EMPA-REG Outcome was the first large-scale randomized controlled trial of an SGLT2 inhibitor to demonstrate cardiovascular benefits of this class. It was designed in accordance the PREVAILING United States (US) Food and Drug Administration (FDA) Guidance to Industry concerning evaluation of the cardiovascular safety of new antihyperglycaemic therapies for type 2 diabetes.

In total, 7020 participants with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) were randomized to either empagliflozin (10 or 25 mg) or a placebo once daily. The primary endpoint in this event-driven trial was a composite of 3-point MACE (major adverse cardiovascular events) defined as time to first nonfatal myocardial infraction (MI), stroke, or death from cardiovascular causes. The key secondary outcome was a 4-point MACE (which also included hospitalization for unstable angina). Both the primary and key secondary endpoints were tested for noninferiority first, and then for superiority (if noninferiority was met) in a hierarchical fashion. Cardiovascular death, all-cause death, and hospitalizations for heart failure were exploratory endpoints.

The primary outcome occurred less frequently in participants randomized to empagliflozin (490 of 4687 [10.5%]) than a placebo (282 of 2333 [12.1%]) (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.74– 0.99; P < 0.001 for noninferiority and P =.04 for superiority). The key secondary outcome occurred in 599 of 4687 patients (12.8%) with empagliflozin and 333 of 2333 patients (14.3%) with a placebo (HR, 0.89; 95% CI, 0.78–1.01; P < 0.001 for noninferiority and P =.08 for superiority). The reduction in the primary endpoint of 3-point MACE was driven predominantly by the lower incidence of cardiovascular (CV) death (HR, 0.62; 95% CI, 0.49–0.77; P < 0.001), with no significant difference in the risk of nonfatal MI (4.8% of participants in the empagliflozin group and 5.4% in the placebo group) or stroke (3.5% of participants in the empagliflozin group and 3.0% in the placebo group). The effects of empagliflozin versus placebo were also consistent across the prespecified subgroups of interest.

In addition, empagliflozin also reduced the risk of death from any cause (HR, 0.68; 95% CI, 0.57–0.82, P < 0.001), and hospitalization for heart failure (HR, 0.65; 95% CI, 0.50–0.85; P =.002).

Overall, empagliflozin was well tolerated, and the proportions of participants who experienced adverse events, serious adverse events, and adverse events leading to the discontinuation of the study medication were similar in the empagliflozin and placebo groups.

In subsequent secondary analyses, the favorable effects of empagliflozin on CV death occurred early, with the first statistically significant benefit seen at 59 days postrandomization. The first statistically significant benefit for heart failure hospitalizations was seen at 17 days postrandomization.

The CANVAS Program consisted of two sister trials, CANVAS and CANVAS-R, which collectively randomized 10,142 participants (4330 in CANVAS and 5812 in CANVAS-R) with type 2 diabetes and either established ASCVD or at high risk for ASCVD to either canagliflozin 100 mg (in CANVAS-R with optional up-titration to 300 mg) or placebo once daily. The primary endpoint was 3-point MACE (time to first event of cardiovascular causes, nonfatal MI, or nonfatal stroke). The primary endpoint was tested for noninferiority first and then for superiority (if noninferiority was met) in a hierarchical fashion. Secondary endpoints (tested hierarchically) included all-cause death, CV death, progression of albuminuria, and the composite of CV death and hospitalization for heart failure. Hospitalization for heart failure was an exploratory endpoint.

The primary outcome occurred less frequently among participants randomized to canagliflozin than a placebo (HR, 0.86; 95% CI, 0.75–0.97; P < 0.001 for noninferiority; P =.02 for superiority), with consistent findings observed across multiple demographic and clinical subgroups. Although the point estimates for the secondary endpoints of all-cause and CV death favored canagliflozin, they were not statistically significant (for all-cause death, HR, 0.87; 95% CI, 0.74–1.01; for CV death, HR, 0.87; 95% CI, 0.72–1.06). It was the same case for the individual endpoints of nonfatal MI and nonfatal stroke. The results for the composite endpoint of CV death or hospitalization for heart failure (HF), and hospitalization for HF alone were considered to be exploratory, but canagliflozin reduced the risk of these outcomes (HR, 0.78; 95% CI, 0.67–0.91; and HR, 0.67; 95% CI, 0.52–0.87, respectively).

