bims-hafaim 2025-01-26 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2025–01–26
eleven papers selected by
Kyle McCommis, Saint Louis University

Metabolomic Analysis of the Effects of Canagliflozin on HFpEF Rats and Its Underlying Mechanism.
Butyrate increases cardiac output and causes vasorelaxation in a healthy porcine model.
Cardiovascular effects of lactate in healthy adults.
Semaglutide in obesity-related heart failure with preserved ejection fraction and type 2 diabetes across baseline HbA1c levels (STEP-HFpEF DM): a prespecified analysis of heart failure and metabolic outcomes from a randomised, placebo-controlled trial.
Empagliflozin in diabetic cardiomyopathy: elucidating mechanisms, therapeutic potentials, and future directions.
Therapeutic potential of ketone bodies on exercise intolerance in heart failure: looking beyond the heart.
The efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients aged over 80 years with heart failure.
Effect of empagliflozin on plasma lipids and lipoproteins in type 2 diabetes and heart failure - Empire HF and SIMPLE.
A new model of experimental diabetic cardiomyopathy using combination of multiple doses of anomer-equilibrated streptozotocin and high fat diet: sex matters.
Comparative Effectiveness of Individual Sodium-Glucose Cotransporter 2 Inhibitors.
Caloric restriction and its mimetics in heart failure with preserved ejection fraction: mechanisms and therapeutic potential.

Endocr Metab Immune Disord Drug Targets. 2025 Jan 17.

Metabolomic Analysis of the Effects of Canagliflozin on HFpEF Rats and Its Underlying Mechanism.

Guorui Zhang, Qingjuan Zuo, Sai Ma, Lili He, Zhongli Wang, Jianlong Zhai, Tingting Zhang, Yan Wang, Yifang Guo.

   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) represents a challenging cardiovascular condition characterized by normal systolic function but impaired diastolic performance. Despite its increasing prevalence, therapeutic options remain limited. This study investigated the metabolic effects of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on cardiac function and energy metabolism in HFpEF.
METHODS: We established a rat model of HFpEF using Dahl salt-sensitive rats and evaluated three experimental groups: control (A), HFpEF (B), and canagliflozin-treated HFpEF (C). This study carried out comprehensive analyses of cardiac structure and function, metabolomic profiling, and detailed assessment of myocardial energy metabolism, including mitochondrial respiratory capacity and ATP synthesis. Additionally, we validated our findings using H9C2 cardiomyocytes under controlled conditions.
RESULTS: Canagliflozin treatment significantly improved cardiac remodeling markers, including reduced myocardial volume and fibrosis area, while enhancing diastolic function (E/A ratio). Metabolomic analysis revealed normalization of hypermetabolic states, with significant reductions in key metabolites, including L-lysine, D-glucose, and uridine. The treatment restored balance in multiple metabolic pathways, particularly affecting β-alanine metabolism, pyrimidine metabolism, and the citrate cycle. Notably, canagliflozin enhanced mitochondrial respiratory function, increased ATP synthesis, and optimized fatty acid utilization, as evidenced by reduced free fatty acid content.
CONCLUSION: Our findings demonstrated that canagliflozin exerts cardioprotective effects through multiple metabolic pathways, suggesting its potential as a therapeutic option for HFpEF. The ability of the drug to optimize energy metabolism and improve mitochondrial function represents a novel mechanism for treating this challenging condition.

Keywords:  Canagliflozin; HFpEF; hypertension; metabonomics.

DOI:  https://doi.org/10.2174/0118715303373321250108174111
Life Sci. 2025 Jan 17. pii: S0024-3205(25)00040-2. [Epub ahead of print]363 123407

Butyrate increases cardiac output and causes vasorelaxation in a healthy porcine model.

Lasse Juul Christensen, Alexander Møller Larsen, Casper Homilius, Nigopan Gopalasingam, Niels Moeslund, Kristoffer Berg-Hansen, Ebbe Boedtkjer, Rebekka Vibjerg Jensen, Mogens Johannsen, Jakob Hansen, Jakob Seefeldt, Hans Erik Bøtker, Julian Schütz, Oskar Kjærgaard Hørsdal, Bent Roni Ranghøj Nielsen.

