To evaluate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) with diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) patients across different subgroups, we searched randomized controlled trials (RCTs) comparing SGLT2i with the control groups among T2DM patients and including DKA as a safety outcome. Pooled risk ratios (RRs) were calculated using random or fixed-effects models, as appropriate. An inverse-variance-weighted Mendelian randomization (MR) analysis was performed to estimate the genetic correlation. Twenty-two trials involving 80,235 patients were included. SGLT2i increased the risk of DKA compared to the control groups (RR 2.32, 95% CI 1.64-3.27). The risk was significantly increased in patients with higher HbA1c levels (> 7.9%) (RR 2.24, 95% CI 1.59-3.14), but not in those with lower HbA1c levels (≤ 7.9%) (RR 1.05, 95% CI 0.49-2.26; interaction P = 0.034). SGLT2i increased DKA risk in chronic kidney disease (CKD) (RR 2.70, 95% CI 1.55-4.71) and high atherosclerotic cardiovascular disease (ASCVD) risk trials (RR 2.46, 95% CI 1.47-4.11) but not significantly in heart failure (HF) trials (RR 1.23, 95% CI 0.51-2.96). Moreover, in the HF trials, SGLT2i consistently did not increase the risk of DKA in any clinical subgroups. Nevertheless, MR analysis still confirmed a genetic association between SGLT2i and the risk of DKA among overall T2DM patients. SGLT2i may increase the risk of DKA in T2DM patients, particularly in patients with higher levels of HbA1c and those with comorbid CKD or at high-risk ASCVD. However, the increased risk was not significant in patients with HF.

The close interplay between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes supports the need to identify beneficial combination therapies of antidiabetic medications targeted for the treatment of MASLD. This study aimed to investigate the complementary effects of combination therapy with pioglitazone (PIO) and empagliflozin (EMPA) on MASLD in individuals with type 2 diabetes.

In a randomized, open-label trial, 50 participants with type 2 diabetes and MASLD were assigned 1:1:1 to receive PIO 15 mg, EMPA 10 mg, or a combination (PIO 15 mg plus EMPA 10 mg) daily for 24 weeks. Liver fat fraction and stiffness were evaluated using magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE), respectively.

Combination therapy resulted in the largest reduction in liver fat and stiffness among treatment groups. Participants experiencing a relative reduction ≥ 30% or an absolute reduction ≥ 5% in liver fat were the most prevalent in the combination group (100.0% vs. 57.1% in PIO and 87.5% in EMPA, p = 0.010). In addition, the combination group showed the highest proportion of individuals with a relative reduction ≥ 30% in liver fat and ≥ 20% in liver stiffness than the monotherapy groups (50.0% vs. 21.4% in PIO and 6.3% in EMPA, p = 0.029). Combination therapy did not induce the changes in subcutaneous fat deposition observed in the monotherapy groups, but it did show the most substantial reduction in visceral fat, concurrently showing the largest increase in adiponectin level across the three groups (p = 0.036).

Combination therapy of PIO with EMPA showed synergistic benefits for MASLD in individuals with type 2 diabetes, compensating for the inadequate or unfavorable effects of monotherapies; ClincialTrials.gov number, NCT03646292.

The trial was registered at ClinicalTrials.gov (registration number: NCT03646292).

Statins, though widely used, may accelerate diabetes progression, necessitating interventions to counteract this effect.

To compare the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2is) and sulfonylureas or meglitinides on diabetes progression in individuals receiving statins.

This retrospective cohort study utilized data from the National Health Insurance Research Database of Taiwan. We included patients with diabetes receiving statins and newly initiated SGLT2is or sulfonylureas/meglitinides between July 1, 2016 and December 31, 2020. Diabetes progression was defined as insulin initiation, increase in antidiabetic medication class, or occurrence of new acute hyperglycemic complications. Propensity score matching was used to adjust baseline characteristics. Cox proportional hazards regression was used to calculate the hazard ratios for diabetes progression between users of SGLT2is and those of sulfonylureas or meglitinides. The statistical significance level was set at 0.05 for all analyses.

SGLT2i users had a significantly lower risk of diabetes progression compared to sulfonylurea/meglitinide users (HR: 0.53, 95% CI: 0.50-0.57, p-value < 0.001). Similar results were found in insulin initiation (HR: 0.48, 95% CI: 0.38-0.61, p-value < 0.001) and increase in antidiabetic medication class (HR: 0.53, 95% CI: 0.50-0.57, p-value < 0.17). However, the risk of new acute glycemic complications did not significantly differ between groups (HR: 2.47, 95% CI: 0.67-9.08, p-value = 0.17).

SGLT2is may be an effective second-line therapy for statin-treated patients by slowing diabetes progression and potentially mitigating statin-induced metabolic disturbances. Further research, including randomized controlled trials or observational studies with comprehensive laboratory data, is needed to confirm these findings and evaluate their broader applicability.

To compare the effects of ipragliflozin, a sodium-dependent glucose transporter-2 inhibitor, and those of metformin on the visceral fat area (VFA), a prospective, multi-centre, open-label, blinded-endpoint, randomized, controlled study was undertaken. The generated data were used to examine the effects of ipragliflozin and metformin on indices of hepatic steatosis and liver fibrosis.