Overall, canagliflozin was well tolerated, with fewer serious adverse events than placebo (HR, 0.93; 95% CI, 0.87–1.00). However, there was a higher risk of lower limb amputation with canagliflozin than a placebo (HR, 1.97; 95% CI, 1.41–2.75), a signal that was not seen in subsequent trials of canagliflozin or in trials of other SGLT inhibitors.

DECLARE was the largest of the SGLT2 inhibitor safety cardiovascular outcome trial (CVOTs), and randomly assigned 17,160 patients with type 2 diabetes and either established ASCVD (~40%) or multiple risk factors for ASCVD (~60%) to dapagliflozin 10 mg or a placebo daily. This event-driven trial had one primary safety endpoint of 3-point MACE (time to first event of CV death, nonfatal MI, or nonfatal stroke), tested for noninferiority. There were also two dual primary efficacy endpoints: 3-point MACE and a composite of CV death or hospitalization for HF. Secondary endpoints included a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 mL per minute per 1.73 m ² , end-stage renal disease, or death from renal or CV causes) and death from any cause.

In the analysis of the primary safety endpoint (3-point MACE), dapagliflozin was noninferior to a placebo (upper boundary of the 95% CI, <1.3; P < 0.001). In the analyses of the dual primary efficacy endpoints, dapagliflozin did not reduce 3-point MACE (HR, 0.93; 95% CI, 0.84–1.03; P =.17), but did lower the risk of CV death or hospitalization for HF (HR, 0.83; 95% CI, 0.73–0.95; P =.005), which was driven by a lower rate of hospitalizations for HF (HR, 0.73; 95% CI, 0.61–0.88), with no between-group difference in CV death (HR, 0.98; 95% CI, 0.82–1.17). No significant reductions were seen with dapagliflozin versus placebo in nonfatal MI, nonfatal stroke, or all-cause death (HR, 0.93; 95% CI, 0.82–1.04). The beneficial effects of dapagliflozin on CV death or hospitalization for HF were consistent across multiple subgroups, including among patients with established ASCVD and those with multiple ASCVD risk factors ( P value for interaction was.99).

Similar to other CVOTs of SGLT2 inhibitors, dapagliflozin was well tolerated, with fewer serious adverse events than a placebo. There were more genital mycotic infections observed with dapagliflozin versus a placebo. Although diabetic ketoacidosis occurred rarely, more dapagliflozin than placebo-treated patients experienced such events (0.3% vs. 0.1%; HR, 2.18; 95% CI, 1.10–4.30; P =.02).

In the VERTIS-CV trial, a total of 8246 participants with type 2 diabetes and established ASCVD were randomly assigned to either ertugliflozin (at the dose of 5 or 15 mg) or a placebo daily. The primary safety endpoint in this event-driven trial was a composite of 3-point MACE (time to first nonfatal MI, stroke, or death from CV causes). Secondary efficacy endpoints, tested hierarchically, included a composite of CV death or hospitalization for HF; CV death; and a composite of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level.

Ertugliflozin was noninferior as compared with a placebo for the primary safety endpoint; 11.9% of participants in the ertugliflozin group and 11.9% in the placebo group experienced a composite of 3-point MACE (HR, 0.97; 95% CI, 0.85–1.11; P < 0.001 for noninferiority). There were no between-group differences in any of the confirmatory secondary endpoints, including occurrence of CV death or hospitalization for HF (HR, 0.88; 95% CI, 0.75–1.03; P =.11 for superiority, or CV death (HR, 0.92; 95% CI, 0.77–1.11). The rates of hospitalizations for HF were lower with ertugliflozin than a placebo (HR, 0.70; 95% CI, 0.54–0.90), although this endpoint was not tested hierarchically and therefore is considered exploratory.

The incidence of serious adverse events and all adverse events were similar between ertugliflozin and placebo, although more urinary tract infections and genital mycotic infections were observed in the ertugliflozin- versus placebo-treated participants.

SCORED was the cardiovascular outcome trial of sotagliflozin, which offers both SGLT1 and SGLT2 inhibition. Unlike other CVOTs of SGLT2 inhibitors, it was designed to primarily test superiority (rather than noninferiority) of sotagliflozin versus placebo.

