EMPEROR-Preserved: Empagliflozin in heart failure with preserved or mildly-reduced ejection fraction

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References:

Bottom Line: In patients with symptomatic heart failure with preserved (≥50%; HFpEF) or mildly-reduced (41-49%; HFmrEF) ejection fraction, empagliflozin reduced the risk of HF hospitalization vs placebo (-3.2%) and increased the probability of a clinically important improvement in quality of life (+3.8%), but did not reduce deaths or total hospitalizations at 2.2 years. Empagliflozin increased the risk of symptomatic hypotension (+1.4%), genital fungal infections (+1.5), and UTIs (+1.8%).

Patients (n=5988)

  • 11,583 screened -> 5988 randomized

    • Most common reasons for exclusion:

      • 78% NT-proBNP below inclusion criteria threshold

      • 5% LVEF <40%

      • 4% exclusion criteria based on safety

  • Enrolment 2017-April 2020

  • 23 countries

  • Included: Symptomatic chronic HFpEF or HFmrEF with elevated natriuretic peptide

    • Chronic HF (≥3 months)

    • NYHA 2-4

    • LVEF >40% without any prior LVEF ≤40%

    • NT-proBNP

      • >300 pg/mL if in sinus rhythm

      • >900 pg/mL if in atrial fibrillation

    • Either

      • Structural heart disease (LAE &/or LVH) documented on echo

      • HF hospitalization within past 12 months

  • Key exclusions:

    • SBP <100 mm Hg

    • eGFR <20

    • BMI ≥45

    • SGLT2i contraindication (history of ketoacidosis, allergy/hypersensitivity)

    • “Cardiovascular (CV) disease/treatment that increase the unpredictability of or change the patients’ clinical course independent of HF” (e.g. MI/stroke/TIA/CV surgery in past 90 days; infiltrative cardiomyopathy; heart transplant recipient/wait list; severe valvular disease)

    • “Untreated CV condition that might influence the course of HF/study drug tolerability” (e.g. AF with uncontrolled HR, SBP ≥180 mm Hg)

    • “Significant comorbidity that might influence clinical course” (e.g. pulmonary disease requiring O2, PO steroids or requiring hospitalization; acute/chronic liver disease)

  • Baseline characteristics:

    • Age 72, 45% female, 76% White/14% Asian

    • NYHA 2 (81%), 3 (18%)

    • Mean LVEF 54% (~1/3 each in categories 41-49%, 50-59%, ≥60%)

    • Median NT-proBNP ~950-1000 pg/mL

    • HF hospitalization in last 12 months ~23%

    • Comorbidities: HTN 90-91%, AF 51%, eGFR <60 50%, diabetes 49%

    • Meds: Beta-blocker 86%, ACEI/ARB 79%, ARNI ~2%, MRA 37-38%, digitalis 9-10%

    • SBP 132, HR 70

Intervention: Empagliflozin 10 mg qAM

Comparator: Matching placebo

Outcomes at median 26.2 months (2.2 years)

Efficacy outcomes

Effect on quality of life (using Kansas City Cardiomyopathy Questionnaire [KCCQ]; range 0 [worst] to 100 [best]):

  • More likely to have a clinically-important (≥5/100) improvement in quality of life with empagliflozin vs placebo

    • KCCQ-overall summary score at 1 year: Empagliflozin 49.6% vs placebo 45.8% (+3.8%)

    • Similar effect over time (e.g. difference +4.7% at 3 months vs 3.8% at 12 months)

    • Similar difference if considering clinically-important decline (-4.8% at 1 year) or different cutoffs for improvement (+2.3% for ≥10-point improvement & +3.6% for ≥15-point improvement)

    • Similar difference if considering KCCQ subscores (e.g. +4.6% for KCCQ-total symptoms score [HF symptom burden + frequency] at 1 year)

Cumulative incidence curve for the primary composite outcome showing immediate separation of empagliflozin and placebo curves (suggesting early benefit)

Cumulative incidence curve for the primary composite outcome showing immediate separation of empagliflozin and placebo curves (suggesting early benefit)

Safety outcomes

Effect on biometrics & biomarkers (difference vs placebo):

  • Body weight: -1.3 kg

  • SBP -1.2 mm Hg

  • A1c: -0.2%

  • NT-proBNP: -20 pg/mL

Internal validity: Low risk of bias

  • Computer-generated random sequence using permuted blocks

    • Stratified by geographic region, diabetes status, eGFR <60 or ≥60, & LVEF <50% or ≥50%

  • Allocation concealment by central randomization via interactive response technology

  • Blinding of participants and treating clinicians with matching placebo

  • Blinded outcome adjudication

  • Intention-to-treat analysis

  • 3% loss-to-follow-up for primary outcome, 0.6% for death

Other considerations

Are the results clinically important?