In total, 103 Japanese patients with type-2 diabetes (T2D), body mass index (BMI) of ≥22 kg/m2 and glycated haemoglobin level of 7%-10% were randomly administered ipragliflozin 50 mg or metformin 1000 mg for 24 weeks. Various parameters, including hepatic steatosis indices, fatty liver index (FLI), hepatic steatosis index (HSI), non-alcoholic fatty liver disease-liver fat score (NAFLD-LFS), liver fibrosis indices, AST to platelet ratio index (APRI) and fibrosis-4 (FIB-4) index, were compared in the sub-analyses. The correlations between changes in each index and VFA were evaluated.

At baseline, patients demonstrated moderate hepatic steatosis, with FLI scores of 52.9 ± 26.6 and 57.8 ± 29.0 in the ipragliflozin and metformin groups, respectively. At 24 weeks, compared with metformin, ipragliflozin showed improvements in hepatic steatosis indices: FLI (-9.24 ± 10.7 vs. -3.45 ± 11.8, p = 0.013), HSI (-1.45 ± 2.32 vs. -0.45 ± 1.87, p = 0.021), NAFLD-LFS (-0.70 ± 1.46 vs. -0.04 ± 0.98, p = 0.011) and liver fibrosis index: APRI (-0.110 ± 0.323 vs. 0.033 ± 0.181, p = 0.010). In the ipragliflozin group, changes in FLI and HSI were correlated with VFA reduction (r = 0.340, p = 0.024; r = 0.367, p = 0.011, respectively).

Compared with metformin, ipragliflozin improved multiple hepatic steatosis and liver fibrosis indices, suggesting that ipragliflozin exerts potential hepatoprotective effects in early-stage liver disease associated with T2D.

The incidence and prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise, and now comprises more than half of all heart failure cases. There are many risk factors for HFpEF, including older age, hypertension, diabetes, dyslipidemia, sedentary behaviour, and obesity. The rising prevalence of obesity in society is a particularly important contributor to HFpEF development and severity. Obesity can adversely affect the heart, including inducing marked alterations in cardiac energy metabolism. This includes obesity-induced impairments in mitochondrial function, and an increase in fatty acid uptake and mitochondrial fatty acid β-oxidation. This increase in myocardial fatty acid metabolism is accompanied by an impaired myocardial insulin signaling and a marked decrease in glucose oxidation. This switch from glucose to fatty acid metabolism decreases cardiac efficiency and can contribute to severity of HFpEF. Increased myocardial fatty acid uptake in obesity is also associated with the accumulation of fatty acids, resulting in cardiac lipotoxicity. Obesity also results in dramatic changes in the release of adipokines, which can negatively impact cardiac function and energy metabolism. Obesity-induced increases in epicardial fat can also increase cardiac insulin resistance and negatively affect cardiac energy metabolism and HFpEF. However, optimizing cardiac energy metabolism in obese subjects may be one approach to preventing and treating HFpEF. This review discusses what is presently known about the effects of obesity on cardiac energy metabolism and insulin signaling in HFpEF. The clinical implications of obesity and energy metabolism on HFpEF are also discussed.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects an ever-increasing part of the global population, affecting millions of individuals worldwide. Despite the progress in the treatment of other liver diseases, there is a scarcity of liver-specific drugs targeting MASLD. In light of that, research has focused both on pipeline drugs targeting multiple different receptors implicated in the pathogenesis of the disease, as well as medications already approved for other indications, that might exert beneficial effects on MASLD. The fact that MASLD is associated with an increased prevalence of obesity and type 2 diabetes mellitus (T2DM) establishes a possible pathway with respect to already available pharmaceutical interventions for this group of patients, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT2-is). Thus, the hitherto at hand, along with the upcoming members of these families, provide much-needed options for our arsenal. This review attempts to explore old and novel dimensions of the pharmaceutical treatment of MASLD in the continuous effort of the medical society to improve patient outcomes.

The metabolic and lipid profiles of horses treated with sodium-glucose cotransporter 2 inhibitors are not well understood. This retrospective study evaluated blood parameters in hyperinsulinemic horses treated with either ertugliflozin (0.05 mg/kg) or dapagliflozin (0.02 mg/kg) orally once daily. Blood samples were collected at baseline (day 0) and after 7 and/or 30 days of treatment. Statistical analyses were conducted using Wilcoxon signed-rank, Mann-Whitney and Spearman's rank correlation tests. Thirty-four horses received dapagliflozin and 24 received ertugliflozin. Significant (p<0.05) within-horse changes between day 0 and day 30 included [median, inter-quartile range (IQR)]: basal serum [Insulin] (uU/ml) reduced 170 (92-280) to 28.7 (14.5-90); [triglycerides] (mmol/l) increased 0.5 (0.3-0.6) to 1.0 (0.6-1.56), [β-hydroxybutyrate] (umol/l) increased 0.22 (0.17-2.7) to 0.30 (0.24-0.35); [total cholesterol] (mmol/l) increased 2.36 (2-2.6) to 2.84 (2.4-3.7); and GGT (IU/ml) increased 21 (16-32) to 25 (18-38). As a percentage of total serum lipids, high-density lipoprotein (HDL) reduced 52.4 % (47.9 %-61.0 %) to 50 % (41 %-54.8 %) and very-low density lipoprotein (VLDL) increased 10.4 % (6.4 %-14.4 %) to 12.3 % (9.9 %-16.8 %) (all p<0.05). Differences between ertugliflozin and dapagliflozin groups were not significant in any of these parameters at days 0, 7 or 30. At day 30, 10/48 (21 %) cases had [triglycerides] > 2.0 mmol/l (maximum = 10.8mmol/l). Day 30 [triglyceride] correlated with day 0: basal insulin (rho=0.47); [triglyceride] (rho=0.42); %VLDL (rho=0.34) day 30: [total cholesterol] (rho=0.67), %HDL (rho=-0.432) and %VLDL (rho=0.708). Our findings suggest that SGLT2 inhibitors induce minor changes in lipid profiles, with occasional cases of marked hypertriglyceridemia, and that dapagliflozin and ertugliflozin exhibit similar biochemical effects.

