Table 2.
Analyses of cardiovascular outcome trials (CVOTs) assessing sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) for peripheral artery disease (PAD)
| Trial(s) | References | Study description | Follow-up | Main findings |
|---|---|---|---|---|
| SGLT2i | ||||
| CANVAS & CANVAS-Renal (canagliflozin) | Matthews et al. [32] | Post-hoc analysis of 2 double-blind, randomized trials involving 10,142 patients with T2DM and a history or a high risk of CV disease who received canagliflozin (100 or 300 mg/day orally) vs. matching placebo | Mean of 3.6 years (5.7 in CANVAS and 2.1 years in CANVAS-R) |
Rates of amputations were 6.30 and 3.37 events per 1000 participant-years with canagliflozin vs. placebo (HR 1.97; 95% CI 1.41–2.75) Risk factors for amputation included: history of amputation (HR 16.27; 95% CI 10.65–24.63), history of peripheral vascular disease (HR 2.77; 95% CI 1.93–3.96), and history of neuropathy (HR 1.86; 95% CI 1.35–2.56) |
| CANVAS & CANVAS-Renal & CREDENCE (canagliflozin) | Yi et al. [14] | Post-hoc analysis of 3 double-blind, randomized trials in 14,543 patients with T2DM, of which 3514 had CKD without PAD and 1156 had CKD and PAD, who received canagliflozin (100 or 300 mg/day orally) vs. matching placebo | Median of 2.5 years |
In those with CKD and PAD, canagliflozin reduced risk of MACE (HR 0.62; 95% CI 0.47–0.83), composite of HHF or CV death (HR 0.62; 95% CI 0.46–0.82), and composite of ESKD or doubling of serum creatinine (HR 0.51; 95% CI 0.33–0.79), with no heterogeneity of effect with canagliflozin between patients with and without PAD (pinteraction > 0.20) No increase in serious AEs or lower-limb amputations was observed with canagliflozin in patients with CKD, regardless of PAD status (p = 0.33) |
| CANVAS & CANVAS-Renal & CREDENCE (canagliflozin) | Barraclough et al. [33] | Post-hoc analysis of 3 double-blind, randomized trials in 14,543 patients with T2DM, of whom 3159 (21.7%) had PAD at baseline, who received canagliflozin vs. matching placebo | Median of 2.5 years |
In patients with PAD, canagliflozin reduced MACE (HR 0.76; 95% CI 0.62–0.92), with similar MACE benefits in patients without PAD (HR 0.86; 95% CI 0.76–0.98) No difference in amputation risk by PAD status (pinteraction of 0.31), but there was an overall increased risk of amputation with canagliflozin (HR 1.50; 95% CI 1.19–1.89). This was due to increase seen in CANVAS program |
| CANVAS & CANVAS-Renal & CREDENCE (canagliflozin) | Arnott et al. [34] | Post-hoc analysis of 3 double-blind, randomized trials, involving 10,142 patients with T2DM in CANVAS and 4401 patients with T2DM in CREDENCE, to determine if there was an explanation as to why the effects of canagliflozin on amputation risk vary between CANVAS and CREDENCE | Median follow-up was 2.4 years in CANVAS and 2.5 years in CREDENCE |
There were 133 amputations in CREDENCE and 187 amputations in CANVAS, with prior amputation as strongest predictor of future amputations Effect of canagliflozin on amputation risk was significantly different between CANVAS and CREDENCE (pheterogeneity of 0.02), but this was not explained by participant or trial differences. There was no evidence that foot disease management protocols in CREDENCE ameliorated amputation risk |
| DAPA-HF & DELIVER (dapagliflozin) | Butt et al. [15] | Post hoc analysis of 2 randomized, double-blind trials in 11,005 patients with symptomatic HF, 809 (7.4%) of whom with history of PAD, who received dapagliflozin (10 mg/day orally) vs. matching placebo | Median of 1.8 years |
Dapagliflozin, compared to placebo, reduced risk of worsening HF or CV death to same extent in patients with (HR 0.71; 95% CI 0.54–0.94) and without (HR 0.80; 95% CI 0.73–0.88) PAD, with no interaction between PAD and effect of treatment (pinteraction of 0.39) Amputation rate did not differ between dapagliflozin and placebo in those with (HR 0.87; 95% CI 0.43–1.75) or without PAD (HR 0.87; 95% CI 0.46–1.64) |
| DECLARE-TIMI 58 (dapagliflozin) | Bonaca et al. [35] | Post hoc analysis of a double-blind, randomized trial involving 17,160 patients with T2DM and a history or a high risk of CV disease, including 1025 (6.0%) with a history of symptomatic lower extremity PAD, who received dapagliflozin (10 mg/day orally) vs. matching placebo | Median of 4.2 years |