  • Maybe; this will very much depend on individual patient/clinician preferences

    • Overall, likely net clinical benefit based on composite of % who died or had a hospitalization due to any cause

      • HF hospitalizations only accounted for 18% of total hospitalization outcomes in this trial, and therefore the 3.2% absolute reduction in the risk of a first HF hospitalization is diluted in total hospitalizations

      • Neutral effect on all-cause death & inconclusive effect on CV deaths

        • CV death accounted for 55% of deaths (sudden death > HF > other), & non-CV deaths accounted for 45% (infection > malignancy > other)

    • QoL improvement with empagliflozin consistent with results of the PRESERVED-HF trial & effects of SGLT2i on QoL in HFrEF trials

      • Brief summary of PRESERVED-HF:

        • P: 324 patients with NYHA 2-4 HF & LVEF >=45% (mixed HFpEF/HFmrEF) + elevated NT-proBNP/BNP + receiving a diuretic + additional enrichment criteria + eGFR >=20 + SBP >=100

        • I: Dapagliflozin 10 mg daily

        • C: Placebo

        • O: KCCQ-23 @ 3 months

          • Mean +4.5/100 in overall-summary score with dapa

          • Clinically-important improvement: Dapa 45.4% vs placebo 34.9% (+10.5%) at 3 months

How do we apply these results to patient care (generalizability)?

  • Although the study defined “preserved” ejection fraction as >40%, the 2021 universal definition and classification of HF further sub-classify HF as HFmrEF if 41-49% (~1/3 of the study population) & HFpEF if ≥50%

    • Subgroup analysis of the primary outcome comparison based on baseline LVEF suggested attenuation of efficacy with increasing LVEF, with uncertain efficacy with LVEF ≥60%

      • Hazard ratio progressively attenuated from LVEF 41-49% (0.71, 95% CI 0.57-0.88), 50-59% (0.80, 95% CI 0.64-0.99), ≥60% (0.87, 0.69-1.10)

      • Risk of the primary outcome increased with lower LVEF, leading to a greater absolute risk reduction in those with lower baseline LVEF (even if we assume constant 21% relative risk reduction regardless of LVEF)

        • LVEF 41-49%: Risk in placebo group 19.5%, absolute risk reduction 4.1%

        • LVEF 50-59%: Risk in placebo group 16.8%, absolute risk reduction 3.5%

        • LVEF ≥60%: Risk in placebo group 14.9%, absolute risk reduction 3.1%

  • Efficacy on primary outcome (in terms of relative effect) similar in females/males, diabetes/no diabetes, AF/no AF, eGFR <60/≥60, & regardless of race/ethnicity

More to come…

EMPEROR-Reduced: Empagliflozin in patients with heart failure with reduced ejection fraction with or without type 2 diabetes

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Packer M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. NEJM 2020;online

Bottom line:

  • Among patients with symptomatic heart failure with reduced ejection fraction (HFrEF) (with or without type 2 diabetes), empagliflozin reduced the risk of a composite of CV death or HF hospitalization vs placebo (NNT 19) at 1.3 years.

  • These results are consistent with those of the DAPA-HF trial, and together these trials show that SGLT2 inhibitors reduce death from any cause (NNT 59) over 1.3-1.5 years.

  • Empagliflozin increased the risk of genital infections (i.e. yeast infections; NNH 91), which are generally self-limiting or resolve with over-the-counter treatment. Empagliflozin did not increase any other adverse effects in this trial.