The renoprotective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in both diabetic and nondiabetic nephropathy are widely recognized due to results from randomized controlled trials notably the DAPA-CKD and EMPA-KIDNEY trials. Research exploring the mechanisms of renoprotection indicates that SGLT2 inhibitors exert protective effects on podocytes by enhancing autophagy and stabilizing the structure of podocytes and basement membranes. Furthermore, reductions in lipotoxicity, oxidative stress, and inflammation have been confirmed with SGLT2 inhibitor treatment. Recent clinical studies have also begun to explore the effects of SGLT2 inhibitors on nondiabetic podocytopathies, such as focal segmental glomerulosclerosis. In this review, we summarize clinical and laboratory studies that focus on the podocyte-protective effects of SGLT2 inhibitors, exploring the potential for broader applications of this novel therapeutic agent in kidney disease.

Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known.

We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45+ cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks.

ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout-Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibition in this model.

Using single-cell RNA sequencing in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.

The sodium-dependent glucose transporters 2 inhibitors (SGLT-2i) is associated with body weight loss but the composition of the losing weight remains unclear.

Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi- item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of SGLT-2i-associated musculoskeletal and connective tissue disorders AEs.

The search retrieved a total of 3,206 cases of musculoskeletal and connective tissue disorder-related AEs during the reporting period. This included 1,061 cases for Canagliflozin, 1,052 cases for Dapagliflozin, 1,074 cases for Empagliflozin, and 19 cases for Ertugliflozin. Fifteen preferred terms (PTs) with significant disproportionality were retained. No musculoskeletal and connective tissue system-related AE signals were reported for Ertugliflozin. We identified a risk of muscle necrosis with Canagliflozin use, a risk of sarcopenia with Dapagliflozin use, and a chance of muscle atrophy with Dapagliflozin and Empagliflozin prescriptions. Most cases occurred within the first month after SGLT-2i initiation, and AEs can persist beyond 360 days of use.

Our study identified potential new musculoskeletal and connective tissue disorder-related AE signals associated with SGLT-2 inhibitors.

Patients hospitalised for COVID-19 are at risk for multiorgan failure and death. Sodium-glucose co-transporter-2 (SGLT2) inhibitors provide cardiovascular and kidney protection in patients with cardiometabolic conditions and could provide organ protection during COVID-19. We aimed to investigate whether SGLT2 inhibitors can reduce the need for organ support in patients hospitalised for COVID-19.

This pragmatic, multicentre, open-label, randomised, controlled, platform trial was conducted across 63 sites in the USA, Spain, Brazil, Italy, and Mexico. Patients aged at least 18 years hospitalised for COVID-19 (moderate or severe illness) were randomly assigned (1:1), via an interactive voice system or web-response system, to receive locally available SGLT2 inhibitor (administered orally, once daily) plus standard-of-care or standard-of-care for 30 days. The primary outcome was organ support-free days evaluated through 21 days, assessed using intention-to-treat approach. This trial is registered on ClinicalTrials.gov, NCT04505774.

The first patient was randomly assigned to the SGLT2 inhibitor domain on Dec 3, 2021. On March 31, 2023, at the recommendation of the data and safety monitoring board, enrolment in the SGLT2 inhibitor domain for both moderately and severely ill hospitalised patients was stopped prematurely for futility due to a low likelihood of finding a treatment benefit. The final randomised population consisted of 575 patients (mean age 72 years [SD 13], 242 (42%) female and 154 (27%) Hispanic; 504 in the moderate illness group and 71 in the severe illness group). 573 patients had a known 21-day outcome; 215 (75%) of 285 patients in the SGLT2 inhibitor plus standard-of-care group did not require respiratory or cardiovascular organ support versus 231 (80%) of 288 patients in the standard-of-care group. The adjusted odds ratio (OR) for an SGLT2 inhibitor effect on organ support-free days was 0·74 (95% Credible Interval [CrI] 0·48-1·13; where OR higher than 1 indicated treatment benefit, yielding a posterior probability of futility P(OR <1·2) of 99% and a posterior probability of inferiority P(OR<1·0) of 91%). There were 37 deaths (13%) in the SGLT2 inhibitor plus standard-of-care group and 42 deaths (15%) in the standard-of-care group at 90 days (hazard ratio 0·91 [95% CrI 0·58-1·43], probability of hazard ratio <1 of 66%). No safety concerns were observed with SGLT2 inhibitors, including no cases of ketoacidosis.