Patients in placebo arm with PAD vs. those without PAD had a higher adjusted risk of CV death/HHF (HR 1.60; 95% CI 1.21–2.12; p = 0.001), progression of kidney disease (HR 1.51; 95% CI 1.13–2.03; p < 0.01), and limb AEs (HR 8.37; 95% CI 6.45–10.87; p < 0.001) Overall, amputation risk was higher in those with vs. without PAD (5.6% vs. 1.1%; HR 4.47; 95% CI 2.86–7.00; p < 0.001). Predictors of amputation were PAD, longer T2DM duration, male sex, history of HF, higher baseline HbA1c, and non-use of statin and/or ezetimibe Benefit of dapagliflozin on HHF or CV death was consistent regardless of PAD status (PAD: HR 0.86; no PAD: HR 0.82; pinteraction of 0.79). Similarly, benefits for reductions in kidney complications with dapagliflozin vs. placebo were consistent (PAD: HR 0.78; no PAD: HR 0.76; pinteraction of 0.84) No differences between dapagliflozin vs. placebo in limb ischemic AEs (HR 1.07; 95% CI 0.90–1.26; p = 0.45) and amputation (HR 1.09; 95% CI 0.84–1.40; p = 0.53), with no significant interactions by presence of PAD or not (pinteraction of 0.30 and 0.093, respectively) |
| EMPA-REG OUTCOME (empagliflozin) | Verma et al. [16] | Post hoc analysis of a double-blind, randomized trial involving 7020 patients with T2DM and established CV disease, 1461 (20.8%) of whom had PAD at baseline, who received empagliflozin (10 or 25 mg/day orally) vs. placebo | Median of 3.1 years |
In patients with PAD, empagliflozin vs. placebo reduced CV death by 43% (HR 0.57; 95% CI 0.37–0.88), all-cause death by 38% (HR 0.62; 95% CI 0.44–0.88), HHF by 44% (HR 0.56; 95% CI 0.35–0.92), and incident or worsening nephropathy by 46% (HR 0.54; 95% CI 0.41–0.71) In patients with PAD, rate of lower-limb amputations was 5.5% with empagliflozin and 6.3% with placebo (HR 0.84; 95% CI 0.54–1.32). In patients without PAD, rate of lower-limb amputations was 0.9% with empagliflozin and 0.7% with placebo (HR 1.30; 95% CI 0.69–2.4) |
| EMPA-REG OUTCOME (empagliflozin) | Inzucchi et al. [36] | Post hoc analysis of a double-blind, randomized trial in 7,020 patients with T2DM and CV disease, who received empagliflozin vs. placebo, aimed to assess lower-limb amputations in EMPA-REG OUTCOME | Median of 3.1 years | Lower-limb amputations were reported in 131 patients: 88/4,687 patients (1.9%) treated with empagliflozin and 43/2,333 (1.8%) treated with placebo. The incidence rate was 6.5 per 1000 patient-years in both groups. In the analysis of time to first event, the risk of lower-limb amputations was similar between empagliflozin and placebo (HR 1.00; 95% CI 0.70–1.44) |
| VERTIS CV (ertugliflozin) | Cannon et al. [37] | Double-blind, randomized trial in 8,246 patients with T2DM and CV disease, 1,541 (18.7%) of whom had PAD, who received ertugliflozin (5 or 15 mg/day orally) vs. placebo | Median of 3.0 years |
MACE occurred in 653 of 5,493 patients (11.9%) in ertugliflozin group and in 327/2745 patients (11.9%) in placebo group (HR 0.97; 95% CI 0.85–1.11) Amputations were performed in 2.0% of ertugliflozin-treated patients and in 1.6% of patients receiving placebo. Vascular disorders occurred in 2.9% of ertugliflozin-treated patients and in 3.6% of patients receiving placebo |
| SOLOIST-WHF (sotagliflozin*) | Bhatt et al. [38] | Double-blind trial, randomizing 1,222 patients with T2DM and worsening HF to 200 or 400 mg of oral sotagliflozin or placebo once daily | Median of 9.0 months | Amputations were performed in 4/605 patients receiving sotagliflozin (0.7%) and 1/611 receiving placebo (0.2%) |
| SOTA-CKD3 (sotagliflozin*) | Cherney et al. [39] | Double-blind trial, randomizing 787 patients with T2DM and an eGFR of 30–59 ml/min/1.73 m2 to 200 or 400 mg of oral sotagliflozin or placebo once daily | 52 weeks |
MACE occurred in 18/527 patients (3.4%) receiving sotagliflozin and in 9/260 patients (3.5%) receiving placebo Amputations were performed in 3/527 patients (0.6%) receiving sotagliflozin and in 3/260 patients (1.2%) receiving placebo |
