tirzeptide good for heart failure preserved EF

 A study from the recent Am Heart Assn meeting confirmed that tirzepatide leads to fewer cardiovascular events in patients having heart failure with preserved ejection fraction (HFpEF) and obesity, in the SUMMIT trial, a drug company supported trial (see heart failure preserved tirzep NEJM2024 in dropbox, or  DOI: 10.1056/NEJMoa2410027)

 

Details:

-- 731 participants who  were at least 40yo with heart failure, a left ventricular ejection fraction (LVEF) of at least 50% and a BMI of at least 30 in an international, double-blind RCT were recruited between April 2021 and June 2023

    -- all participants had to have a 6-minute walk distance of 100-425 meters; a Kansas City Cardiomyopathy Questionnaire clinic summary score of 80 or less (scores range from 0-100, the higher scores reflecting a better quality of life); and at least one of an elevated N-terminal pro-B type natriuretic peptide (NT-proBNP) level (defined as >200 pg/ml in patients with sinus rhythm or >600 pg/ml in patients with atrial fibrillation), a left atrial enlargement assessed by two-dimensional echocardiography), or an elevated filling pressures at rest or during exercise (assessed by invasive or noninvasive measurements). Patients were also required to have had heart-failure decompensation within 12 months before entry or to have an estimated glomerular filtration rate (eGFR) of less than 70 ml

-- patients were randomized to either tirzepatide (starting at 2.5mg/week and titrated up every month to a dose of 15mg after week 20, if tolerated) vs placebo

-- mean age 66, 54% female, 70% white/18% Asian/7% Native American, Alaska Native, or Pacific Islander/ 5% Black

-- 53% from Latin America/20% US/17% Asia

-- NYHA functional class: Class II in 73%, Class III or IV in 27%; LVEF 61%; CAD in 30%, median NT-proBNP 180 pg/ml

-- KCCQ-CSS score 54; 6-minute walk distance 303 meters, hsCRP 5.8, systolic BP 128 mmHg, heart rate 71

-- hospitalization or urgent care for worsening heart failure in past 12 months 47%, atrial fib 25%, diabetes 48%

-- meds: diuretics 73%, RAAS system and neprilysin inhibitors 70%, mineralocorticoid-receptor antagonists (MRAs) 35%, SGLT-2s 17%

 

-- Patients were evaluated every 1-6 months for body weight, heart failure symptoms, worsening heart failure events, changes in heart failure medications, and adverse events; the 6-minute walk distance, KCCQ-CSS, and high-sensitivity C-reactive protein (CRP) level were assessed at baseline and at 24 and 52 weeks

 

primary endpoints:

    -- a composite of adjudicated death from cardiovascular causes or a worsening heart failure event (assessed in a time-to-first-event analysis), where a worsening heart failure event was defined as exacerbated symptoms of heart failure resulting in hospitalization, intravenous therapy in an urgent care setting, or intensification of oral diuretic therapy

    -- change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score

Secondary endpoints: change in body weight, 6-minute walk distance, decrease in hsCRP

 -- median duration of follow-up: 104 weeks

 

Results:

-- By the end of the trial, 70 patients (19.2%) in the tirzepatide group and 78 patients (21.3%) in the placebo group had discontinued the trial regimen

-- At the final visit, 212 (72.1%) of the 294 patients in the tirzepatide group who were still receiving treatment were receiving the target dose of 15 mg, and 289 patients (78.7%) were still taking placebo

-- mean change in body weight: -13.9% on tirzepatide and -2.2% on placebo

 

-- adjudicated worsening heart-failure event resulting in hospitalization, intravenous drugs in an urgent care setting, or intensification of oral diuretic therapy:

    -- tirzepatide group: 29 patients (8.0%), 4.5 events/100 person-yrs

    -- placebo group: 52 patients (14.2%), 8.2 events/100 person-yrs

        -- hazard ratio 0.54, (0.34 to 0.85), a 46% decrease; however, for this event and for all of the other individual primary endpoints assessed, these did not have a prespecified plan to adjust for multiple comparisons for analyses so were reported as point estimates with confidence intervals and not given p-values

 

-- adjudicated death from cardiovascular causes (of the total of 15 cardiovascular deaths, 11 were not  preceded by worsening heart failure):

    -- tirzepatide group: 8 patients (2.2%)

