Semaglutide articles

Tirzepatide articles

Bottom line:

In patients with symptomatic HF, ejection fraction >=45% & BMI >=30, semaglutide & tirzepatide both improved quality of life, reduced weight, & reduced worsening HF events, but increased the risk of discontinuation due to GI intolerance.
For every 100 patients treated with semaglutide or tirzepatide for 1 year, 12-15 patients will get a noticeable improvement in their quality of life because of treatment, 3-4 will avoid a HF event, & 5-8 patients will discontinue semaglutide/tirzepatide due to intolerable side-effects (mostly gastrointestinal).
The impact of semaglutide/tirzepatide on mortality in patients with HF is unknown.

Patients

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% 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 are consistent with the primary outcome of SUMMIT
- 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)

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%

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

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

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
- The STEP-HFpEF trial showed a clinically meaningful improvement in quality of life in patients with HFpEF and obesity receiving semaglutide, which seems to be mediated by extent of weight loss.