The impact of sodium glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists on insulin utilisation and costs in Australia: a national retrospective observational cross-sectional study.

Background: Global insulin requirements for type 2 diabetes were predicted to increase by more than 20% from 2018 to 2030. However, this did not anticipate the rapid increase in use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors that has occurred over recent years. The current study aims to examine changes in insulin utilisation and costs in Australia from 2003 to 2023. Methods: We conducted a large-scale observational study of national insulin utilisation and expenditure in Australia from 2003 to 2023 using the Australian Pharmaceutical Benefits Scheme. The proportion of insulin-treated people with type 2 diabetes between 2013 and 2023 was estimated using National Diabetes Services Scheme data. Joinpoint models and interrupted time series analysis were used to examine utilisation trends. Findings: Insulin utilisation (units of insulin per person with diabetes) increased by an average of 2.71% per annum (95% CI 1.97, 3.73) from 2003 to 2015, then fell by 2.70% per annum (95% CI -4.55, -1.39) from 2015 to 2023. The proportion of insulin-treated people with type 2 diabetes increased by 1.00% per annum (95% CI 0.81, 1.25) from 2013 to 2020, then fell by 0.66% per annum (95% CI -1.62, -0.04) from 2020 to 2023. A 43% reduction in inflation-adjusted insulin expenditure was observed between 2015 and 2023 due to a combination of reduced utilisation and reduction in the price of insulin glargine. Interpretation: Projected global insulin requirements and costs may be less than previously anticipated if reduced use of insulin in Australia is similarly observed in other countries. Funding: No funding was received for this study.

Hyperkalemia and maintenance of renin-angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors.

BACKGROUND: Post-hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i). METHODS: Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014-2021). The outcomes were incident hyperkalaemia (potassium > 5.0 mmol/L), mild hyperkalemia (potassium > 5-≤5.5 mmol/L) and moderate to severe hyperkalemia (potassium > 5.5 mmol/L). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs). RESULTS: 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one third of participants in each arm discontinued treatment within a year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64-0.93), including both mild (0.76; 0.62-0.93) and moderate/severe (0.53; 0.40-0.69) hyperkalemia events. Of 19.116 participants that used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83-1.14). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. CONCLUSIONS: In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy.

Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Heart Failure in Patients With Type 2 Diabetes Mellitus: A Systematic Review.

Type 2 diabetes mellitus (T2DM) is a major global health concern with a strong association with increased cardiovascular morbidity and mortality. The prevalence of heart failure is significantly higher in the T2DM population compared to non-diabetic individuals. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have emerged as a promising therapeutic class for managing T2DM, with potential cardioprotective effects. This systematic review aims to comprehensively evaluate the impact of SGLT-2 inhibitors on cardiovascular outcomes in adult patients with T2DM. A comprehensive electronic search was conducted across multiple databases and registries from May 8 to June 6, 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Studies published between January 2019 and June 6, 2024 that evaluated the effects of SGLT-2 inhibitors on cardiovascular outcomes in adults with T2DM were included. The risk of bias was assessed using appropriate tools based on the study design. A narrative synthesis was planned to summarize the findings. The search strategy identified 25 studies (22 randomized controlled trials, three cohort studies) for inclusion in the systematic review. Most of the included studies demonstrated a low overall risk of bias, although some observational studies had some limitations. The studies investigated the effects of various SGLT-2 inhibitors, including empagliflozin, canagliflozin, dapagliflozin, and others, on cardiovascular endpoints such as heart failure-related hospitalizations, mortality, cardiac structure and function, and biomarkers. The findings suggest that SGLT-2 inhibitors may have a beneficial impact on reducing the risk of heart failure-related hospitalizations and potentially improving other cardiovascular outcomes in patients with T2DM. This comprehensive systematic review provides valuable insights into the emerging role of SGLT-2 inhibitors in mitigating cardiovascular complications associated with T2DM. The findings have important clinical implications and may inform evidence-based guidelines and treatment strategies aimed at improving cardiovascular outcomes in this high-risk patient population.

The effects of sodium-glucose cotransporter 2 inhibitors on the 'forgotten' right ventricle.

With the progress in diagnosis, treatment and imaging techniques, there is a growing recognition that impaired right ventricular (RV) function profoundly affects the prognosis of patients with heart failure (HF), irrespective of their left ventricular ejection fraction (LVEF). In addition, right HF (RHF) is a common complication associated with various diseases, including congenital heart disease, myocardial infarction (MI), pulmonary arterial hypertension (PAH) and dilated cardiomyopathy (DCM), and it can manifest at any time after left ventricular assist devices (LVADs). The sodium-glucose cotransporter 2 (SGLT2) inhibition by gliflozins has emerged as a cornerstone medicine for managing type 2 diabetes mellitus (T2DM) and HF, with an increasing focus on its potential to enhance RV function. In this review, we aim to present an updated perspective on the pleiotropic effects of gliflozins on the right ventricle and offer insights into the underlying mechanisms. We can ascertain their advantageous impact on the right ventricle by discussing the evidence obtained in animal models and monumental clinical trials. In light of the pathophysiological changes in RHF, we attempt to elucidate crucial mechanisms regarding their beneficial effects, including alleviation of RV overload, reduction of hyperinsulinaemia and inflammatory responses, regulation of nutrient signalling pathways and cellular energy metabolism, inhibition of oxidative stress and myocardial fibrosis, and maintenance of ion balance. Finally, this drug class's potential application and benefits in various clinical settings are described, along with a prospective outlook on future clinical practice and research directions.