    -- placebo group: 5 patients (1.4%)

        -- HR 1.58 (0.52 to 4.83), not apparently statistically significant, though see caveat above about individual components of the primary endpoint

 

-- adjudicated death from cardiovascular causes or a worsening heart failure event resulting in hospitalization, intravenous drugs in an urgent care setting, or intensification of oral diuretic therapy (a primary endpoint):

    -- tirzepatide group: 36 patients (9.9%), 5.5 events/100 person-yrs

    -- placebo group: 56 patients (15.3%), 8.8 events/100 person-yrs

        -- HR 0.62 (0.41 to 0.95), a 38% decrease

 

 

as is evident in this graph, the curves begin to splay apart at about 24 weeks, then seem to continue to improve for tirzepatide

  

-- mean (±SD) change in the KCCQ-CSS at 52 weeks (of note, the baseline was a pretty miserable 54, where 50-74 means "fair to good health" and 25-49 = "poor to fair health"), another primary endpoint:

    -- tirzepatide group: 19.5±1.2 (ie moving very close to the "good to excellent health" range of 75-100)

    -- placebo group: 12.7±1.3 (also a pretty impressive improvement), however:

        --between-group difference: 6.9 (3.3 to 10.6) P<0.001

-- mean change in 6-minute walk at 52 weeks (a secondary endpoint):

    -- tirzepatide group: 26.0±3.8 meters

    -- placebo group: 10.1±3.9 meters

        -- between-group difference: 18.3 (9.9 to 26.7), P<0.001

-- mean change in hsCRP at 52 weeks (a secondary endpoint):

    -- tirzepatide group: −38.8±4.5%

    -- placebo group: 12.7±1.3

        --between-group difference: −34.9% (−45.6 to −22.2%), p<0.001

  

-- no significant difference in NT-proBNP, systolic blood pressure or heart rate (though not stratified by presence of atrial fibrillation)

  

-- adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug:

    --  tripeptide group: 23 patients (6.3%), though these symptoms tended to get better over time, as has been found in prior studies (only 4% of those of tirzepatide in this current study  stopped the med because of GI symptoms)

    -- placebo group: 5 patients (1.4%)

 

Commentary:

-- there is a clear and continuous relationship between HFpEF with increasing BMI, with weight loss by metabolic bariatric surgery and GLP-1 receptor agonists decreasing systematic inflammation, epicardial adipose volume, heart failure symptoms and incidence, as well as major adverse events from heart failure, in 2 trials of semaglutide (eg see http://gmodestmedblogs.blogspot.com/2023/10/heart-failure-preserved-in-obese.html )

-- it is not surprising that tirzepatide does decrease cardiovascular events in patients with preserved ejection fraction and obesity, since it is so evident that the usual GLP-1 receptor agonists do

    -- though, tirzepatide does add a GIP-1 agonist to the GLP-1, and there are somewhat different actions of these 2 agonists, as per the recent blog https://gmodestmedblogs.blogspot.com/2024/11/glp-1-agonists-improve-skeletal-muscle.html. Of note, both GLP-1 and GIP receptors are abundant on cardiac epicardial adipocytes and could lead to increased cardioprotection by the combined action, as in  tirzepatide

        -- hence the importance of this study, especially since tirzepatide has emerged as the most potent med for weight loss

    -- and, there are significant concerns that BMI is not a great surrogate marker for the obesity that is most related to adverse cardiovascular events (visceral obesity, with its attendant systemic inflammation), see https://gmodestmedblogs.blogspot.com/2024/11/diabetes-risk-bmi-less-good-predictor.html

-- this current study found both an improvement in the cardiovascular endpoints with tirzepatide, along with assessment of quality of life (per the KCCQ-CSS), exercise tolerance (per the 6-minute walk distance) and systemic inflammation (per the hsCRP)

-- the study did not require high levels of NT-proBNP in the participants because natriuretic peptides may not be meaningfully elevated in many patients with obesity-related HFpEF, despite increased cardiac filling pressures and substantial functional impairment (for example, a small study of 78 patients with dyspnea and severe obesity found that there was no difference in NT-proBNP or resting echocardiogram in those with HFpEF; both the HFpEF group and the non-HFpEF group had quite low values of 75 pg/mL: https://www.ahajournals.org/doi/full/10.1161/CIRCHEARTFAILURE.123.011366 )