The event-driven trial randomly assigned 10,584 participants with type 2 diabetes and CKD, as well as ASCVD risk factors to either sotagliflozin (200 mg, up-titrated to 400 mg) or a placebo daily. The primary endpoint (revised during the trial) was the composite of the total number of CV deaths, and HF events (hospitalizations or urgent visits for HF). The final secondary endpoints (following the protocol amendment) included the total number of HF events; CV death; total number of CV deaths, hospitalizations for HF, nonfatal MI, and nonfatal stroke; the total number of CV deaths, and expanded definition of HF events; time to first kidney endpoint (sustained decrease of at least 50% in the eGFR, long-term dialysis, renal transplantation, or a sustained eGFR of less than 15 mL per minute per 1.73 m ² ); all-cause deaths; and the total number of CV deaths, nonfatal MIs, and nonfatal strokes.

The trial ended early owing to loss of funding. This resulted in the protocol amendment, which included the change in the primary and secondary endpoints (as listed above); in addition, planned adjudication of endpoints was not completed, and investigator-reported events were used instead for all efficacy analyses.

Sotagliflozin reduced the risk of the primary efficacy endpoint (total number of CV deaths and HF events) by 26% (HR, 0.74; 95% CI, 0.63–0.88; P < 0.001). Sotagliflozin also reduced the risk of total HF events (HR, 0.67; 95% CI, 0.55–0.82; P < 0.001). There was no significant between-group difference in CV death (HR, 0.90; 95% CI, 0.73–1.12) or all-cause death (HR, 0.99; 95% CI, 0.83–1.18). Although considered exploratory, the analyses of time to first CV death or HF event (HR, 0.77; 95% CI, 0.66–0.91), and time to first event of 3-point MACE (HR, 0.84; 95% CI, 0.72–0.99) were favorable for sotagliflozin versus a placebo. Interestingly, and in contrast to the trials of pure SGLT2 inhibitors, the exploratory endpoints of time to first MI and time to first stroke were also favorable for sotagliflozin versus a placebo, potentially reflecting its different mechanism of action (which also includes SGLT1 inhibition).

Overall, sotagliflozin was well tolerated, with similar rates of adverse events and serious adverse events as compared with placebo. The rates of diarrhea (likely as a result of SGLT1 inhibition), genital mycotic infections, diabetic ketoacidosis (which occurred rarely), and volume depletion were higher with sotagliflozin than placebo.

A number of meta-analyses of SGLT2 inhibitor CVOTs among participants with type 2 diabetes have been conducted, including by several trialist groups. These studies have confirmed, using very large sample sizes, that SGLT inhibitors modestly reduce the risk of ASCVD events, such as 3-point MACE (by ~10%), with a much larger (>20%) reduction in the risk of CV death or HF hospitalizations, and a very large, more than 30%, reduction in HF hospitalizations ( Fig. 12.1 ).

Effects of SGLT2 inhibitors on MACE (A), CV mortality (B), and hospitalization for heart failure (C). CI , Confidence interval; CV , cardiovascular; MACE , major adverse cardiovascular events; SGLT2 , sodium-glucose cotransporter-2.

Cumulative data from five large CV outcomes trials involving SGLT2 inhibitors in high-risk people with type 2 diabetes (EMPA-REG OUTCOME [empagliflozin], CANVAS program [canagliflozin], DECLARE-TIMI 58 [dapagliflozin], CREDENCE [canagliflozin], and VERTIS CV [ertugliflozin]). The overall relative risk reductions were 10% for MACE, 15% for CV mortality, and a more robust 32% for HF. There was a significant variability across the trials for the first two outcomes but greater consistency for the HF outcome.

From McGuire DK, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis, JAMA Cardiol . 2021;6(2):148–158.

DAPA-HF was the first trial to report the effects of SGLT2 inhibitors in patients with established HFrEF. In this multicenter, randomized, international, event-driven trial, 4744 participants with symptomatic HFrEF (left ventricular ejection fraction of 40% or less) and elevated natriuretic peptides were assigned to dapagliflozin 10 mg or a placebo daily. The primary endpoint was a composite of time to first CV death or worsening HF event (hospitalizations or urgent visit due to HF).