SGLT2 inhibitors did not significantly increase days free of organ support or reduce mortality in patients hospitalised with COVID-19. SGLT2 inhibitors were well tolerated with no observed safety concerns. Overall, these findings do not support the use of SGLT2 inhibitors as standard care in patients hospitalised with COVID-19.

National Institutes of Health.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19.

Eligible RCTs that estimated the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo on 28-day all-cause mortality (primary outcome) were included in this prospective meta-analysis. The primary safety outcome was ketoacidosis by 28 days. Trials were identified through systematic searches of ClinicalTrials.gov, EudraCT, and the WHO ISRCTN registry between Nov 1, 2022 and Jan 31, 2023. The search terms were "random*" AND "COVID" AND each SGLT2i, not restricted by trial status or language. Individual searches were then combined. Prespecified summary outcome data, overall and within subgroups of interest, were provided by each trial. The primary analyses were inverse variance weighted meta-analysis of odds ratios (ORs). Risk of bias was assessed using the Cochrane Risk of Bias tool. This study was registered with PROSPERO, CRD42023406442.

Three eligible trials randomly assigned 6096 participants (3025 to the SGLT2 inhibitor group and 3071 to the usual care or placebo group). 2381 (39%) patients were women and 1547 (25%) had type 2 diabetes at randomisation. By 28 days, there were 351 deaths in the SGLT2 inhibitor group and 382 deaths in the usual care or placebo group (summary OR 0·93 [95% CI 0·79-1·08]; p=0·33, I2 for inconsistency across trials 0%). The risk of bias was assessed as being low. Ketoacidosis was observed in seven participants in the SGLT2 inhibitor group and two patients in the usual care or placebo group.

Although administration of SGLT2 inhibitor was safe, we found no clear evidence that adding SGLT2 inhibitor therapy improved outcomes in patients hospitalised with COVID-19 compared with usual care or placebo. These data do not support the use of SGLT2 inhibitors as standard treatment in adults hospitalised for COVID-19.

None.

The development and progression of heart failure is characterized by metabolic and physiologic adaptations allowing patients to cope with cardiac insufficiency. This review explores the changes in metabolism in heart failure and the potential role of biomarkers, particularly ketone bodies, in staging and prognosticating heart failure progression.

Recent insights into myocardial metabolism shed light on the heart's response to stress, highlighting the shift towards reliance on ketone bodies as an alternative fuel source. Elevated blood ketone levels have been shown to correlate with the severity of cardiac dysfunction, emphasizing their potential as prognostic indicators. Furthermore, studies exploring therapeutic interventions targeting specific metabolic pathways offer promise for improving outcomes in heart failure. Ketones have prognostic utility in heart failure, and potentially, an avenue for therapeutic intervention. Challenges remain in deciphering the optimal balance between metabolic support and exacerbating cardiac remodeling. Future research endeavors must address these complexities to advance personalized approaches in managing heart failure.

Quantification of body compartments, particularly the interaction between adipose tissue and skeletal muscle, is emerging as novel a biomarker of metabolic health. The present study evaluated the impact of liver transplant (LT) on body compartments.

Totally 66 adult LT recipients were enrolled in whom body compartments including visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), muscle fat infiltration (MFI), fat-free muscle volume (FFMV), and liver fat (LF) were quantified via whole body magnetic resonance imaging (MRI). To provide non-LT comparison, each LT recipient was matched to at least 150 non-LT controls for same sex, age, and body mass index (BMI) from the UK Biobank registry.

LT recipients (vs matched non-LT controls) had significantly higher subcutaneous (13.82 ± 5.47 vs 12.10 ± 5.10 L, P < 0.001) and visceral fat (7.59 ± 3.75 vs 6.72 ± 3.06 L, P = 0.003) and lower LF (5.88 ± 7.14 vs 8.75 ± 6.50%, P < 0.001) and muscle volume (11.69 ± 2.95 vs 12.12 ± 2.90 L, P = 0.027). In subgroup analysis, patients transplanted for metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis (vs non-MASH cirrhosis) had higher ASAT, VAT, and MFI. A trend toward higher LF content was noted; however, this did not reach statistical significance (6.90 ± 7.35 vs 4.04 ± 6.23%, P = 0.189). Finally, compared with matched non-LT controls, patients transplanted for MASH cirrhosis had higher ASAT and VAT; however, FFMV and MFI were similar.

Using non-LT controls, the current study established the higher-than-expected adiposity burden among LT recipients, which is even higher among patients transplanted for MASH cirrhosis. These findings provide data needed to design future studies developing radiomics-based risk-stratification strategies in LT recipients.

The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET).

In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups.

A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.01), an effect observed in both gray and white matter regions.

Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.

Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown.

To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction.

Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023.

Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first.