   BACKGROUND: Butyrate, a short-chain fatty acid, has shown potential to improve left ventricular (LV) function and induce vasorelaxation in rodents. Butyrate may either be produced by the microbiome in the colon, be ingested or administered intravenously. This study aimed to evaluate effects of butyrate on cardiac output (CO) and associated hemodynamic variables in a porcine model.
METHODS: In a randomized, blinded crossover study, ten healthy 60-kg pigs were given three hour infusions of 600 mM butyrate and equimolar sodium chloride (control). CO was measured by thermodilution via a pulmonary artery catheter. LV contractility was assessed using pressure-volume admittance catheterization. Additionally, isolated porcine coronary arteries were exposed to butyrate in a wire myograph to evaluate vasorelaxation.
RESULTS: Butyrate infusion increased plasma butyrate concentration to 0.53 mM (95 % confidence interval (CI): 0.49 to 0.58 mM, P < 0.58 mM, P < 0.001) and CO by 1.6 L/min (95 % CI: 1.0 to 2.1 L/min, P < 0.001) compared with the control. Heart rate, LV ejection fraction, cardiac efficiency and dP/dtmax rose, while systemic vascular resistance, arterial elastance, mean arterial pressure and LV end-systolic volume decreased. Load-independent LV contractility and stroke volume did not significantly differ. In the myograph, porcine coronary arteries relaxed in response to butyrate in a concentration-dependent manner.
CONCLUSION: Butyrate increases cardiac output and lowers vascular resistance in a large animal model, through increased HR and systemic vasorelaxation. Load-independent LV contractility was not significantly altered. We observed indices of increased end-organ perfusion. These potentially beneficial cardiovascular properties of butyrate should be further studied.

Keywords:  Butyrate; Cardiac output; Heart failure; Hemodynamics; Metabolism; Pressure volume relationship

DOI:  https://doi.org/10.1016/j.lfs.2025.123407
Crit Care. 2025 Jan 17. 29(1): 30

Cardiovascular effects of lactate in healthy adults.

Kristoffer Berg-Hansen, Nigopan Gopalasingam, Mette Glavind Bülow Pedersen, Jakob Tobias Nyvad, Nikolaj Rittig, Esben Søndergaard, Henrik Wiggers, Niels Møller, Roni Nielsen.

   BACKGROUND: Low-volume hypertonic solutions, such as half-molar lactate (LAC), may be a potential treatment used for fluid resuscitation. This study aimed to evaluate the underlying cardiovascular effects and mechanisms of LAC infusion compared to sodium-matched hypertonic sodium chloride (SAL).
METHODS: Eight healthy male participants were randomized in a controlled, single-blinded, crossover study. Each participant received a four-hour infusion of LAC and SAL in a randomized order. Assessor-blinded echocardiography and blood samples were performed. The primary endpoint was cardiac output (CO) measured by echocardiography.
RESULTS: During LAC infusion, circulating lactate levels increased by 1.9 mmol/L (95% CI 1.8-2.0 mmol/L, P < 0.001) compared with SAL. CO increased by 1.0 L/min (95% CI 0.5-1.4 L/min, P < 0.001), driven primarily by a significant increase in stroke volume of 11 mL (95% CI 4-17 mL, P = 0.002), with no significant change in heart rate. Additionally, left ventricular ejection fraction improved by 5 percentage points (P < 0.001) and global longitudinal strain by 1.5 percentage points (P < 0.001). Preload indicators were elevated during SAL infusion compared with LAC infusion. Concomitantly, afterload parameters, including systemic vascular resistance and effective arterial elastance, were significantly decreased with LAC infusion compared with SAL, while mean arterial pressure remained similar. Indicators of contractility improved during LAC infusion.
CONCLUSIONS: In healthy participants, LAC infusion enhanced cardiac function, evidenced by increases in CO, stroke volume, and left ventricular ejection fraction compared with SAL. Indicators of contractility improved, afterload decreased, and preload remained stable. Therefore, LAC infusion may be an advantageous resuscitation fluid, particularly in patients with cardiac dysfunction.
CLINICAL TRIAL REGISTRATIONS: https://clinicaltrials.gov/ct2/show/NCT04710875 . Registered 1 December 2020.

