BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.
- MeSH
- glukagonu podobné peptidy * MeSH
- kvalita života * MeSH
- lidé MeSH
- natriuretický peptid typu B MeSH
- obezita farmakoterapie MeSH
- srdeční selhání * diagnóza farmakoterapie MeSH
- tepový objem MeSH
- zánět MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Klíčová slova
- semaglutid,
- MeSH
- agonisté receptoru pro glukagonu podobný peptid 1 farmakologie terapeutické užití MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- glukagonu podobné peptidy farmakologie terapeutické užití MeSH
- hypoglykemika MeSH
- kongresy jako téma MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- zprávy MeSH
BACKGROUND: Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure-related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. OBJECTIVES: This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. METHODS: This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). RESULTS: In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). CONCLUSIONS: Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470]).
- MeSH
- C-reaktivní protein metabolismus MeSH
- dvojitá slepá metoda MeSH
- glukagonu podobné peptidy * terapeutické užití MeSH
- hmotnostní úbytek MeSH
- lidé středního věku MeSH
- lidé MeSH
- obezita * komplikace patofyziologie MeSH
- senioři MeSH
- srdeční selhání * farmakoterapie patofyziologie MeSH
- tepový objem * fyziologie účinky léků MeSH
- výsledek terapie MeSH
- zánět * farmakoterapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
OBJECTIVE: Semaglutide, a glucagon-like peptide-1 receptor agonist is approved for weight loss and diabetes treatment, but limited literature exists regarding semaglutide use in patients with advanced chronic kidney disease (CKD). Therefore, this project assessed the safety and efficacy of semaglutide among patients with estimated glomerular filtration rate (eGFR) 15-29 mL/min/1.73 m2 (CKD stage 4), eGFR<15 mL/min/1.73 m2 (CKD stage 5) or on dialysis. METHODS: This is a retrospective electronic medical record based analysis of consecutive patients with advanced CKD (defined as CKD 4 or greater) who were started on semaglutide (injectable or oral). Data was collected between January 2018 and January 2023. Investigators verified CKD diagnosis and manually extracted data. Data were analyzed using Fisher's exact test, paired t test, linear mixed effects models and Wilcoxon signed rank test. RESULTS: Seventy-six patients with CKD 4 or greater who initiated semaglutide were included. Most patients had a history of type 2 diabetes mellitus (96.0%), and most were males (53.9%). The mean age was 66.8 y (SD 11.5) with the mean body mass index was 36.2 (SD 7.5). The initial doses were 3 mg orally and 0.25 mg by injection. Maximum prescribed dose was 1 mg (injectable) in 28 (45.2%) patients and 14 mg (orally) in 2 (14.2%) patients. Patients received semaglutide for a median duration of 17.4 (IQR 0.43, 48.8) months. Forty-eight (63.1%) patients reported no adverse effects associated with the therapy. Mean weight decreased from 106.2 (SD 24.2) to 101.3 (SD 27.3) kg (P < .001). Eight patients (16%) with type 2 diabetes mellitus T2DM discontinued insulin after starting semaglutide. Mean hemoglobin A1c (HbA1c) decreased from 8.0% (SD 1.7) to 7.1% (SD 1.3) (P < .001). Adverse effects were the primary reason for semaglutide discontinuation (37.0%), with nausea, vomiting, and abdominal pain being the most common complaints. CONCLUSIONS: Based on this retrospective study semaglutide appears to be tolerated by most individuals with CKD 4 or greater despite associated gastrointestinal side effects similar to those observed in patients with better kidney function and leads to an improvement of glycemic control and insulin discontinuation in patients with T2DM. Modest weight loss (approximately 4.6% of the total body weight) was observed on the prescribed doses. Larger prospective randomized studies are needed to comprehensively assess the risks and benefits of semaglutide in patients with CKD 4 or greater and obesity.