The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models.

Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group.

The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin.

ClinicalTrials.gov Identifier: NCT05558098.

To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin.

Crossover trials with two periods, each treatment period lasting 4 weeks, with a 4-week washout period, were conducted. Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG + CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (Δ) in β-hydroxybutyric acid (β-HBA) before and after the CANA or PIOG + CANA treatments. The secondary outcomes were Δchanges in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and Δchanges in factors related to SGLT2 inhibitor-induced ketone body production including non-esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention-to-treat principle.

Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m2 were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels of ketone bodies (except for acetoacetate) in the PIOG + CANA group were significantly smaller than in the CANA group (219.84 ± 80.21 μmol/L vs. 317.69 ± 83.07 μmol/L, p < 0.001 in β-HBA; 8.98 ± 4.17 μmol/L vs. 12.29 ± 5.27 μmol/L, p = 0.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG + CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in Δchanges in serum NEFA levels with the differences in Δchanges in ketones of β-HBA and acetoacetate.

Supplementation of pioglitazone could alleviate canagliflozin-induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.

Sodium glucose cotransporter-2 inhibitors (SGLT-2i) are antidiabetic medications with remarkable cardiovascular (CV) benefits proven by multiple randomised controlled trials and real-world data. These drugs are also useful in the prevention of CV disease (CVD) in patients with diabetes mellitus (DM). Although DM as such is a huge risk factor for CVD, the CV benefits of SGLT-2i are not just because of antidiabetic effects. These molecules have proven beneficial roles in prevention and management of nondiabetic CVD and renal disease as well. There are various molecular mechanisms for the organ protective effects of SGLT-2i which are still being elucidated. Proper understanding of the role of SGLT-2i in prevention and management of CVD is important not only for the cardiologists but also for other specialists caring for various illnesses which can directly or indirectly impact care of heart diseases. This clinical review compiles the current evidence on the rational use of SGLT-2i in clinical practice.

The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from "nonalcoholic fatty liver disease" (NAFLD) to "metabolic dysfunction-associated fatty liver disease" (MAFLD) and, finally, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut-liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.

Sodium-glucose co-transporters type 2 inhibitors (SLGT2i) are highly effective in controlling type 2 diabetes, but reported beneficial cardiovascular effects suggest broader actions on insulin resistance. Weight loss may be initially explained by glycosuria-induced net caloric output and secondary volumetric reduction, but its maintenance could be due to loss of visceral fat mass. Structured ultrasound (US) imaging of abdominal adipose tissue ("eco-obesity") is a recently described methodology used to measure 5 consecutive layers of abdominal fat, not assessable by DEXA or CT scan: superficial subcutaneous (SS), deep subcutaneous (DS), preperitoneal (PP), omental (Om) and right perirenal (RK). PP, Om and RK are predictors of metabolic syndrome (MS) with defined cut-off points. To assess the effect of SLGT2i on every fat depot we enrolled 29 patients with type 2 Diabetes (HbA1c 6.5-9%) and Obesity (IMC > 30 kg/m2) in an open-label, randomized, phase IV trial (EudraCT: 2019-000979-16): the Omendapa trial. Diabetes was diagnosed < 12 months before randomization and all patients were treatment naïve. 14 patients were treated with metformin alone (cohort A) and 15 were treated with metformin + dapaglifozin (cohort B). Anthropometric measures and laboratory tests for glucose, lipid profile, insulin, HOMA, leptin, ultrasensitive-CRP and microalbuminuria (MAL) were done at baseline, 3rd and 6th months. At 6th month, weight loss was -5.5 ± 5.2 kg (5.7% from initial weight) in cohort A and -8.4 ± 4.4 kg (8.6%) in cohort B. Abdominal circumference showed a -2.7 ± 3.1 cm and -5.4 ± 2.5 cm reduction, respectively (p = 0.011). Both Metformin alone (-19.4 ± 20.1 mm; -21.7%) or combined with Dapaglifozin (-20.5 ± 19.4 mm; -21.8%) induced significant Om fat reduction. 13.3% of cohort A patients and 21.4% of cohort's B reached Om thickness below the cut-off for MS criteria. RK fat loss was significantly greater in cohort B group compared to cohort A, at both kidneys. Only in the Met + Dapa group, we observed correlations between Om fat with leptin/CRP/MAL and RK fat with HOMA-IR. US is a useful clinical tool to assess ectopic fat depots. Both Metformin and Dapaglifozin induce fat loss in layers involved with MS but combined treatment is particularly effective in perirenal fat layer reduction. Perirenal fat should be considered as a potential target for cardiovascular dapaglifozin beneficial effects.

Both high and low levels of serum potassium measurements are linked with a higher risk of adverse clinical events among patients with type 2 diabetes. The study was aimed at evaluating the implications of the various degrees of initial estimated glomerular filtration rate (eGFR) change on subsequent serum potassium homeostasis following sodium-glucose cotransporter-2 inhibitor (SGLT2i) initiation among patients with type 2 diabetes.

