At the American College of Cardiology’s 74th Annual Scientific Session in Chicago, further results and analyses were presented from the SUMMIT trial. SUMMIT was the first trial in patients with heart failure with preserved ejection fraction (HFpEF) and obesity with heart failure outcomes as the primary prespecified endpoint. The trial examined the effect of Eli Lilly’s glucagon-like peptide-1 receptor agonist (GLP-1RA) tirzepatide, which is marketed as Mounjaro, on the clinical trajectory of patients with HFpEF and obesity. The study had previously identified that tirzepatide was able to reduce the composite of cardiovascular (CV) death and worsening HF events by 38% (P=0.026), an effect that was consistent across various definitions of events.
Obesity often leads to both HFpEF and chronic kidney disease (CKD); CKD may influence the clinical course of obesity-related HFpEF, and incretin-based drugs may influence renal function. This study had dual objectives: 1) to evaluate the influence of CKD on the clinical responses to tirzepatide in patients with obesity-related HFpEF; and 2) to investigate the complexity of tirzepatide-related changes in renal function. Key opinion leaders (KOLs) interviewed by GlobalData have often commented on the need for a therapy that can achieve a broader cardiometabolic approach in treating disease such as CV-kidney metabolic syndrome, which the SUMMIT trial investigates, and tirzepatide’s success in treating this broader metabolic syndrome is likely to achieve favourable opinion and uptake from physicians.
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The SUMMIT trial randomly assigned 731 patients with HFpEF: chronic HF, left ventricular failure (LVEF) 50% or higher, and body mass index at or above 30kg/m2. Patients were also required to have one of the following: 1) left atrial enlargement; 2) elevated left ventricular (LV) pressures; or 3) NT-proBNP greater than 200pg/mL in sinus rhythm or greater than 600pg/mL in AF. Patients received either placebo or tirzepatide for a median of 104 weeks and were followed for cardiovascular death or worsening heart failure events and for changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) after 52 weeks. Because of the confounding variables produced by obesity, and changes in muscle mass, estimated glomerular filtration rate (eGFR) was assessed at the point of randomisation and after 12, 24, and 52 weeks by both creatinine-based and cystatin C–based eGFR calculation formulae. The enrichment criteria used to identify participants at high risk of events included: 6 minute walk test (6MWT) ≥100 and ≤425 meters, KCCQ-CSS ≤80 and HF decompensation within 12 months or eGFR <70m/min/1.73m2. If they met these criteria, participants were then randomised for the duration of double-treatment and follow-up. Patients were on a starting dose of 2.5mg/week, which was uptitrated by 2.5mg every four weeks, as tolerated, until it reached 15mg/week by 20 weeks, and the double-blind treatment was maintained until the last patient completed 52 weeks.
Patients with CKD (based on creatinine or cystatin C) had greater severity of heart failure, as reflected by: 1) worse functional class, KCCQ-CSS scores, and 6-minute walk distance; 2) higher levels of NT-proBNP and cardiac troponin T; and 3) a two-fold increase in the risk of worsening heart failure events. CKD did not influence the effect of tirzepatide to reduce the relative risk of major adverse heart failure events and to improve KCCQ-CSS, quality of life, and functional capacity, but the absolute risk reduction in the primary events was numerically greater in patients with CKD. Regarding renal function assessments, baseline eGFR-cystatin C was consistently approximately 9mL/min/1.73m2 lower than that of eGFR-creatinine, with significant individual variance. Furthermore, tirzepatide increased eGFR at 52 weeks, assessed by both creatinine-based and cystatin C–based formulae, but with considerable discordance in individual patients. Tirzepatide produced a decline in eGFR at 12 weeks with eGFR-creatinine (but not eGFR-cystatin C), and it led to an improvement in eGFR at 52 weeks in all patients (when assessed by cystatin C), but only in patients with CKD (when assessed by eGFR-creatinine).
This substudy from the SUMMIT trial demonstrates long-term tirzepatide improves renal function (both by cystatin C and creatinine), but the measurement of eGFR in patients with obesity receiving GLP-1RAs is likely to be skewed by the effects of fat and muscle mass and the changes in body composition on the synthesis of both cystatin C and creatinine. GlobalData predicts that tirzepatide is likely to be increasingly prescribed for broader cardiometabolic disease and beyond the traditional prescribing of GLP-1RAs for type 2 diabetes (T2D), steadily becoming one of the leading GLP-1 therapies in the market.
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