Keywords:  Afterload; Cardiac output; Echocardiography; Lactate; Left ventricular ejection fraction; Preload

DOI:  https://doi.org/10.1186/s13054-025-05259-0
Lancet Diabetes Endocrinol. 2025 Jan 20. pii: S2213-8587(24)00304-8. [Epub ahead of print]

Semaglutide in obesity-related heart failure with preserved ejection fraction and type 2 diabetes across baseline HbA1c levels (STEP-HFpEF DM): a prespecified analysis of heart failure and metabolic outcomes from a randomised, placebo-controlled trial.

STEP-HFpEF Trials Committees and Investigators

BACKGROUND: About half of patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF) have type 2 diabetes. In the STEP-HFpEF DM trial of adults with obesity-related HFpEF and type 2 diabetes, subcutaneous once weekly semaglutide 2·4 mg conferred improvements in heart failure-related symptoms and physical limitations, bodyweight, and other heart failure outcomes. We aimed to determine whether these effects of semaglutide differ according to baseline HbA1c.
METHODS: STEP-HFpEF DM, a double-blind, randomised, placebo-controlled trial conducted at 108 clinical research sites across 16 countries in Asia, Europe, and North and South America, included individuals aged 18 years or older with documented HFpEF (left ventricular ejection fraction ≥45%), type 2 diabetes, and obesity (BMI ≥30 kg/m2). Participants were randomly assigned (1:1), with a block size of four within each stratum using an interactive web response system, stratified by baseline BMI (<35 kg/m2vs ≥35 kg/m2), to receive either semaglutide 2·4 mg or placebo subcutaneously. The effects of semaglutide versus placebo on the efficacy endpoints were evaluated by HbA1c categories at baseline: low (<6·5%; <48 mmol/mol), medium (6·5% to <7·5%; 48 mmol/mol to <58 mmol/mol), and high (≥7·5%; ≥58 mmol/mol). The dual primary endpoints were change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and bodyweight percentage from baseline to 52 weeks and were assessed in all randomly assigned participants by intention to treat. Hypoglycaemia events were also analysed to assess safety in all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04916470.
FINDINGS: Between June 27, 2021 and Sept 2, 2022, 616 participants were enrolled and randomly assigned (mean age 68·4 years [SD 8·9]; 273 [44%] were female, 343 [56%] were male, and 519 [84%] were White). The low baseline HbA1c group included 227 participants (112 assigned to semaglutide and 115 to placebo), the medium baseline HbA1c group included 226 participants (124 assigned to semaglutide and 102 to placebo), and the high baseline HbA1c group included 163 participants (74 assigned to semaglutide and 89 to placebo). The median duration of follow-up in the overall trial was 401 days (IQR 400-405). The change in KCCQ-CSS from baseline to 52 weeks was 12·4 points (95% CI 8·8 to 16·0) with semaglutide versus 5·7 points (2·1 to 9·2) with placebo (mean difference 6·7 points [1·6 to 11·8]) in the low baseline HbA1c group, 14·5 points (11·0 to 17·9) versus 8·5 points (4·8 to 12·2; 6·0 points [0·9 to 11·1]) in the medium baseline HbA1c group, and 14·5 points (10·0 to 19·0) versus 4·8 points (0·7 to 8·9; 9·6 points [3·5 to 15·7]) in the high baseline HbA1c group (pinteraction=0·64; ptrend=0·46). The change in bodyweight percentage from baseline to 52 weeks was -10·8 (95% CI -12·1 to -9·5) with semaglutide versus -3·3% (-4·6 to -2·0) with placebo (mean difference -7·5% [-9·4 to -5·6]) in the low baseline HbA1c group, -9·6% (-10·8 to -8·3) versus -3·3% (-4·7 to -1·9; -6·3 [-8·2 to -4·4]) in the medium baseline HbA1c group, and -8·6% (-10·2 to -7·0) versus -3·6% (-5·2 to -2·1; -5·0 [-7·2 to -2·7]) in the high baseline HbA1c group (pinteraction=0·22; ptrend=0·083). Hypoglycaemia events occurred in 30 (10%) of 310 participants (70 events; 22·9 events per 100 person-years) in the semaglutide group compared with 21 (7%) of 306 participants in the placebo group (90 events; 29·5 events per 100 person-years).
INTERPRETATION: Semaglutide 2·4 mg improved heart failure-related symptoms and physical limitations, and reduced bodyweight in patients with obesity-related HFpEF and type 2 diabetes, all independently of baseline HbA1c, and resulted in lower rates of hypoglycaemia than placebo, despite a well controlled baseline HbA1c and broad use of concomitant glucose-lowering medications.
FUNDING: Novo Nordisk.