Patients (n=3730 randomized from 7220 screened)

  • Inclusion criteria

    • Heart failure (NYHA 2-4) with reduced ejection fraction (≤40% or less)

    • Receiving background guideline-directed medical therapy (GDMT) & cardiac device therapy as indicated

    • Elevated NT-proBNP with threshold dependent on heart rhythm & LVEF

      • Normal sinus rhythm (AF)

        • LVEF ≤30%: ≥600 pg/mL (≥1200 pg/mL)

        • LVEF 31-35%: ≥1000 pg/mL (≥2000 pg/mL)

        • LVEF 36-40%: ≥2500 pg/mL (≥5000 pg/mL)

  • Key exclusion criteria

    • eGFR <20

    • Symptomatic hypotension or SBP <100 mm Hg

    • BMI ≥45

    • Heart transplant recipient, listed for heart transplant, LVAD in situ

    • Infiltrative or accumulation cardiomyopathy, muscular dystrophy, HoCM, or cardiomyopathy with reversible causes (e.g. Takotsubo, tachyarrhythmia-related)

  • Baseline

    • Age 67, 24% female, 70% white & 18% Asian

    • NYHA 2 (75%), 3 (24%), 4 (0.5%)

    • Mean LVEF 27% (~73% ≤30%)

    • Ischemic cardiomyopathy 52%, HF hospitalization in last year 31%, AF 37%, diabetes 50%

    • HFrEF medications: ACEI/ARB 70%, ARNI 19%, BB 95%, MRA 71% (% achieving target doses not described)

    • Devices: ICD 31%, CRT 12%

    • SBP 122, HR 71

Interventions: Empagliflozin vs placebo

  • Intervention: Empagliflozin 10 mg PO once daily (fixed dose)

  • Control: Matching placebo

  • Co-intervention in both groups: Background HFrEF GDMT

Outcomes @ median 16 months

Efficacy

  • Primary outcome (CV death or HF hospitalization): Empagliflozin 19.4% vs placebo 24.7%

    • Hazard ratio (HR) 0.75 (95% confidence interval [CI] 0.65-0.86)

    • NNT 19 over 16 months (or NNT~25/year)

  • Death from any cause: 13.4% vs 14.2% (HR 0.92, 95% CI 0.77-1.10)

  • KCCQ-Clinical Summary Score change at 1 year: +5.8 vs +4.1 (difference 1.7, 95% CI +0.5 to +3.0)

    • KCCQ-CSS is out of 100, minimal clinically important difference ≥5)

  • HF hospitalization: 13.2% vs 18.3% (HR 0.69, 95% CI 0.59-0.81)

  • Composite renal outcome (chronic dialysis, renal transplant, sustained eGFR reduction ≥40%)

  • Mean change in eGFR (mL/min/1.73 m^2)/year: -0.55 vs -2.28, difference 1.73 (1.10-2.37)

  • Quality of life (Kansas City Cardiomyopathy Questionnaire measured at month 3, 8, 12 & end-of-study):

Safety

  • Genital infections: 1.7% vs 0.6% (p=.005)

    • Complicated in 0.3% in both groups

  • No difference:

    • Stopped study drug prematurely: Empagliflozin 16,3% vs placebo 18.0%

    • Symptomatic hypotension: 5.7% vs 5.5%

    • SBP change: -0.7 mm Hg (-1.8 to +0.4)

    • Volume depletion: 10.6% vs 9.9%

    • Ketoacidosis: 0 in both groups

    • UTI: 4.9% vs 4.5%

    • Hypoglyemic event: 1.4% vs 1.5%

    • Lower limb amputation: 0.7% vs 0.5%

Internal validity: Low risk of bias

  • Allocation concealment by use of an interactive-response system (low risk of allocation bias)

  • Blinding of participants & clinicians with use of matching placebo (low risk of performance & detection bias)

  • Use of ITT analysis with 1.1% lost to follow-up (low risk of attrition bias)

Other considerations

  • Practical tip: Empagliflozin is currently available in 10-mg and 25-mg tablets. The 10 mg/d dose used in EMPEROR-Reduced was based on the lack of difference between 10 mg/d and 25 mg/d in the EMPA-REG trial. The 25-mg tablets can be split in half, and the patient can be instructed to take half a 25-mg tablet (=12.5 mg) once a day. This simple intervention would cut the cost of this therapy by half (e.g. reducing the cost to ~$500/year in Canada).

  • Results of a meta-analysis (without systematic review) of the 2 large HFrEF SGLT2i trials, EMPEROR-Reduced & DAPA-HF, showed no heterogeneity in efficacy outcomes between these trials. These replicate findings confirm the efficacy of SGLT2 inhibitors in HFrEF, strongly suggest a class effect, and also show no heterogeneity in the effect on death from any cause.

