STEP-HFpEF: Semaglutide in patients with HF & ejection fraction >=45% & obesity, with or without diabetes

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Pooled analysis of STEP-HFpEF & STEP-HFpEF DM. Lancet 2024

STEP-HFpEF main paper. NEJM 2023;389:1069-84.

STEP-HFpEF DM main paper. NEJM 2024;390:1394-407.

Bottom line: In patients with symptomatic HF, ejection fraction >=45% & BMI >=30, semaglutide improved quality of life & reduced weight (average ~11% weight loss at 1 year), but increased the risk of discontinuation due to GI intolerance. For every 100 patients treated for 1 year, 12 patients will get a noticeable improvement in their quality of life because of semaglutide, & 8 patients will discontinue it due to intolerable side-effects (mostly gastrointestinal).

Patients (n=1145 randomized)

  • 13 countries, 2021-2022

  • Included:

    • Age >=18 years

    • Symptomatic (NYHA 2-4) HF with left ventricular ejection fraction >=45%

    • At least one of the following:

      • Elevated LV filling pressures;

      • Elevated BNP/NTproBNP plus echocardiographic abnormalities;

      • HF hospitalization in the last 12 months, plus ongoing treatment with diuretics OR echo abnormalities

    • BMI >=30

    • Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score (CSS) <90/100

    • 6-minute walk distance (6MWD) >=100 meters

    • STEP-HFpEF excluded patients with diabetes (prior dx, A1c >=6.5% at screening), whereas STEP-HFpEF DM required types 2 diabetes & A1c <=10%

  • Key exclusions:

    • ESRD or dialysis dependence

  • Baseline:

    • Age 70 y, male ~50%

    • White 90%, Black 4%

    • LVEF median 57% (45-49% in 16%)

    • NYHA 2 (69%), 3 (31%)

    • KCCQ-CSS median 59/100, 6MWD median 295 meters

    • HF hospitalization in last year 17%

    • Weight median 104 kg, BMI median 37 (66% BMI >=35)

    • Comorbidities: AF 45%, CAD 21%, HTN 84%

    • Meds: Loop diuretic 62%, ACE/ARB/ARNI 79%, beta-blocker 81%, MRA 34%, SGLT2i 20% (4% in those without T2DM)

Intervention: Semaglutide subcutaneous once weekly at “weight loss doses”

  • Starting dose: 0.25 mg q1w

  • Titration: Uptitrated every 4 weeks (to 0.5 -> 1.0 -> 1.7 -> 2.4 mg q1w) as tolerated

  • Target dose: 2.4 mg q1w (reached after 16 weeks)

    • 84% of those still taking the drug at 1 year received the target dose

Comparator: Matching placebo

Outcomes @ median 1.1 year

Co-primary outcomes: Mean change from baseline to week 52:

  • KCCQ-CSS mean difference +7.5

    • Clinically-important improvement (>=5-point improvement) in KCCQ-CSS: 74% vs 57% (+17%)

      • >=10-point improvement: 61% vs 43% (+18%)

    • Consistent mean improvement over placebo across KCCQ-Overall Summary Score (+7.4) & across all sub-scores

  • Weight mean difference -8.4% or -8.9 kg (greater weight loss in non-diabetic patients)

    • >=20% reduction: 12.2% vs 1.2% (NNT ~9)

Key secondary outcomes

  • 6MWD: mean +17 meters with semaglutide vs placebo

  • Exploratory composite (time to first HF hospitalization, urgent visit, or CV death): 2% vs 6% (hazard ration 0.31, 95% confidence interval 0.15-0.62)

Safety

  • Serious adverse events: Semaglutide 28.7 vs 52.7 %/y

  • Discontinued due to GI adverse events: 10.7 vs 3.3 %/y

Internal validity = low risk of bias

  • Computer-generated random sequence generation

  • Allocation concealment by centralized interactive web-based response system

  • Blinding by matching placebo & titration schedule

  • Intention-to-treat analysis

  • Loss to follow-up (LTFU): KCCQ data missing for 8% on semaglutide & 11% on placebo at 1 year

Generalizability & other considerations

  • Similar improvement (no significant treatment-subgroup interaction) in QoL with semaglutide across studied LVEF in mildly-reduced/preserved range (45% to >=60%)

  • In STEP-HFpEF, similar improvement in QoL with semaglutide regardless of BMI (but all >=30), but KCCQ-CSS improvement in the semaglutide group was associated with weight loss >=5%

    • Impossible to say whether lesser KCCQ improvement in patients who lost <5% of their body weight due to an actual cause-effect relationship between weight loss & QoL improvement, or whether this is confounded by some other factor (e.g. lower adherence to semaglutide could explain lack of both weight loss & QoL improvement)