- MeSH
- chronická renální insuficience * farmakoterapie komplikace MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- dialýza ledvin MeSH
- glukagonu podobné peptidy * terapeutické užití škodlivé účinky aplikace a dávkování MeSH
- hodnoty glomerulární filtrace účinky léků MeSH
- hypoglykemika terapeutické užití škodlivé účinky aplikace a dávkování MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- renální insuficience MeSH
- retrospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Chuť i míra hladu, ale i rychlost metabolizmu jsou geneticky determinovány a regulace probíhá na třech úrovních v mozku a také ve střevě, a to pomocí střevních hormonů a neuromodulátorů. Hubnutí není fyziologický proces, tělo je nastaveno tak, že bychom měli neustále přibírat až na hmotnost, která je nám zřejmě geneticky předurčena. Poslední roky se objevují nové moderní a velmi bezpečné léky na hubnutí a na léčbu obezity jako nemoci. Začíná převládat názor, že obezitu je třeba léčit doživotně, za pomoci nejen změny životního stylu, ale také za použití léků nebo postupů bariatrické chirurgie.
Appetite and hunger, as well as metabolic rate, are genetically determined and regulated at three levels in the brain and also in the bowel by bowel hormones and neuromodulators. Weight loss is not a physiological process, the body is set up to enable continuous weigh gaining up to the weight that is probably genetically predetermined for us. In recent years, new modern and very safe drugs are emerging for weight loss and for treating obesity as a disease. The opinion that obesity should be treated for life, not only with lifestyle changes but also with drugs or bariatric surgery procedures, is becoming predominant.
- MeSH
- bupropion terapeutické užití MeSH
- fentermin terapeutické užití MeSH
- glukagonu podobný peptid 1 terapeutické užití MeSH
- látky proti obezitě aplikace a dávkování terapeutické užití MeSH
- liraglutid terapeutické užití MeSH
- nadváha etiologie farmakoterapie genetika psychologie terapie MeSH
- naltrexon terapeutické užití MeSH
- obezita etiologie farmakoterapie genetika psychologie terapie MeSH
- orlistat terapeutické užití MeSH
BACKGROUND: Antipsychotics are indispensable in the treatment of severe mental illneses, however adverse metabolic effects including diabetes, weight gain, dyslipidemia, and related cardiovascular morbidity are common, and current pharmacological strategies for their management are unsatisfactory. Glucagon-like 1 peptide receptor agonists (GLP-1 RAs) are approved for the treatment of type 2 diabetes and obesity hold promise for the management of antipsychotic-associated adverse metabolic effects. METHODS: To characterize the molecular effects and identify biomarkers for GLP-1 RA preventive treatment, Sprague-Dawley female rats were treated with long-acting formulations of the antipsychotic olanzapine and the GLP-1 RA dulaglutide for 8 days. A pair-feeding protocol evaluated the combined effects of dulaglutide and food restriction on an olanzapine-induced metabolic phenotype. Body weight and food consumption were recorded. Biochemical analysis included a lipid profile, a spectrum of gastrointestinal and adipose tissue-derived hormones, and fibroblast growth factor 21 serum levels. RESULTS: Olanzapine induced hyperphagia, weight gain, increased serum triglycerides and HDL cholesterol. Food restriction affected the OLA-induced phenotype but not serum markers. Dulaglutide led to a modest decrease in food intake, with no effect on weight gain, and did not reverse the OLA-induced changes in serum lipid parameters. Concomitant dulaglutide and food restriction resulted in weight loss, decreased feed efficiency, and lower total and HDL cholesterol. CONCLUSIONS: A combined strategy of dulaglutide and food restriction manifested a massive synergistic benefit. GLP-1RAs represent a promising strategy and deserve thorough future research. Our findings underline the potential importance of lifestyle intervention in addition to GLP-1 RA treatment.
- MeSH
- antipsychotika farmakologie škodlivé účinky MeSH
- benzodiazepiny farmakologie škodlivé účinky MeSH
- glukagonu podobné peptidy * analogy a deriváty farmakologie MeSH
- hmotnostní přírůstek účinky léků MeSH
- imunoglobuliny - Fc fragmenty * farmakologie MeSH
- kalorická restrikce metody MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- olanzapin * farmakologie škodlivé účinky MeSH
- potkani Sprague-Dawley * MeSH
- přijímání potravy účinky léků MeSH
- receptor pro glukagonu podobný peptid 1 agonisté metabolismus MeSH
- rekombinantní fúzní proteiny * farmakologie MeSH
- tělesná hmotnost účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