We used medical data from a multicenter health care provider in Taiwan and recruited 5529 patients with type 2 diabetes with baseline/follow-up eGFR data available after 4 to 12 weeks of SGLT2i treatment from June 1, 2016, to December 31, 2018. SGLT2i treatment was associated with an initial mean (SEM) eGFR decline of -3.5 (0.2) mL/min per 1.73 m2 in overall study participants. A total of 36.7% (n=2028) of patients experienced no eGFR decline, and 57.9% (n=3201) and 5.4% (n=300) of patients experienced an eGFR decline of 0% to 30% and >30%, respectively. Patients with an initial eGFR decline of >30% were associated with higher variability in consequent serum potassium measurement when compared with those without an initial eGFR decline. Participants with a pronounced eGFR decline of >30% were associated with a higher risk of hyperkalemia ≥5.5 (adjusted hazard ratio,4.59 [95% CI, 2.28-9.26]) or use of potassium binder (adjusted hazard ratio, 2.65 [95% CI, 1.78-3.95]) as well as hypokalemia events <3.0 mmol/L (adjusted hazard ratio, 3.21 [95% CI, 1.90-5.42]) or use of potassium supplement (adjusted hazard ratio, 1.87 [95% CI, 1.37-2.56]) following SGLT2i treatment after multivariate adjustment.

Physicians should be aware that the eGFR trough occurs shortly, and consequent serum potassium changes following SGLT2i initiation.

To examine the effect of empagliflozin on liver fat content in individuals with and without type 2 diabetes (T2D) and the relationship between the decrease in liver fat and other metabolic actions of empagliflozin.

Thirty individuals with T2D and 27 without were randomly assigned to receive in double-blind fashion empagliflozin or matching placebo (2:1 ratio) for 12 weeks. Participants underwent 75-g oral glucose tolerance testing and measurement of liver fat content with MRS before therapy and at study end. Hepatic glucose production before the start of therapy was measured with 3-3H-glucose.

Empagliflozin caused an absolute reduction of 2.39% ± 0.79% in liver fat content compared with an increase of 0.91% ± 0.64% in participants receiving placebo (P < 0.007 with ANOVA). The decrease in liver fat was comparable in both individuals with diabetes and those without (2.75% ± 0.81% and 1.93% ± 0.78%, respectively; P = NS). The decrease in hepatic fat content caused by empagliflozin was strongly correlated with baseline liver fat content (r = -0.62; P < 0.001), decrease in body weight (r = 0.53; P < 0.001), and improvement in insulin sensitivity (r = -0.51; P < 0.001) but was not related to the decrease in fasting plasma glucose or HbA1c or the increase in hepatic glucose production.

Empagliflozin is effective in reducing liver fat content in individuals with and without T2D. The decrease in liver fat content is independent of the decrease in plasma glucose concentration and is strongly related to the decrease in body weight and improvement in insulin sensitivity.

Dapagliflozin exerts cardioprotective effects in Type 2 Diabetes Mellitus (T2DM). However, whether these effects prevent electrocardiographic changes associated with T2DM altogether remain unknown. Our aim was to investigate the prophylactic effect of dapagliflozin pretreatment on the rat ECG using a high-fat, high-fructose (HFHf) diet and a low dose streptozotocin (STZ) model of T2DM.

Twenty-five (25) rats were randomized into five (5) groups: normal control receiving a normal diet while the other groups received an 8-week HFHf and 40mg/kg STZ on day 42, and either: saline for the diabetic control (1 mg/kg/d), low dose (1.0 mg/kg/d) and high dose dapagliflozin (1.6 mg/kg/d), or metformin (250 mg/kg/d). Oral glucose tolerance (OGT), electrocardiograms (ECGs), paracardial adipose mass, and left ventricular fibrosis were determined. Data were analyzed using GraphPad version 9.0.0.121, with the level of significance at p < 0.05.

Compared to the diabetic control group, a high dose of dapagliflozin preserved the OGT (p = 0.0001), QRS-duration (p = 0.0263), QT-interval (p = 0.0399), and QTc intervals (p = 0.0463). Furthermore, the high dose dapagliflozin group had the lowest paracardial adipose mass (p = 0.0104) and fibrotic area (p = 0.0001). In contrast, while metformin showed favorable effects on OGT (p = 0.0025), paracardial adiposity (p = 0.0153) and ventricular fibrosis (p = 0.0291), it did not demonstrate significant antiarrhythmic effects.

Pretreatment with higher doses of Dapagliflozin exhibits prophylactic cardioprotective characteristics against diabetic cardiomyopathy that include antifibrotic and antiarrhythmic qualities. This suggests that higher doses of dapagliflozin could be a more effective initial therapeutic option in T2DM.