SGLT2i HF mortality.png

  • Most exclusions at screening were due to patients not meeting the trial’s fairly strct NT-proBNP criteria (n=3314; 74.6% of those excluded)

    • However, this does not impact generalizability, as results are consistent with DAPA-HF, which had more lenient NT-proBNP criteria (>900 if AF/atrial flutter, >400 if HF hospitalization within 1 year, otherwise >600)

DAPA-HF & DEFINE-HF: Dapagliflozin in heart failure with reduced ejection fraction

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McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. NEJM 2019

Bottom line:

  • Among patients with symptomatic heart failure with reduced ejection fraction (HFrEF), the SGTL2 inhibitor dapagliflozin reduced the risk of a composite of CV death, HF hospitalization or urgent visit for HF requiring IV diuretics vs placebo (NNT 21), death (NNT 44) & HF hospitalizations (NNT 28) at 1.5 years in patients with OR WITHOUT diabetes.

  • Dapagliflozin also improves quality of life beyond the clinically important difference as early as 12 weeks (NNT 10-14), without any differences in adverse effects (e.g. hypovolemia, kidney injury, severe hypoglycemia).

Patients (n=4744)

  • From Feb 2017-Aug 2018, 8134 screened -> 4744 randomized

  • Included

    • HF with ejection fraction of 40% or less (HF with reduced ejection fraction [HFrEF])

    • NYHA functional class 2-4

    • NT-proBNP

      • >900 pg/mL if AF/atrial flutter

      • >400 pg/mL if HF hospitalization within 1 year

      • >600 pg/mL if neither of the above

    • +/- type 2 diabetes

    • Stable doses (at least 4 weeks) of standard HF medications (ACEI/ARB/ARNI + beta-blocker as tolerated, + MRA)

  • Key exclusion criteria: Type 1 diabetes, symptomatic hypotension or SBP <95, eGFR <30

  • Baseline (average/proportions)

    • 66 y/o

    • Female 23%

    • White 70%, Asian 24%, Black 5%

    • North America 14%

    • HF characteristics

      • Etiology: Ischemic (56%), non-ischemic (36%), unknown (8%)

      • Prior HF hospitalization 47%

      • NYHA 2 (68%), 3 (32%), 4 (<1%)

      • LVEF 31%

      • NT-proBNP ~1400

    • PMHx: Diabetes 42%, AF 38%

    • Clinical variables: SBP 122, eGFR 66

    • Therapies

      • Diuretic 93%, digitalis 19%

      • ACEI 56%, ARB 27%, ARNI 11%

      • Beta-blocker 96%

      • MRA 71%

      • ICD 26%, CRT 7%

      • Antihyperglycemics (% of those with T2DM): Metformin (51%), sulfonylurea (22%), DPP4i (16%), GLP1RA (1%), insulin (27%)

Intervention & Control

  • Intervention: Dapagliflozin 10 mg daily

    • Dose reduced to 5 mg/d or temporary discontinuation if acute, unexpected decline in eGFR, volume depletion, or hypotension (or to avoid these)

  • Control: Matching placebo

  • Standardized monitoring: Follow-up at 14 days & 60 days (focus on HF/volume assessment, adverse events, & evaluation of renal function & potassium), then q4 months

Outcomes

CV outcomes @ median 18 months

  • Primary outcome (CV death, HF hospitalization, or urgent visit for HF resulting in IV therapy): Dapagliflozin 16.3% vs placebo 21.2%

    • Hazard ratio (HR) 0.74 (95% confidence interval 0.65-0.85); Absolute difference 4.9%, NNT 21

    • CV death: 9.6% vs 11.5%; HR 0.82 (0.69-0.98)

    • HF hospitalization: 9.7% vs 13.4%; HR 0.70 (0.59-0.83)

    • Consistent across subgroups (HR 0.75 for type 2 diabetes, HR 0.73 for those without diabetes)

  • All-cause mortality: Dapagliflozin 11.6% vs placebo 13.9%; HR 0.83 (0.71-0.97)

Quality of life (QoL) @ month 8

  • Measured using Kansas City Cardiomyopathy Questionnaire [KCCQ] total symptom score, range from 0 [worst] to 100 [best], Minimal clinically-important difference is a 5-point improvement/worsening)

  • Mean change: +6.1 vs +3.3 (/100); “win ratio” 1.18 (1.11-1.26)