DOI: https://doi.org/10.1016/S2213-8587(24)00304-8
Mol Biol Rep. 2025 Jan 24. 52(1): 158

Empagliflozin in diabetic cardiomyopathy: elucidating mechanisms, therapeutic potentials, and future directions.

Aiswarya Jaiswal, Poonam Yadav, Pushkar Singh Rawat, Maninder Kaur, Srivalliputturu Sarath Babu, Amit Khurana, Jasvinder Singh Bhatti, Umashanker Navik.

  Diabetic cardiomyopathy (DCM) represents a significant health burden, exacerbated by the global increase in type 2 diabetes mellitus (T2DM). This condition contributes substantially to the morbidity and mortality associated with diabetes, primarily through myocardial dysfunction independent of coronary artery disease. Current treatment strategies focus on managing symptoms rather than targeting the underlying pathophysiological mechanisms, highlighting a critical need for specific therapeutic interventions. This review explores the multifaceted role of empagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, in addressing the complex etiology of DCM. We discuss the key mechanisms by which hyperglycemia contributes to cardiac dysfunction, including oxidative stress, mitochondrial impairment, and inflammation, and how empagliflozin mitigates these effects. Empagliflozin's effects on reducing hospitalization for heart failure and potentially lowering cardiovascular mortality mark it as a promising candidate for DCM management. By elucidating the underlying mechanisms through which empagliflozin operates, this review underscores its therapeutic potential and paves the way for future research into its broader applications in diabetic cardiac care. This synthesis aims to foster a deeper understanding of DCM and encourage the integration of empagliflozin into treatment paradigms, offering hope for improved outcomes in patients suffering from this debilitating condition.

Keywords:  Diabetic cardiomyopathy; Empagliflozin; Fibrosis; Inflammation; Mitochondria dysfunction; Oxidative stress

DOI:  https://doi.org/10.1007/s11033-025-10260-5
Cardiovasc Res. 2025 Jan 18. pii: cvaf004. [Epub ahead of print]

Therapeutic potential of ketone bodies on exercise intolerance in heart failure: looking beyond the heart.

Shubham Soni, Rachel J Skow, Stephen Foulkes, Mark J Haykowsky, Jason R B Dyck.

  Recent evidence suggests that ketone bodies have therapeutic potential in many cardiovascular diseases including heart failure (HF). Accordingly, this has led to multiple clinical trials that use ketone esters to treat HF patients, which we term ketone therapy. Ketone esters, specifically ketone monoesters, are synthetic compounds which, when consumed, are de-esterified into two β-hydroxybutyrate (βOHB) molecules and increase the circulating βOHB concentration. While many studies have primarily focused on the cardiac benefits of ketone therapy in HF, ketones can have numerous favorable effects in other organs such as the vasculature and skeletal muscle. Importantly, vascular and skeletal muscle dysfunction are also heavily implicated in the reduced exercise tolerance, the hallmark feature in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction, suggesting that some of the benefits observed in HF in response to ketone therapy may involve these non-cardiac pathways. Thus, we review the evidence suggesting how ketone therapy may be beneficial in improving cardiovascular and skeletal muscle function in HF and identify various potential mechanisms that may be important in the beneficial non-cardiac effects of ketones in HF.