Long-term efficacy of SGLT2 inhibitors for elderly patients with acute decompensated heart failure: The OASIS-HF study.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been widely demonstrated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization, regardless of left ventricular ejection fraction (LVEF). However, data on the extent to which rehospitalization is suppressed following HF hospitalization are limited. This study investigated the effects of SGLT2i on rehospitalization and cardiovascular death. METHODS AND RESULTS: The OASIS-HF study, a multicentre, prospective observational cohort study, enrolled 361 patients aged ≥75 years hospitalized for acute decompensated HF. The impact on composite events of HF rehospitalization or cardiovascular death and the number of annual rehospitalizations were evaluated between the conventional medical therapy and SGLT2i groups. The change in eGFR slope at the 1-year mark after the initiation of treatment in both groups was also assessed. Over an average follow-up period of 24.9 months, composite events occurred in 70 (35.4%) of the conventional therapy group and 36 (22.1%) of the SGLT2i group (log-rank: P = 0.016). The average number of rehospitalizations for HF per year was 0.22 ± 0.13 vs. 0.14 ± 0.08, respectively (P = 0.019). The change in eGFR over 1 year was significantly slower in the SGLT2i group compared with the conventional group (-3.55 ± 8.46 vs. -1.42 ± 7.28 mL/min/1.73 m2, P = 0.025). CONCLUSIONS: The SGLT2i are not only associated with the reduction of the composite events of HF rehospitalization or cardiovascular death and protect against worsening renal function but also with a decrease in long-term repeated HF rehospitalizations.

Real-world data on Empagliflozin and Dapagliflozin use in patients with HEART failure: The RED-HEART study.

AIMS: We aimed to determine the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and to identify clinical factors associated with their use in patients with heart failure (HF) in a real-life setting. METHODS: Real-world data on Empagliflozin and Dapagliflozin use in patients with HEART failure: The RED-HEART study is a multicentre, cross-sectional and observational study that included HF patients in the outpatient setting regardless of ejection fraction from 19 cardiology centres between August 2023 and December 2023. RESULTS: The study population consisted of 1923 patients with HF, predominantly men (61.2%), with a median age of 66 (range: 19-101) years. Overall, 925 patients (48.1%) were receiving SGLT2is. Among the study population, 22.1% had HF with preserved ejection fraction, 21.5% had HF with mildly reduced ejection fraction, 56.4% had HF with reduced ejection fraction and the use of SGLT2is was 42.0%, 47.9% and 50.6% in each group, respectively (P = 0.012). The use of SGLT2is was 76.6% in patients with HF and diabetes, 19.8% in patients with HF and chronic kidney disease and 26.8% in patients without diabetes and chronic kidney disease (P < 0.001). Higher education level [odds ratio (OR): 1.80; 95% confidence interval (CI): 1.06-3.05; P = 0.027], higher household income (OR: 3.46; 95% CI: 1.27-9.42; P = 0.015), New York Heart Association functional class IV (OR: 2.72; 95% CI: 1.16-6.35; P = 0.021), diabetes (OR: 9.42; 95% CI: 6.72-13.20; P < 0.001), the use of angiotensin receptor-neprilysin inhibitors (ARNis) (OR: 4.09; 95% CI: 2.39-7.01; P < 0.001), the use of mineralocorticoid receptor antagonists (MRAs) (OR: 2.02; 95% CI: 1.49-2.75; P < 0.001), the use of loop diuretics (OR: 1.62; 95% CI: 1.18-2.22; P = 0.003) and the use of thiazide diuretics (OR: 1.72; 95% CI: 1.30-2.29; P < 0.001) were independently associated with the use of SGLT2is. Conversely, atrial fibrillation (OR: 0.63; 95% CI: 0.45-0.88; P = 0.008), chronic kidney disease (OR: 0.53; 95% CI: 0.37-0.76; P = 0.001), the use of dihydropyridine calcium channel blockers (OR: 0.68; 95% CI: 0.48-0.98; P = 0.042) and the use of statins (OR: 0.67; 95% CI: 0.49-0.91; P = 0.010) were independently associated with the non-use of SGLT2is. CONCLUSIONS: The RED-HEART study provided comprehensive real-world data about implementing SGLT2is in patients with HF. These results suggest that there is a need for organized action and close collaboration between healthcare providers to improve the implementation of SGLT2is, especially in patients with HF with preserved ejection fraction and chronic kidney disease.

Reversible complete left bundle branch block and a wide QRS complex following administration of sodium-glucose cotransporter-2 inhibitor and volume reduction in a patient with systolic heart failure: a case report.