  • Improvement 5+ points: Dapagliflozin 58.3% vs placebo 50.9%, odds ratio (OR) 1.15 (1.08-1.23)

  • Deterioration 5+ points: Dapagliflozin 25.3% vs placebo 32.9%, OR 0.84 (0.78-0.90)

Safety @ median 18 months (none statistically significant vs placebo)

  • Discontinuation due to adverse events: 4.7% vs 4.9%

  • Volume depletion: 7.5% vs 6.8% (p=0.4); serious in 1.2% vs 1.7%

  • Worsening renal function (sustained eGFR reduction >50%, ESRD [eGFR <15 >28 days], or death from renal disease): 1.2% vs 1.6%

  • Amputations: 0.5% in both groups

  • Fournier’s gangrene: 0 vs <0.1%

  • Bone fractures: 2.1% in both groups

  • Major hypoglycemia: 0.2% in both groups

  • DKA: 0.1% vs 0

Lab changes (difference vs placebo)

  • Weight -0.9 kg, SBP -1.3 mm Hg

  • NT-proBNP -303 pg/mL

  • HbA1c -0.24%

  • SCr +1.8 umol/L

Internal validity: Low risk of allocation, performance, detection & attrition bias

  • Computer-generated randomization, stratified by presence of type 2 diabetes

  • Allocation concealed by interactive voice/web-response system

  • Participants, clinicians unaware of treatment assignment (blinded)

  • Blinded adjudication of outcomes

  • Loss-to-follow-up <0.8%

  • Analysis of the intention-to-treat (ITT) population

Other trial of dapagliflozin in HFrEF: DEFINE-HF (PMID: 31524498)

  • Participants (n=263)

    • Included: HF with LVEF 40% or less, NYHA 2-3, elevated natriuretic peptide (NT-proBNP 400+ pg/mL or BNP 100+ pg/mL), +/- T2DM

    • Excluded: Type 1 diabetes, HF hospitalization within last 30 days, eGFR <30

    • Baseline characteristics:

      • 61 y/o, male 73%, white 55%/black 40%

      • ischemic etiology 53%, prior HF hospitalization ~80%, HF duration 7 years

      • NYHA 2 (70%), 3 (30%), KCCQ overall summary score 67/100

      • LVEF 26%

      • T2DM 62%, AF 40%

      • SBP 123, HR 72, eGFR 65-70, HbA1c ~7%

      • Meds: ACEI/ARB 60%/ARNI 30%, BB 95-100%, MRA 60%, ICD 60%, CRT 20-30%

  • Dapagliflozin 10 mg/d (intervention) vs placebo (control)

  • Outcomes @ 12 weeks:

    • QoL measured using KCCQ overall summary score

      • Mean 3-point improvement with dapagliflozin vs placebo

      • Improvement of 5+ points: Dapagliflozin 43% vs placebo 33% (NNT 10)

      • Difference in KCCQ sub-domains of clinical summary score, total symptom score, physical limitation score & QoL score, but not social limitation score

    • No difference between dapagliflozin vs placebo in:

      • Change in NT-proBNP

      • Any adverse effects

  • Internal validity: Low risk of bias.

DECLARE-TIMI 58 - Dapagliflozin & CV events in type 2 diabetes

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Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. NEJM

Bottom line: In patients with type 2 diabetes with existing ASCVD or with multiple CV risk factors, dapagliflozin did not reduce the risk of a composite of major adverse cardiovascular events; however, it did reduce the risk of HF hospitalizations (NNT 125) at 4.2 years. Dapaglifozin increases the risk of fungal genital infections (NNH 125) & DKA (NNH 500).

Overall assessment of the evidence for SGLT2 inhibitors shows several differences between agents in this class; empagliflozin appears to have the greatest potential for benefit, whereas canagliflozin has the highest potential for harm.