Keywords:  Ketone bodies; exercise intolerance; heart failure; skeletal muscle; vasculature; β-hydroxybutyrate

DOI:  https://doi.org/10.1093/cvr/cvaf004
ESC Heart Fail. 2025 Jan 20.

The efficacy and safety of sodium-glucose cotransporter 2 inhibitors in patients aged over 80 years with heart failure.

Kenji Nakano, Kenji Kanenawa, Akihiro Isotani, Takashi Morinaga, Kaori Yamamoto, Norihisa Miyawaki, Euihong Ko, Miho Nakamura, Yuichi Tanaka, Kenichi Ishizu, Toru Morofuji, Masaomi Hayashi, Masato Fukunaga, Makoto Hyodo, Shinichi Shirai, Kenji Ando.

   AIMS: Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) have demonstrated effectiveness in reducing cardiovascular death and heart failure hospitalization (HFH). However, the efficacy and safety of SGLT2 inhibitors in elderly patients with poor general status, such as very low bodyweight or low nutritional status, who are not included in randomized controlled trials, has not yet been examined. In a real-world setting, the introduction of SGLT2 inhibitors to such elderly patients is a very difficult decision to make. We therefore examined the efficacy and safety of these drugs in elderly heart failure patients in a real-world setting.
METHODS AND RESULTS: In Kokura Memorial Hospital, a retrospective study was conducted on 1559 patients over 80 years old hospitalized for HF between 2018 and 2023. Among them, 1326 were included in the non-SGLT2i group and 233 in the SGLT2i group. A multivariate Cox regression model was used to compare the risk of primary composite outcome (all-cause death and HFH) and secondary safety composite outcome (ischaemic stroke, urinary tract infection and dehydration) at 1 year post-discharge between the two groups. The cumulative 1 year incidence of the composite outcome was significantly higher in the non-SGLT2i group (47.3% vs. 31.6%, P < 0.01). SGLT2 inhibitors independently reduced the risk of all-cause death [adjusted hazard ratio (HR): 0.58, 95% confidence interval (CI): 0.39-0.87, P < 0.01] and HFH (adjusted HR: 0.69, 95% CI: 0.52-0.91, P < 0.01), whereas the risk of safety composite events was not increased (adjusted HR: 0.80, 95% CI: 0.49-1.29, P = 0.36). Subgroup analysis showed no significant interactions between age, diabetes, body mass index, left ventricular ejection fraction, clinical frailty scale, geriatric nutritional risk index and SGLT2 inhibitors consistently reduced composite outcomes across all strata. Similarly, SGLT2 inhibitors did not increase safety composite outcomes at any strata.
CONCLUSIONS: SGLT2 inhibitors reduce the risk of all-cause death and HFH without increasing adverse events, even in patients over 80 years old. It may be that SGLT2 inhibitors are effective and safe in patients who are basically hesitant to be introduced to SGLT2 inhibitors, such as those with high frailty, low nutritional status or very low bodyweight.

Keywords:  all‐cause death; elderly; extremely low bodyweight; frailty; heart failure; sodium‐glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1002/ehf2.15218
J Clin Lipidol. 2024 Dec 21. pii: S1933-2874(24)00303-9. [Epub ahead of print]

Effect of empagliflozin on plasma lipids and lipoproteins in type 2 diabetes and heart failure - Empire HF and SIMPLE.

Frida Emanuelsson, Jesper Jensen, Massar Omar, Mikkel Jürgens, Caroline Kistorp, Niels H Brandt-Jacobsen, Jacob Eifer Møller, Morten Schou, Louise Ellegaard Bechmann, Emil List Larsen, Børge G Nordestgaard, Marianne Benn.