In 2020, breast cancer (BC) has surpassed lung cancer as the most diagnosed cancer in the world. Tumor microenvironment (TME) plays a critical role in resistance to standard therapies and tumor progression. Two key factors within the TME include adenosine, an immunosuppressive molecule, and glucose, which serves as the primary energy source for tumor cells. In this scenario, inhibiting the purinergic pathway and glucose uptake might be a promising strategy. Therefore, we sought to evaluated different treatment approaches in BC cells (Dapagliflozin, a SGLT2 inhibitor; Paclitaxel, the standard chemotherapy for BC; and ARL67156/APCP, inhibitors of CD39 and CD73, respectively). The expression of some membrane markers relevant to resistance was assessed. BC cell-lines (MCF-7 and MDA-MB-231) were co-treated and cell viability, cell cycle, and annexin/PI assays were performed. Our analysis showed promising results, where the combination of these compounds led to cell death by apoptosis/necrosis and cell cycle arrest. Dapagliflozin showed more impact on early apoptosis, whereas Paclitaxel led to late apoptosis/necrosis as the main mechanism of cell death. Inhibiting purinergic signaling also contributed to reducing cell viability together with the other drugs, suggesting it could have an influence on breast cancer survival mechanisms. Indeed, the overexpression of the NT5E gene in patients with ER+ tumors is strongly associated with reduced overall survival and progression-free interval. However, more studies are needed to fully understand the interactions and mechanism underlying these co-treatment multi-targeting approaches.

Pharmacologic inhibition of the sodium-glucose transporter 2 (SGLT2) in the proximal tubule brings about physiologic changes predicted to both increase and decrease kidney K + excretion. Despite these effects, disorders of plasma K + concentration are an uncommon occurrence. If anything, these drugs either cause no effect or a slight reduction in plasma K + concentration in patients with normal kidney function but seem to exert a protective effect against hyperkalemia in the setting of reduced kidney function or when given with drugs that block the renin-angiotensin-aldosterone axis. In this review, we discuss the changes in kidney physiology after the administration of SGLT2 inhibitors predicted to cause both hypokalemia and hyperkalemia. We conclude that these factors offset one another, explaining the uncommon occurrence of dyskalemias with these drugs. Careful human studies focusing on the determinants of kidney K + handling are needed to fully understand how these drugs attenuate the risk of hyperkalemia and yet rarely cause hypokalemia.

To investigate the renal, cardiovascular, and safety outcomes when sodium-glucose cotransporter-2 inhibitors (SGLT2is) were added to insulin therapy in patients with type-2 diabetes mellitus (T2DM).

We searched Embase, PubMed, and Cochrane libraries for reports published up to Feb 2023. Randomized controlled trials (RCTs) comparing SGLT2is and insulin combination therapy (SGLT2is + INS group) with insulin therapy alone (INS group) in T2DM were included.

Fourteen RCTs involving six thousand one hundred twenty subjects with durations of 12-104 weeks were included. Compared with the insulin group, the SGLT2is + INS group showed decreased glycosylated hemoglobin values and insulin dosages (P < 0.00001). Meanwhile, the SGLT2is + INS group had a reduced urinary albumin/creatinine ratio (UACR) by 25.42 mg/g and uric acid concentration (P = 0.030; P = 0.001, respectively) but the estimated glomerular filtration rate (eGFR) and renal-related adverse events were unaffected (P = 0.070; P = 0.880, respectively). Blood pressure and body weight were lower in the SGLT2is + INS group (P < 0.01). However, the risk of genital infection was bigger when SGLT2is were added to insulin therapy (P < 0.00001), but the risks of severe hypoglycemia or urinary tract infection were equal between the two groups (P > 0.05).

Adding SGLT2is to insulin therapy in T2DM patients showed better glucose control and decreased albuminuria, uric acid, blood pressure, and body weight without a reduction in the eGFR.

Methotrexate (MTX), a folic acid antagonist, is commonly prescribed as a cytotoxic drug to treat several conditions such as leukemia and inflammation-related diseases, including rheumatoid arthritis and psoriasis. However, its use in clinical practice has been limited due to its fatal side effects, especially hepatotoxicity. Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has recently been reported to exhibit anti-inflammatory and anti-oxidative properties. This study was aimed to evaluate the effect of Empagliflozin on liver injury induced by MTX in rats. The rats were divided into five groups as control, MTX (20 mg/kg; i.p.), Empagliflozin (30 mg/kg/day; i.p.), MTX and Empagliflozin (10 and 30 mg/kg/day; i.p.). Histopathologic alterations were examined for assessment of the liver injury. Furthermore, the levels of tissue malondialdehyde (MDA) and activity of anti-oxidative enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase, as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were evaluated. Our results revealed that treatment with Empagliflozin significantly improved histopathologic alterations, and elevated levels of AST and ALT induced by MTX administration. Additionally, altered activities of SOD, GPx, and catalase were significantly improved followed by Empagliflozin treatment. However, the higher dose of Empagliflozin was observed to have several benefits compared to the lower dose. Our data suggest that Empagliflozin might possess a protective role against MTX-induced hepatotoxicity by inhibiting oxidative stress in liver tissue.