Context: Summaries of EMPA-REG with empagliflozin & CANVAS with canagliflozin

Patients (n=17,160)

  • Included

    • T2DM with HbA1c 6.5%-12.0%

    • + CrCl 60+ mL/min

    • + either

      • Established atherosclerotic cardiovascular disease (ASCVD; IHD, ischemic CVA, PAD) & 40+ y/o

      • Multiple risk factors: Male 55+ y/o or female 60+ y/o + tobacco use, HTN, or LDL >3.3 mmol/L

  • Key exclusion criteria:

    • Adherence <80% during run-in or considered “at risk for poor medication adherence”

    • Previous SGLT2 inhibitor use

    • Steroid use with equivalent of prednisone 10+ mg/d

    • ACS, decompensated HF or stroke within 8 weeks

    • BP >180/100

    • Recurrent UTIs

  • Baseline characteristics:

    • 64 y/o, male (63%), white (80%), North American (32%)

    • ASCVD (41%): CAD (33%), PAD (6%), CVA (8%)

    • HF (10%)

    • Diabetes duration median 11 y,

    • HbA1c median 8.3%

    • BP 135/85

    • eGFR 85 (7% with eGFR <60)

    • Meds

      • Antihyperglycemics: Metformin (82%), sulfonylurea (43%), insulin (41%), DPP-4i (17%), GLP1 agonist (4%)

      • ASA (61%), ACEI/ARB (81%), beta-blocker (53%), statin or ezetimibe (75%), diuretic (41%)

Intervention & control

  • I: Dapagliflozin 10 mg once daily

  • C: Matching placebo

  • Co-interventions: Other antihyperglycemics per standard of care, excluding SGTL2i or glitazones

Results @ median 4.2 years

Efficacy

  • No reduction in major adverse cardiovascular events (composite of CV death, MI or ischemic stroke): Dapagliflozin 8.8% vs placebo 9.4%

    • Hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03

    • CV death: 2.9% in both groups

    • MI: 4.6% vs 5.1% (HR 0.89, 95% CI 0.77-1.01)

    • Ischemic stroke: 2.7% in both groups

  • Reduction in composite of CV death or HF hospitalization: 4.9% vs 5.8%

    • HR 0.83 (95% CI 0.73-0.95)

    • Driven by a reduction in HF hospitalization: 2.5% vs 3.3% (NNT 125, HR 0.73, 95% CI 0.61-0.88)

    • Originally a secondary outcome; switched to co-primary outcome before unblinding of outcomes due to favorable results on this outcome in EMPA-REG & CANVAS.

  • No reduction in death: 6.2% vs 6.6% (HR 0.93, 95% CI 0.82-1.04)

Safety

  • Increased:

    • Diabetic ketoacidosis (DKA): 0.3% vs 0.1% (NNH 500; HR 2.18, 95% CI 1.10-4.30)

    • Genital infection (generally fungal): 0.9% vs 0.1% (NNH 125)

  • Reduced:

    • Serious adverse events: 34.1% vs 36.2% (HR 0.91, 95% CI 0.87-0.96)

  • No difference in

    • D/C due to adverse event: 8.1% vs 6.9% (HR 1.15, 95% CI 1.03-1.28)

    • Amputation: 1.4% vs 1.3%

    • Symptomatic volume depletion: 2.5% vs 2.4%

    • UTI: 1.5% vs 1.6%

Effect on surrogate endpoints:

  • HbA1c -0.4%

  • Wt -1.8 kg

  • SBP/DBP -2.7/-0.7

Internal validity

  • Low risk of allocation, performance, detection & attrition bias

    • Computer-generated block-randomization sequence;

    • Centralized randomization by interactive voice/web response system to blinded kit containing intervention or matching placebo;

    • Low loss-to-follow-up (0.3%);

    • Analyzed by intention-to-treat.

  • Single-blind (patient) placebo run-in phase lasting 4-8 weeks to assess for non-adherence

    • Unclear risk of selection bias: 25,698 entered run-in phase -> 17,160 randomized (i.e. high rate of exclusion during placebo run-in)

Other Evidence

  • A meta-analysis of the 3 major CV outcome trials of SGLT2 inhibitors (CANVAS, DECLARE & EMPA-REG) shows the following overall patterns:

    • CV efficacy

      • Only empagliflozin clearly reduces all-cause & CV mortality (in patients with existing ASCVD, RRR 32%);

      • SGLT2 inhibitors reduce the risk of major adverse CV events (composite of CV death/MI/stroke) in patients with existing ASCVD (RRR 14%), but not in those without ASCVD;

      • SGLT2 inhibitors do not reduce/increase stroke;

      • All SGLT2 inhibitors reduce the risk of HF hospitalization (RRR ~30%), regardless of prior ASCVD or HF.

    • Safety

      • All SGLT2 inhibitors increase the risk of DKA (RR increase by 120%);

      • Only canagliflozin increases the risk of amputations (RR increase 26%) & fractures (RR increase by 11%).