   OBJECTIVE: Beyond glucose-lowering, sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardioprotective effects with unclear mechanisms. We examined changes in an extensive panel of plasma lipids, lipoproteins, and apolipoproteins and whether these changes were independent of weight loss, hemoglobin A1c, and hematocrit in patients treated with empagliflozin versus placebo to better understand the observed cardioprotective effects.
METHODS: Post-hoc analyses of two double-blind, placebo-controlled trials, the Empire HF trial including 190 patients with heart failure and reduced ejection fraction and the SIMPLE trial including 90 patients with type 2 diabetes randomized to, respectively, 10 mg and 25 mg empagliflozin daily or placebo for 12 weeks.
RESULTS: In studies combined, empagliflozin reduced age and sex adjusted body weight by 1.40 kg (SEM: 0.10; p < 0.001) and hemoglobin A1c by 2.71 mmol/mol (SEM: 0.24; p < 0.001); and increased hematocrit by 1.9% (SEM: 0.12; p < 0.001) compared to placebo. No mean changes were seen in concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, small dense LDL cholesterol, very low-density lipoprotein cholesterol, triglyceride rich lipoprotein cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, apolipoprotein B, lipoprotein(a), HDL cholesterol, and triglycerides adjusted for body weight, hemoglobin A1c, and hematocrit with empagliflozin compared to placebo.
CONCLUSION: Empagliflozin treatment reduced body weight and hemoglobin A1c; and increased hematocrit. No changes were seen in concentrations of lipids and lipoproteins with empagliflozin compared to placebo. This suggests that the cardioprotective effects of SGLT2 inhibitors are independent of lipid and lipoprotein concentrations.

Keywords:  Cholesterol; Heart failure; Lipoprotein(a); Sodium-glucose cotransporter-2 inhibition; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.jacl.2024.12.015
Diabetes. 2025 Jan 21. pii: db240385. [Epub ahead of print]

A new model of experimental diabetic cardiomyopathy using combination of multiple doses of anomer-equilibrated streptozotocin and high fat diet: sex matters.

Loucia Karatzia, Fenn Cullen, Megan Young, Shing Hei Lam, Valle Morales, Katiuscia Bianchi, Sian M Henson, Dunja Aksentijevic.

Diabetes mellitus (DM) leads to a more rapid development of DM cardiomyopathy (dbCM) and progression to heart failure in women than men. Combination of high-fat diet (HFD) and freshly-injected streptozotocin (STZ) has been widely used for DM induction, however emerging data shows that anomer-equilibrated STZ produces an early onset and robust DM model. We designed a novel protocol utilising a combination of multiple doses of anomer-equilibrated STZ injections and HFD to develop a stable murine DM model featuring dbCM analogous to humans. Furthermore, we examined the impact of biological sex on the evolution of cardiometabolic dysfunction in DM. Our study included six experimental protocols (8 weeks) in male and female C57BL/6J mice (n=109): Fresh STZ+HFD, Anomer-equilibrated STZ+HFD, HFD, Fresh STZ, Anomer-equilibrated STZ, Control diet+vehicle. Animals were characterised by extensive phenotyping in vivo and ex vivo. Anomer-equilibrated STZ+HFD led to induction of stable experimental murine DM characterised by impaired glucose homeostasis, cardiometabolic dysfunction and altered metabolome of liver, skeletal muscle, kidney and plasma. dbCM was more severe in female mice including systolic dysfunction and reduced cardiac energy reserve. This study established a novel, robust model of inducible murine DM and emphasised the impact of biological sex on DM progression and severity.

DOI: https://doi.org/10.2337/db24-0385
JAMA Intern Med. 2025 Jan 21.

Comparative Effectiveness of Individual Sodium-Glucose Cotransporter 2 Inhibitors.

HoJin Shin, Julie M Paik, Brendan M Everett, Elyse DiCesare, Caroline Alix, Robert J Glynn, Deborah J Wexler, Elisabetta Patorno.