There is a bidirectional pathophysiological interaction between the heart and the kidneys, and prolonged physiological stress to the heart and/or the kidneys can cause adverse cardiorenal complications, including but not limited to subclinical cardiomyopathy, heart failure and chronic kidney disease. Whilst more common in individuals with Type 2 diabetes, cardiorenal complications also occur in the absence of diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially approved to reduce hyperglycaemia in patients with Type 2 diabetes. Recently, these agents have been shown to significantly improve cardiovascular and renal outcomes in patients with and without Type 2 diabetes, demonstrating a robust reduction in hospitalisation for heart failure and reduced risk of progression of chronic kidney disease, thus gaining approval for use in treatment of heart failure and chronic kidney disease. Numerous potential mechanisms have been proposed to explain the cardiorenal effects of SGLT2i. This review provides a simplified summary of key potential cardiac and renal mechanisms underlying the cardiorenal benefits of SGT2i and explains these mechanisms in the clinical context. Key mechanisms related to the clinical effects of SGLT2i on the heart and kidneys explained in this publication include their impact on (1) tissue oxygen delivery, hypoxia and resultant ischaemic injury, (2) vascular health and function, (3) substrate utilisation and metabolic health and (4) cardiac remodelling. Knowing the mechanisms responsible for SGLT2i-imparted cardiorenal benefits in the clinical outcomes will help healthcare practitioners to identify more patients that can benefit from the use of SGLT2i.

Non-alcoholic fatty liver disease (NAFLD) has become a leading cause of liver disease, affecting 30% of the global population. NAFLD prevalence is particularly high in obese individuals and patients with type 2 diabetes mellitus (T2DM). NAFLD ranges from simple fat deposition in the liver to necroinflammation and fibrosis (non-alcoholic steatohepatitis (NASH)), NASH-cirrhosis, and/or hepatocellular carcinoma. Insulin resistance plays a key role in NAFLD pathogenesis, alongside dysregulation of adipocytes, mitochondrial dysfunction, genetic factors, and changes in gut microbiota. Since insulin resistance is also a major predisposing factor of T2DM, the administration of anti-diabetic drugs for the management of NAFLD seems reasonable.

In this review we provide the NAFLD-associated mechanisms of action of some of the most widely used anti-diabetic drugs, namely metformin, pioglitazone, sodium-glucose transport protein-2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor analogs (GLP1 RAs), and dipeptyl-peptidase-4 inhibitors (DPP4i) and present available data regarding their use in patients with NAFLD, with and without T2DM.

Both metformin and DPP4i have shown rather contradictory results, while pioglitazone seems to benefit patients with NASH and is thus the only drug approved for NASH with concomitant significant liver fibrosis by all major liver societies. On the other hand, SGLT2i and GLP1 RAs seem to be beneficiary in patients with NAFLD, showing both remarkable results, with SGLT2i proving to be more efficient in the only head-to-head study so far.

In patients with NAFLD and diabetes, pioglitazone, GLP1 RAs, and SGLT2i seem to be logical treatment options. Larger studies are needed before these drugs can be recommended for non-diabetic individuals.

Diabetes mellitus is a risk factor for muscle loss and sarcopenia. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) or "gliflozins" are one of the newest anti-hyperglycemic drugs. They reduce blood glucose levels by inhibiting renal glucose reabsorption in the early proximal convoluted tubule. Various randomized trials showed that SGLT2i have cardio-protective and reno-protective action. SGLT2i also affect body composition. They usually decrease body fat percentage, visceral and subcutaneous adipose tissue. However, regarding the muscle mass, there are conflicting findings some studies showing detrimental effects and others showed neutral or beneficial effects. This issue is extremely important not only because of the wide use of SGLT2i around globe; but also skeletal muscle mass consumes large amounts of calories during exercise and is an important determinant of resting metabolic rate and skeletal muscle loss hinders energy consumption leading to obesity. In this systematic review, we extensively reviewed the experimental and clinical studies regarding the impact of SGLT2i on muscle mass and related metabolic alterations. Importantly, studies are heterogeneous and there is unmet need to highlight the alterations in muscle during SGLT2i use.

Diabetes is associated with an increased risk of deleterious changes in muscle mass and function or sarcopenia, leading to physical inactivity and worsening glycaemic control. Given the negative energy balance during sodium-glucose cotransporter-2 (SGLT2) inhibition, whether SGLT2 inhibitors affect skeletal muscle mass and function is a matter of concern. However, how SGLT2 inhibition affects the skeletal muscle function in patients with diabetes remains insufficiently explored. We aimed to explore the effects of canagliflozin (CANA), an SGLT2 inhibitor, on skeletal muscles in genetically diabetic db/db mice focusing on the differential responses of oxidative and glycolytic muscles.

Db/db mice were treated with CANA for 4 weeks. We measured running distance and handgrip strength to assess skeletal muscle function during CANA treatment. At the end of the experiment, we performed a targeted metabolome analysis of the skeletal muscles.

CANA treatment improved the reduced endurance capacity, as revealed by running distance in db/db mice (414.9 ± 52.8 vs. 88.7 ± 22.7 m, P < 0.05). Targeted metabolome analysis revealed that 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate (AICARP), a naturally occurring AMP-activated protein kinase (AMPK) activator, increased in the oxidative soleus muscle (P < 0.05), but not in the glycolytic extensor digitorum longus muscle (P = 0.4376), with increased levels of AMPK phosphorylation (P < 0.01).

This study highlights the potential role of the AICARP/AMPK pathway in oxidative rather than glycolytic skeletal muscles during SGLT2 inhibition, providing novel insights into the mechanism by which SGLT2 inhibitors improve endurance capacity in patients with type 2 diabetes.