen exchangers in the heart, which may protect against sodium overload in a failing cardiomyocyte and improve calcium availability in the mitochondria, which are needed for energy generation [11].

We now have compelling evidence to start SGLT2i in patients with T2DM and kidney disease or heart failure. In the 2020 Standards of Medical Care in Diabetes [12], the American Diabetes Association (ADA) recommends SGLT2i for patients with T2DM and chronic kidney disease (defined as an eGFR 30–60 mL/min/1.73 m² or UACR > 30 mg/g, particularly > 300 mg/g) on the basis of findings from the CREDENCE study [4]. Additionally, the ADA recommends SGLT2i for patients with heart failure (particularly, left ventricular ejection fraction < 45%) on the basis of findings from DAPA-HF [3]. Finally, the ADA recommends treatment of patients with an SGLT2i regardless of baseline hemoglobin A1c or individualized A1c target to reduce diabetic kidney disease progression, hospitalization for heart failure, MACE, and/or cardiovascular death. The ADA continues to recommend SGLT2i after metformin and lifestyle changes regardless of comorbidities, although the European Society of Cardiology suggests SGLT2i as first-line treatment for those with or those at high or very high risk for atherosclerotic cardiovascular disease [13]. High risk for atherosclerotic cardiovascular disease is defined as duration of diabetes for at least 10 years with any other risk factor (age, hypertension, dyslipidemia, smoking, or obesity). Very high risk is defined as three or more risk factors or organ damage (proteinuria, eGFR < 30 mL/min/1.73 m², left ventricular hypertrophy, or retinopathy).

How do we implement these new recommendations to patients with T2DM? The pleiotropic benefits of SGLT2i presents a happy conundrum for providers who care for patients with T2DM with multiple comorbid conditions. Some patients with T2DM may see several care specialists, including endocrinologists, nephrologists, and cardiologists, but a majority of these patients may only see their primary care physician. We believe any provider caring for a patient with T2DM should consider prescribing an SGLT2i, but these medications do require careful monitoring for adverse effects by both the patient and provider. SGLT2i have been associated with significant risk for genital mycotic infections, particularly in women with previous episodes of genital infections and uncircumcised men. In addition, although rare, SGLT2i have been associated with increased risk for necrotizing fasciitis of the perineum or Fournier’s gangrene. SGLT2i also increase risk for hypoglycemia in patients on concurrent sulfonylureas and insulin and pose risk for diabetic ketoacidosis during stress (e.g., perioperative setting or intercurrent illness with reduced food and fluid intake and reduced insulin doses). Providers should also be aware that SGLT2i treatment can lead to an acute fall in eGFR that is similar to that observed with initiation of ACEi and ARB. However, this limited fall in eGFR in the short term is not a side effect, per se, but instead reflects a decrease in hyperfiltration that will ultimately slow progression of kidney disease in the long term. Finally, canagliflozin may increase the risk for amputations on the basis of findings in CANVAS [2] but not in CREDENCE [4]. Thus, providers cannot casually initiate SGLT2i without discussing risks, monitoring for complications, or adjusting medications.

Although team-based or patient-centered care is not a new concept, it is an unfamiliar approach in the new era of diabetes care with the SGLT2i. We now have an intervention that improves the metabolic profile, reduces cardiovascular outcomes, and delays the progression of kidney failure for patients with T2DM and diabetic kidney disease. In our health care systems, we need to empower all clinical care groups to consider therapy with an SGLT2i, if indicated, rather than wait or defer a decision to start SGLT2i to one of the other specialists or primary care physician.

Real-world evidence demonstrates that SGLT2i are currently underutilized for eligible patients [14, 15] and that the decision to start SGLT2i is typically deferred to the endocrinologist [15]. Thus, we propose a new decision framework, CKD-PCP (Fig. 1), that encourages each provider to focus on the key area of interest yet ensures that the metabolic profile, cardiovascular and kidney outcomes are comprehensively addressed. CKD-PCP thus has dual meaning: it applies to providers who most often care for patients with T2DM (Cardiologists, Kidney specialists, Diabetologists, and Primary Care Physicians) and it refers to the benefits of SGLT2i (treatment of Cardiovascular disease, Kidney disease, Diabetes, and reduction of blood Pressure, Calories, and Plasma volume).

Without head-to-head comparisons between the four commercially available SGLT2i, the selection of a particular agent in this class remains at the discretion of the provider. Data is currently available for the benefits of SGLT2i in patients with T2DM and kidney disease (canagliflozin) or patients without diabetes and heart failure (dapagliflozin). We now await the full results DAPA-CKD to understand how dapagliflozin benefits the kidney function of patients with and without T2DM.