| SOTA-CKD4 (sotagliflozin*) | Cherney et al. [40] | Double-blind trial, randomizing 277 patients with T2DM and an eGFR of 15–30 ml/min/1.73 m2 to 200 or 400 mg of oral sotagliflozin or placebo once daily | 52 weeks |
MACE occurred in 7/184 patients (3.8%) receiving sotagliflozin and in 12/93 patients (12.9%) receiving placebo Amputations were performed in 3/184 patients (1.6%) receiving sotagliflozin and in 0/93 patients (0%) receiving placebo |
| GLP-1RA | ||||
| LEADER & SUSTAIN-6 (liraglutide and semaglutide) | Verma et al. [17] | Post hoc analysis of 2 randomized, double-blind trials in patients with T2DM at high CV risk or with CV disease. LEADER included 9,340 patients, 1,184 (12.7%) of whom had PAD, who received SC liraglutide (≤ 1.8 mg/day) vs. placebo. SUSTAIN-6 included 3,297 patients, 460 (14.0%) of whom had PAD, who received SC semaglutide (0.5 or 1.0 mg/week) vs. placebo | Median of 3.8 years in LEADER and 2.1 years in SUSTAIN-6 |
Patients with PAD were at a ~ 35% increased risk of MACE vs. those without PAD (LEADER: HR 1.36; 95% CI 1.17–1.58; p < 0.0001; SUSTAIN-6: HR 1.33; 95% CI 0.94–1.83; p = 0.09) Effects of both therapies on MACE were consistently beneficial in patients with PAD (liraglutide: HR 0.77; 95% CI 0.58–1.01; semaglutide: HR 0.61; 95% CI 0.33–1.13) and without PAD (liraglutide: HR 0.89; 95% CI 0.79–1.00; semaglutide: HR 0.77; 95% CI 0.58–1.01; pinteraction of 0.34 for liraglutide and 0.49 for semaglutide) |
| LEADER (liraglutide) | Dhatariya et al. [41] | Post hoc analysis of a double-blind, randomized trial in 9,340 patients with T2DM at high CV risk, aimed at assessing the impact of SC liraglutide (1.8 mg/day) vs. placebo on the incidence of DFUs and their sequelae | Median of 3.8 years |
Similar rates of patients reported DFUs (176/4668 [3.8%] with liraglutide vs. 191/4,672 [4.1%] with placebo; HR 0.92; 95% CI 0.75–1.13; p = 0.41) Analysis of DFU-related sequelae demonstrated a significant reduction in amputations with liraglutide vs. placebo (HR 0.65; 95% CI 0.45–0.95; p = 0.028). However, there was no difference between treatments in DFU requiring peripheral revascularization (HR 0.87; 95% CI 0.48–1.58; p = 0.64) |
| EXSCEL (exenatide) | Badjatiya et al. [18] | Post hoc analysis of a double-blind, randomized trial involving 14,752 patients with T2DM, 2,800 (19.0%) of whom had documented PAD, who received SC exenatide (2 mg/week) vs. placebo | Median of 3.2 years |
Patients with PAD were less likely to be on a statin (65.8% vs. 75.3%), a β-blocker (45.4% vs. 58.1%), an angiotensin-converting enzyme inhibitor (45.2% vs. 49.5%), or aspirin (57.3% vs. 65.0%) vs. patients without PAD Compared to patients without PAD, those with PAD had higher rates of MACE (13.6% vs. 11.4%; HR 1.13; 95% CI 1.00–1.27; p = 0.047), all-cause mortality (10.0% vs. 6.8%; HR 1.38; 95% CI 1.20–1.60; p < 0.001), and amputations (5.0% vs. 0.9%; HR 5.48; 95% CI 4.16–7.22; p < 0.001) Exenatide and placebo resulted in similar rates of amputations in those with PAD (5.0% with exenatide vs. 4.9% with placebo; HR 0.99; 95% CI 0.71–1.38) and in those without PAD (0.9% in both groups; HR 0.96; 95% CI 0.66–1.41; pinteraction of 0.92). Patients treated with exenatide or placebo also had similar rates of MACE, regardless of PAD status (pinteraction of 0.42) |
AE, adverse event; CANVAS, CANagliflozin cardioVascular Assessment Study; CI, confidence interval; CKD, chronic kidney disease; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; CV, cardiovascular; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; DFU, diabetic foot ulcer; eGFR, estimated glomerular filtration rate; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; ESKD, end-stage kidney disease; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HbA1c, glycated hemoglobin; HF, heart failure; HHF, hospitalization for heart failure; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; MACE, major adverse cardiovascular events; SC, subcutaneous; SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; T2DM, type 2 diabetes mellitus; VERTIS CV, Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes; vs., versus
*Sotagliflozin is a dual inhibitor of SGLT1 and SGLT2