-- clearly some patients with HFpEF do have quite high NT-proBNP levels, as is true in many of my patients, but per this current and some other studies, relying on a high NT-proBNP level may miss some people with HFpEF who have normal NT-proBNP levels.https://gmodestmedblogs.blogspot.com/2023/03/nt-probnp-predicts-future-heart-failure_9.html [this study did not differentiate HF subtypes of reduced vs preserved EF, though there is reasonable evidence that increases in NT-proBNP are associated with worse outcomes: see HFpEF changes in BNP predictive EurJHeartFaillure2015 in dropbox, or https://pubmed.ncbi.nlm.nih.gov/25921853/ .

 

-- a few other potential issues:

    -- as noted in many prior blogs, there is reasonable concern and pretty compelling argument that creatinine is significantly inferior to cystatin C in predicting both renal and more global bad outcomes such as atherosclerotic cardiovascular disease, heart failure, cardiovascular death, and all-cause mortality  (see https://gmodestmedblogs.blogspot.com/2023/12/cystatin-c-better-predictor-of-bad.html ). Of course, most pubished studies have used creatinine-based eGFR assessments, but perhaps changes in them are not as accurate as following changes in cystatin-C.  This current study only used the baseline creatinine-based eGFR, which seems to be significantly flawed.

    -- there is no comment on the diuretics used. i assume these were loop diuretics. there is a reasonable argument, however, that we should be using torsemide for heart failure, since it has increased bioavailability, a longer half-life, reduces aldosterone production (and MRAs do help with HFpEF), decreases  sympathetic activation (and increased sympathetic tone foretells a worse heart failure prognosis: https://pmc.ncbi.nlm.nih.gov/articles/PMC5873965/), reduces myocardial fibrosis, improves ventricular remodeling, and reduces blood natriuretic peptides more: https://gmodestmedblogs.blogspot.com/2023/01/heart-failure-torsemide-vs-furosemide.html

 

Limitations:

--one of the issues with an international study is making sure that all sites are on the same page. there are concerns about major lapses in optimizing medical therapy in the study (which i would guess would be better optimized in the US):

    -- diuretics 73% (were these loop diuretics?), RAAS system and neprilysin inhibitors 70% (sacubitril/valsartan is superior to just RAAS inhibitors as monotherapy), MRAs (a primary HFpEF treatment) 35%, SGLT-2s 17% (SGLT-2s are perhaps the preferred initial therapy in HFpEF)

        -- but no comment on meds or analysis breaking down by which meds were being used (though many of them were not used much....) or if there were difference by comorbidities (eg atrial fibrillation, diabetes, hypertension)

-- there was no baseline assessment or potential changes in diet and exercise, which might have affected the results:

    -- no evaluation of diet of the participants or other means of weight loss participants may have tried,  all of which can help with heart failure symptoms [this study only mentioned the baseline values. were the willing participants in this study on placebo trying to lose weight by other means? this could distort the interpretation of the results, diluting the potential benefit of tirzepatide.]

    -- and no evaluation of  exercise of the participants, since there does seem to be benefit of exercise in those with HFpEF: https://www.ahajournals.org/doi/10.1161/CIR.0000000000001122 

 

so,

-- tirzepatide passed the test. it is very helpful to add it to the list of meds for those with HFpEF (though i suspect many of us had already made the leap). it is the best of the GLP-1 type meds in terms of weight loss, and i have certainly found that diabetes control is also better with tirzepatide when the regular GLP-1s are insufficient

-- and, in light of the recent blog on GLP-1s, studies do suggest that the array of GLP-1s (and tirzepatide) seem to be pretty great in protecting and perhaps augmenting skeletal muscle (though there really do need to be more decisive studies done with MRI documentation of skeletal muscle for all of the weight loss approaches: https://gmodestmedblogs.blogspot.com/2024/11/glp-1-agonists-improve-skeletal-muscle.html )

-- of course, a big obstacle to these meds is their exorbitant cost (see https://gmodestmedblogs.blogspot.com/2024/04/drug-co-shenanigans-dm-meds.html , which documents the actual low cost of semaglutide production, on the order of $0.89 to $4.73/month, vs the price in the US of $1000/month), and the result that many insurance companies do not cover them except in very circumscribed reasons

 

 

geoff

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