  • Individual-patient-level meta-analysis of patients with HFmrEF/HFpEF in STEP-HFpEF, STEP-HFpEF-DM, SELECT, and FLOW trials

    • Reduction in HF composite (time to first worsening HF or CV death): HR 0.69 (0.53-0.89); absolute risk reduction ~0.9%/y

    • But no significant reduction in CV death (HR 0.82, 0.57-1.16)

SELECT: Semaglutide in patients with CV disease & overweight/obesity

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SELECT. N Engl J Med 2023; 389:2221-2232

Bottom line: In overweight/obese patients with existing CV disease, semaglutide reduced the risk of death & cardiovascular events and reduced weight, but increased the risk of discontinuation due to GI intolerance. For every 1000 patients treated for 3.3 years, 9 deaths and 10 non-fatal MIs would be avoided, but 84 more patients receiving semaglutide would stop the drug due to GI intolerance.

Patients (n=17,604 randomized)

  • 41 countries, Oct 2018-March 2021

  • Included:

    • Age >=45 years

    • BMI >=27

    • Established cardiovascular disease: Prior MI or stroke (ischemic or hemorrhagic), or symptomatic PAD

  • Key exclusions:

    • Diabetes: Prior diagnosis, A1c >=6.5% at screening, or treatment with GLP1 RA or any other glucose-lowering drug

    • NYHA 4 HF

    • ESRD/dialysis

  • Baseline:

    • Age 62 y, male 72%

    • White 84%, Asian 8%, Black 4%

    • Weight mean 97 kg, BMI mean 33.3 (71.5% BMI >=30)

    • MI 76%, stroke 23%, symptomatic PAD 9%, HF 24%

    • EQ-5D-VAS 77/100

    • ASA 78%, P2Y12i 33-34%, statin 90%, beta-blocker 70%

Intervention: Semaglutide subcutaneous once weekly

  • Starting dose: 0.24 mg q1w

  • Titration: Uptitrated every 4 weeks (to 0.5 -> 1.0 -> 1.7 -> 2.4 mg q1w) as tolerated

  • Target dose: 2.4 mg q1w (reached after 16 weeks)

    • 77% of those still taking the drug at year 2 received the target dose

Comparator: Matching placebo

Outcomes @ median 3.3 years

All % present semaglutide first, then placebo

  • Death: 4.3% vs 5.2%, HR 0.81 (0.71-0.93), i.e. -0.3%/y

  • Primary outcome: Composite of CV death, non-fatal MI, or non-fatal stroke:

    • 6.5% vs 8.0%, HR 0.80 (95% CI 0.72-0.90), -1.5% or ~ -0.5%/y

    • CV death: 2.5% vs 3.0%, HR 0.85 (0.71-1.01)

    • Non-fatal MI: 2.7% vs 3.7%, HR 0.72 (0.61-0.85)

    • Non-fatal stroke: 1.7% vs 1.9%, HR 0.93 (0.74-1.15)

    • Subgroup: Visually fairly consistent results across all subgroups (including sex, age, BMI, with vs without HF), though p-values for interaction by subgroup not provided

  • HF composite (CV death, HF hospitalization or urgent medical visit for HF: 3.4% vs 4.1%, HR 0.82 (0.71-0.96)

  • Renal composite (renal death, dialysis, transplantation, eGFR <15, persistent eGFR reduction >=50%, or persistent uACR >300 mg/g): 1.8% vs 2.2%, HR 0.78 (0.63-0.96)

  • Safety

    • Serious adverse events: 33.4% vs 36.4% (-3%)

    • Treatment discontinuation: 26.7% vs 23.6% (+4.1%)

    • Adverse event leading to discontinuation: 16.6% vs 8.2% (+8.4%)

    • Gallbladder-related disorder: 2.8% vs 2.3% (+0.5%)

    • Acute pancreatitis: 0.2% vs 0.3%

  • Mean difference in %change in weight at 2 years: -8.5% vs placebo

Internal validity

  • Computer-generated random sequence generation

  • Allocation concealment by centralized interactive web-based response system

  • Blinding by matching placebo & titration schedule

  • Intention-to-treat analysis

  • 2.2% lost to follow-up

Generalizability

  • All patients in this trial had some form of prior CVD, mostly atherosclerotic/ischemic disease, and were inherently at “high” risk of recurrent CV event. “Primary prevention” patients, or those with CAD or cerebrovascular disease without prior MI or stroke would inherently be at lower risk & therefore may experience lower absolute benefit.

  • Subgroup based on history of HF & HF subtype:

    • Consistent reductions in MACE & HF events regardless of history of HF (with vs without) or HF subtype (HFrEF vs HFmrEF/pEF); all p-interaction >0.10

  • Details on the subgroup of patients with HF are currently sparse, and it is unclear if this benefit extends across the spectrum of LVEF