Dapagliflozin significantly reduced the risk of the primary efficacy endpoint, which occurred in 16.3% of participants in the dapagliflozin group and 21.2% in the placebo group (HR, 0.74, 95% CI, 0.65–0.85; P < 0.001). Importantly, dapagliflozin significantly improved each of the components of the primary composite endpoint, including worsening HF events (HR, 0.70; 95% CI, 0.59–0.83) and CV death (HR, 0.82; 95% CI, 0.69–0.98). Dapagliflozin also reduced all-cause death (HR, 0.83; 95% CI, 0.71–0.97). The benefits of dapagliflozin were consistent across multiple subgroups, including among patients both with and without diabetes. Dapagliflozin also significantly improved HF-related symptoms as measured by the Kansas City Cardiomyopathy Questionnaire –Total Symptom Score (KCCQ-TSS). Dapagliflozin was well tolerated, with fewer serious adverse events than placebo.

Subsequent secondary analyses demonstrated that the benefits of dapagliflozin emerged within 2 weeks of randomization, were highly consistent regardless of baseline guideline-directed medical therapy for HFrEF, and regardless of baseline HbA1c. In addition, dapagliflozin also significantly reduced the risk of sudden death and serious ventricular arrhythmias.

In the EMPEROR-REDUCED, an international, multicenter, event-driven trial, a total of 3730 participants with symptomatic HFrEF (left ventricular ejection fraction of 40% or less) and elevated natriuretic peptides were randomized to either empagliflozin 10 mg or a placebo daily. The primary endpoint was time to first event of CV death or hospitalization for HF.

The results were overall consistent with those of DAPA-HF. Empagliflozin significantly reduced the risk of the primary efficacy endpoint (19.4% participants in the empagliflozin group versus 24.7% in the placebo group; HR, 0.75; 95% CI, 0.65–0.86; P < 0.001); this was consistent across multiple subgroups, including patients with and without diabetes. Empagliflozin also reduced the total number of HF (HR, 0.70; 95% CI, 0.58–0.85; P < 0.001). The point estimates for CV death and all-cause death were favorable for empagliflozin versus placebo, but did not reach statistical significance. Empagliflozin also had a favorable effect on the kansas city cardiomyopathy questionnaire (KCCQ), and was well tolerated.

Subsequent meta-analysis of the DAPA-HF and EMPEROR-REDUCED trials confirmed large benefits of SGLT2 inhibitors on CV death or hospitalizations for HF, as well as CV death and all-cause mortality, independent of diabetes status.

EMPEROR-PRESERVED was the first large, international multicenter, event-driven trial to test the effects of SGLT2 inhibitors in patients with HFmrEF and HFpEF, a group that now represents the majority of patients with HF but until recently had no disease-modifying treatments available.

In the EMPEROR-PRESERVED trial, 5988 participants with symptomatic HFmrEF/HFpEF (ejection fraction higher than 40%) and elevated natriuretic peptides were randomized to empagliflozin 10 mg or placebo daily. The primary endpoint was the same as in EMPEROR-REDUCED, time to first CV death or hospitalization for HF.

Fewer empagliflozin- versus placebo-treated participants experienced the primary endpoint (13.8% vs 17.1%, HR, 0.79; 95% CI, 0.69–0.90; P < 0.001). This was driven predominantly by lower risk of HF hospitalizations (HR, 0.71; 95% CI, 0.60–0.83), with no significant reduction in CV death (HR, 0.91; 95% CI, 0.76–1.09), or all-cause death (HR; 1.00, 95% CI, 0.87–1.15). Similar to the SGLT2 inhibitor trials in patients with HFrEF, the effects were consistent in participants with and without diabetes. Subsequent analyses demonstrated that the effects of empagliflozin on the primary endpoint occurred early, with the first statistically significant benefit observed at 18 days postrandomization. Empagliflozin was well tolerated, with fewer serious adverse events than with a placebo.

DELIVER was the largest trial of SGLT2 inhibitors in patients with HFmrEF/HFpEF. Overall, 6263 participants with symptomatic HFmrEF/HFpEF (left ventricular ejection fraction of greater than 40%) and elevated natriuretic peptides were randomized to dapagliflozin 10 mg or a placebo daily. The primary endpoint was the same as in DAPA-HF: time to first event of CV death or worsening HF (hospitalization or urgent visit due to HF).