Importance: Evidence on cardiovascular benefits and safety of sodium-glucose cotransporter 2 (SGLT-2) inhibitors is mainly from placebo-controlled trials. Therefore, the comparative effectiveness and safety of individual SGLT-2 inhibitors remain unknown.
Objective: To compare the use of canagliflozin or dapagliflozin with empagliflozin for a composite outcome (myocardial infarction [MI] or stroke), heart failure hospitalization, MI, stroke, all-cause death, and safety outcomes, including diabetic ketoacidosis (DKA), lower-limb amputation, bone fracture, severe urinary tract infection (UTI), and genital infection and whether effects differed by dosage or cardiovascular disease (CVD) history.
Design, Setting, and Participants: This comparative effectiveness study using target trial emulation included adults with type 2 diabetes (T2D) using 3 US claims databases using data from August 2014 through June 2020. The study was conducted from August 2023 to July 2024, with a follow-up period of up to 8 years, and the analysis was completed in July 2024.
Exposures: First dispensing of canagliflozin, dapagliflozin, or empagliflozin without any use of SGLT-2 inhibitors during the prior 365 days.
Main outcomes and measures: Database-specific models were weighted using propensity score matching-weights to adjust for 129 confounders. Hazard ratios and 95% CIs for outcomes were estimated using weighted Cox proportional hazards models. HRs were pooled across databases using a fixed-effect meta-analysis.
Results: : Across the databases, 232 890 patients receiving canagliflozin, 129 881 patients receiving dapagliflozin, and 295 043 patients receiving empagliflozin were identified. Compared with empagliflozin initiators, those receiving canagliflozin or dapagliflozin were less likely to have diabetes-related conditions or a history of CVD at baseline. For MI/stroke risk, both canagliflozin (HR, 0.98; 95% CI, 0.91-1.05) and dapagliflozin (HR, 0.95; 95% CI, 0.89-1.03) were comparable to empagliflozin. For heart failure hospitalization, dapagliflozin initiators had a higher risk (HR, 1.19; 95% CI, 1.02-1.39), particularly at the low dose of 5 mg (HR, 1.30; 95% CI, 1.12-1.50). These findings were consistent across subgroups of CVD history. For safety events, compared with empagliflozin, canagliflozin initiators had a lower risk of genital infections (HR, 0.94; 95% CI, 0.91-0.97) but a higher risk of severe UTIs (HR, 1.13; 95% CI, 1.03-1.24), and dapagliflozin initiators had lower risks of genital infections (HR, 0.92; 95% CI, 0.89-0.95) and DKA (HR, 0.78; 95% CI, 0.68-0.90).
Conclusions and Relevance: This study found that individual SGLT-2 inhibitors demonstrated comparable cardiovascular effectiveness at clinically effective doses, though low-dose dapagliflozin showed a reduced benefit for heart failure hospitalization compared with empagliflozin.

DOI: https://doi.org/10.1001/jamainternmed.2024.7357
Cardiovasc Diabetol. 2025 Jan 18. 24(1): 21

Caloric restriction and its mimetics in heart failure with preserved ejection fraction: mechanisms and therapeutic potential.

Alexander Fuerlinger, Alina Stockner, Simon Sedej, Mahmoud Abdellatif.

  The global increase in human life expectancy, coupled with an unprecedented rise in the prevalence of obesity, has led to a growing clinical and socioeconomic burden of heart failure with preserved ejection fraction (HFpEF). Mechanistically, the molecular and cellular hallmarks of aging are omnipresent in HFpEF and are further exacerbated by obesity and associated metabolic diseases. Conversely, weight loss strategies, particularly caloric restriction, have shown promise in improving health status in patients with HFpEF and are considered the gold standard for promoting longevity and healthspan (disease-free lifetime) in model organisms. In this review, we implicate fundamental mechanisms of aging in driving HFpEF and elucidate how caloric restriction mitigates the disease progression. Furthermore, we discuss the potential for pharmacologically mimicking the beneficial effects of caloric restriction in HFpEF using clinically approved and emerging caloric restriction mimetics. We surmise that these compounds could offer novel therapeutic avenues for HFpEF and alleviate the challenges associated with the implementation of caloric restriction and other lifestyle modifications to reduce the burden of HFpEF at a population level.

Keywords:  Aging; Caloric restriction mimetics; Fasting; GLP-1A; HFpEF; Obesity; SGLT2

DOI:  https://doi.org/10.1186/s12933-024-02566-8