Fewer patients experienced the primary endpoint with dapagliflozin than placebo (16.4% vs 19.5%, HR, 0.82; 95% CI, 0.73–0.92; P < 0.001). This was driven predominantly by fewer events of worsening HF with dapagliflozin versus placebo (HR, 0.79; 95% CI, 0.69–0.91), with no significant reduction in CV death (HR, 0.88; 95% CI, 0.74–1.05). There was no significant reduction in all-cause death (HR, 0.94; 95% CI, 0.83–1.07). Dapagliflozin improved HF-related symptoms as measured by KCCQ-TSS, and was well tolerated.

The benefits of dapagliflozin on the primary efficacy endpoint were consistent across multiple subgroups, including those with mildly reduced, preserved and completely normal ejection fraction, those with and without diabetes, participants randomized in the hospital versus ambulatory setting, and participants who had HF with improved ejection fraction (who were excluded from most other HFmrEF/HFpEF trials).

Subsequent meta-analysis of the EMPEROR-PRESERVED and DELIVER trials confirmed large benefits of SGLT2 inhibitors on reducing the risk of CV death and HF hospitalizations, driven primarily by the large reduction in HF hospitalizations (30% relative risk reduction), with a modest beneficial effect on CV death (12% relative risk reduction) ( Fig. 12.2 ).

Effects of SGLT2 inhibitors on CV mortality or hospitalization for heart failure from four dedicated HF trials using the SGLT2 inhibitors, dapagliflozin or empagliflozin. CI , Confidence interval; CV , cardiovascular; SGLT2 , sodium-glucose cotransporter-2.

Cumulative data from five large heart failure ( HF ) outcomes trials involving SGLT inhibitors in people with HF. The HF with reduced ejection fraction (HFrEF; < 40%) trials were DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin). The HF with preserved ejection fraction (HFpEF; > 50%) trials also included those with mildly reduced ejection fraction (HFmrEF; 41%–49%) and were EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin). One study, SOLOIST, enrolled hospitalized HF patients, not distinguishing by ejection fraction and tested the effects of a combined SGLT-1 and SGLT-2 inhibitor, sotagliflozin. The overall relative risk reduction in the primary outcomes from these trials (CV mortality or HF hospitalization) was 25% for the two HFrEF trials, 20% for the two HFpEF/HFmrEF trials, and 23% overall, with notable consistency across the five studies.

From Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet . 2022;400(10354):757–767. Erratum in Lancet . 2023;401(10371):104.

Pooled analyses both from the DAPA-HF/DELIVER and the EMPEROR Program demonstrated that the beneficial effects of dapagliflozin and empagliflozin are consistent across the entire range of left ventricular ejection fraction.

SOLOIST was the HF outcome trial of sotagliflozin, which offers both SGLT1 and SGLT2 inhibition. Unlike other HF outcome trials, it focused on participants with type 2 diabetes, and those either hospitalized or within few days of discharge after an episode of worsening HF; it also included participants with HF regardless of left ventricular ejection fraction. The primary endpoint (following a protocol amendment) was the total number of CV deaths and hospitalizations and urgent visits for HF. A total of 1222 participants were randomized to sotagliflozin 200 mg (titrated to 400 mg) or a placebo daily

The trial ended early owing to loss of funding. This resulted in the protocol amendment, which included the change in the primary and secondary endpoints (as listed above); in addition, planned adjudication of endpoints was not completed and investigator-reported events were used instead for all efficacy analyses.

Sotagliflozin significantly reduced the risk of the primary endpoint as compared with a placebo (HR, 0.67; 95% CI, 0.52–0.85; P < 0.001). This was driven predominantly by a large reduction in HF events, with no significant difference in CV death. The benefits of sotagliflozin were consistent across multiple subgroups, including across the range of left ventricular ejection fraction.

In the EMPULSE multicenter, international trial, 530 patients hospitalized with acute HF (regardless of ejection fraction, both with de novo or worsening of chronic HF) were randomized to empagliflozin 10 mg or placebo daily. The primary endpoint was “total clinical benefit,” defined as a hierarchical composite of death from any cause, number of HF events and time to first HF event, or a 5-point or greater difference in change from baseline in the KCCQ-TSS at 90 days, assessed with a win ratio.

Empagliflozin resulted in more participants experiencing the clinical benefit versus placebo (win ratio 1.36; 95% CI, 1.09–1.68; P =.0054). This benefit was consistent across both acute de novo and decompensated chronic HF, and regardless of ejection fraction. Importantly, empagliflozin was well tolerated in this acute setting, with fewer serious adverse events than a placebo (32.3% vs. 43.6%, respectively).

Several dedicated multicenter, randomized controlled trials focused on the outcomes of HF-related symptoms and function. In the DEFINE-HF (HFrEF) and PRESERVED-HF (HFmrEF and HFpEF) trials which enrolled participants across multiple centers in the United States, dapagliflozin was demonstrated to significantly improve HF-related health status as measured by KCCQ. Dapagliflozin also significantly improved 6-minute walking distance in patients with HFmrEF/HFpEF, but not those with HFrEF.

The DETERMINE trial showed improved HF-related health status in participants with HFrEF, but not HFpEF with dapagliflozin versus placebo, whereas the EMPERIAL trials of empagliflozin did not demonstrate significant improvements in KCCQ in participants with either HFrEF or HFpEF. Neither trial program showed significant improvements with SGLT2 inhibitors versus a placebo in the 6-minute walking distance. The likely explanation between these results versus more favorable effects of dapagliflozin in the DEFINE-HF and PRESERVED-HF trials is the considerably greater burden of HF symptoms and physical limitations at baseline in these latter studies.

The first trial to demonstrate a clear beneficial effect on adverse renal outcomes was EMPA-REG OUTCOME. As noted previously, this trial randomized 7020 patients with type 2 diabetes and established CV disease and estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m ² to the SGLT2 inhibitor empagliflozin or a placebo. It was designed, per regulatory mandate, as a CV outcome trial, primarily to assess long-term CV safety of the medication. The primary outcome and related secondary CV outcomes have already been described. Incident or worsening nephropathy and incident albuminuria were the prespecified renal outcomes. The former was defined as a progression to persistent macroalbuminuria, the doubling of the serum creatinine concentration (with an estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 kg/m ² ) of body surface area; the initiation of renal replacement therapy (dialysis, transplantation); or death from renal disease. Relevant baseline characteristics included a mean age of 63 years, 28% were females, and mean eGFR 72 mL/min/1.73 kg/m ² ; 24% of participants had an eGFR <60 mL/min/1.73 kg/m ² ; and 33% had urine albumin:creatinine ratio > 30 mg/g. Over a mean follow-up of 3.1 years, the main renal outcome occurred in 12.7% of the empagliflozin group versus 18.8% in the placebo group (HR, 0.61; 95% CI, 0.53, 0.70; P < 0.001), yielding a 39% relative risk reduction. As for individual components of the renal composite outcome, risk of the progression to macroalbuminuria was reduced by 38% (11.2% vs. 16.2%), the risk of doubling of serum creatinine was decreased by 44% (1.5% vs. 2.6%; P < 0.001) and the risk of initiating renal replacement therapy was 55% lower (0.3% vs. 0.6%; P =.04), all in favor of empagliflozin. Although the number of events was relatively small, the investigators also reported significant reductions with empagliflozin on the “harder” kidney outcome of doubling of serum creatinine, initiation of renal replacement therapy, or renal death (i.e., removing macroalbuminuria from the composite; HR, 0.54; 95% CI, 0.40, 0.75; P < 0.001).

These results were consistent across a variety of prespecified subgroups including age, sex, race/ethnicity, baseline eGFR (<45, 45–<60, 60–<90, and > 90 mL/min/1.73 kg/m ² ), baseline albuminuria status (<30, > 30 mg/g Cr), and prevalent use of renin-angiotensin system blockers like ACE inhibitors or ARBs. The investigators also reported an initial “dip” in eGFR in the active therapy group with subsequent stabilization versus a slow reduction over time in the placebo patients. By the end of the trial, eGFR was actually lower in the placebo than in the empagliflozin group.

There have been multiple follow-up studies focusing on the kidney from this key trial. For example, the cardiovascular benefits from empagliflozin (reductions in MACE, CV death, and HF hospitalization) were similar in those with or without baseline CKD. Further exploration into the initial eGFR “dip” has also been conducted. Risk factors for a larger initial dip included diuretic use and more advanced CKD (i.e., higher kidney disease: improving global outcomes (KDIGO) risk category) at baseline. Both the beneficial CV and kidney effects and safety parameters with empagliflozin were consistent across subgroups based on these predictive factors, suggesting that the initial decrease in eGFR is not a clinical concern. In a post hoc analysis, the short-term reduction in urinary albumin-to-creatinine ratio was actually found to be significantly associated with a decreased risk of CV and renal outcomes, so it may portend ultimate benefit. Finally, as has been shown with the SGLT2 inhibitor’s CV benefits, the impact on kidney outcomes appeared to be independent of the drug’s effects to lower HbA1c.

The positive effects of SGLT2 inhibitors on the kidney were subsequently confirmed by the CANVAS program, which combined data from two trials: CANVAS and CANVAS-R. The former enrolled patients with type 2 diabetes and either CV disease (about two-thirds) or at high CV risk (about one-third). In all 10,142 were enrolled and followed for a mean of 3.5 years. The primary CV outcome has been discussed earlier. A secondary renal outcome was the composite of a sustained 40% reduction in eGFR, renal replacement therapy, or death due to renal causes. The mean age of participants in the trial was 63.3 years, with a mean duration of diabetes of 13.5 years, and 36% were females. At baseline, the mean eGFR was 77 mL/min/1.73 kg/m ² and 30% had at least microalbuminuria. The risk for the renal outcome was reduced by 40% with canagliflozin versus a placebo (5.54 vs. 9.01 events per 1000 patient-years; HR, 0.60; 95% CI, 0.47–0.77). Regression of albuminuria was more likely to occur in the canagliflozin group (HR, 1.70; 95% CI, 1.51–1.91). As with EMPA-REG OUTCOME, subgroup analyses in CANVAS also found no significant heterogeneity of the canagliflozin kidney benefit across multiple baseline features, including eGFR and albuminuric category.

In DECLARE, the SGLT2i dapagliflozin was studied in a somewhat lower-risk population of patients comprising a total of 17,160 individuals with type 2 diabetes, in which about 60% did not have any known underlying atherosclerotic cardiovascular disease. Follow-up in DECLARE was 4.2 years, longer than in either of the other two trials. A prespecified renal outcome consisted of at least 40% in eGFR to <60 mL/min/1.73 kg/m ² , end-stage renal disease (defined as dialysis or kidney transplantation), or confirmed sustained eGFR <15 mL/min/1.73 kg/m ² or renal death. At baseline, the mean age was 64 years, duration of diabetes 10.5 years, with 37% females, and mean eGFR higher than in the prior two studies at 85 mL/min/1.73 kg/m. The renal outcome occurred in 3.7% in the dapagliflozin group and in 7.0% in the placebo group, yielding a 46% relative reduction (HR, 0.53; 95% CI, 0.43, 0.66; P < 0.0001). The risk of end-stage renal disease or renal death was reduced by 59% in the dapagliflozin group (0.1% vs. 0·3% with a placebo; HR, 0.41; 95% CI, 0.20, 0.82; P =.012). As with both EMPA-REG OUTCOME and CANVAS, the kidney benefit was shared across multiple baseline risk groups.

The generally healthier population and higher mean eGFR in DECLARE allowed the investigators to determine if dapagliflozin could prevent new CKD from developing. Those in the lowest KDIGO risk group randomized to dapagliflozin indeed experienced a 46% reduction in their risk of developing the kidney-specific outcome (HR, 0.54; 95% CI, 0.38, 0.77) versus a placebo. Moreover, those participants with baseline eGFR >60 mL/min/1.73 kg/m ² randomized to the dapagliflozin group were at 44% reduced risk for a >57% decline in eGFR (HR, 0.52; 95% CI, 0.30, 0.91).

The VERTIS CV trial, testing the CV safety/efficacy of ertugliflozin proved neutral for major adverse CV events. The prespecified renal outcome (doubling of serum creatinine, renal dialysis or kidney transplantations, or renal death) was nonsignificantly reduced by active therapy (HR, 0.81; 95% CI, 0.63, 1.04). In a reanalysis of the data, however, using the more standard 40% reduction in eGFR in lieu of doubling in creatinine, the data appeared more similar to other SGLT2 inhibitor trials, however (6.0 vs. 9.0 events per 1000 patient-years; HR, 0.66; 95% CI, 0.50, 0.88).