Background: Guidelines recommend optimal medical therapy before cardiac resynchronization therapy (CRT) implantation. Herein, we report the potential effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in improving the QRS duration and volume reduction in a patient with complete left bundle branch block (CLBBB) and reduced cardiac function. Case summary: A 68-year-old man with a history of ischaemic cardiomyopathy and decreased cardiac function had exacerbation of heart failure (HF) at an outpatient clinic. His QRS duration increased remarkably with a CLBBB of 143 ms on an electrocardiogram, and left ventricular desynchrony was assessed by echocardiography, suggesting an indication of CRT implantation. Administration of an SGLT2i and multimodal treatment for HF stabilized his HF condition and improved the QRS duration and volume reduction thereafter. The CLBBB recovered to incomplete LBBB with a QRS duration of 112 ms on electrocardiography after 6 months. The patient has been stably followed up with continuous medications, including SGLT2i, without requiring CRT implantation or worsening of HF for 12 months. Discussion: This case presents a unique scenario wherein electrical and mechanical reverse remodelling occurred in a patient with systolic HF and CLBBB, highlighting the potential benefits of SGLT2i in HF management. It may be important to carefully consider CRT indications when seeking other options to treat HF conditions and recognize an unusual phenomenon of reverse LBBB in clinical cases.

A systematic review on effect of sodium-glucose cotransporter-2 inhibitors on the metabolic and endocrinological profile of patients with polycystic ovarian syndrome.

BACKGROUND: Polycystic ovarian syndrome (PCOS) has been a common metabolic and endocrinal disorder, prevalent amongst women belonging to the reproductive age group. The aim of this systematic review was to assess the safety and efficacy profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors (Canagliflozin, Dapagliflozin, Empagliflozin, and Licogliflozin) for the treatment of women suffering from PCOS. METHODS: A literature search in PubMed, Science Direct, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted for randomized clinical trials of SGLT-2 inhibitors in PCOS patients by applying predetermined inclusion and exclusion criteria. The articles in English language were included. RESULTS: Four randomized controlled trials including 146 subjects were included in the review. The clinical studies indicated a significant decrease in the levels of total testosterone, free androgen index, total body fat, homeostasis model assessment-estimated insulin resistance (HOMA-IR), body mass index (BMI), dehydroepiandrosterone sulfate (DHEAS) and fasting plasma glucose (FPG). However, no significant difference was reported in levels of sex hormone-binding globulin (SHBG). Overall, there was improvement in metabolic and endocrine profiles, suggesting a potentially beneficial impact of SGLT2 inhibitors in the management of PCOS. CONCLUSION: There is a requirement for large extensive clinical trials to demonstrate the efficacy of SGLT-2 inhibitors in PCOS patients.

Effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular and cerebrovascular diseases: a meta-analysis of controlled clinical trials.

Objective: Evaluate the effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i) on cardiovascular and cerebrovascular diseases. Methods: Articles of SGLT2i on cardiovascular and cerebrovascular diseases were searched. Two authors independently screened the literature, extracted the data, assessed the quality of the study and performed statistical analyses using Review Manager 5.4. Results: Random-effect model was used to merge the OR values, and the pooled effect showed that SGLT2i had significant preventive effects on cardiovascular death (OR=0.76, 95%CI 0.64 to 0.89), myocardial infarction (OR=0.90, 95%CI 0.84 to 0.96), heart failure (OR=0.69, 95%CI 0.64 to 0.74) and all-cause mortality (OR=0.65, 95%CI 0.58 to 0.73). Empagliflozin, dapagliflozin and canagliflozin all reduced the incidence of heart failure (OR=0.72, 95%CI 0.64 to 0.82; OR=0.56, 95%CI 0.39 to 0.80; OR=0.62, 95%CI 0.53 to 0.73), but only dapagliflozin displayed a favorable effect on inhibiting stroke (OR=0.78, 95%CI 0.63 to 0.98). SGLT2i could prevent stroke (OR=0.86, 95%CI 0.75 to 0.99), heart failure (OR=0.63, 95%CI 0.56 to 0.70) and all-cause mortality (OR=0.64, 95%CI 0.57 to 0.72) compared to DPP-4i. Furthermore, SGLT2i could reduce the incidence of heart failure (OR=0.72, 95%CI 0.67 to 0.77) and cardiovascular death (OR=0.72, 95%CI 0.54 to 0.95) in patients with high-risk factors. Conclusions: SGLT2i affects cardiovascular death, myocardial infarction, heart failure and all-cause mortality. Only dapagliflozin displayed a favorable effect on inhibiting stroke. SGLT2i could prevent stroke, heart failure and all-cause mortality compared to DPP-4i. In addition, SGLT2i significantly reduced the development of heart failure and cardiovascular death in patients with high-risk factors. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42024532783.

Impact on ventricular arrhythmic burden of SGLT2 inhibitors in patients with chronic heart failure evaluated with cardiac implantable electronic device monitoring.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have revolutionized the therapeutic scenario of heart failure, demonstrating favorable effects on mortality and quality of life. Previous studies have yielded conflicting data regarding the effects on ventricular arrhythmias. METHODS: A prospective observational study was conducted to investigate the anti-arrhythmic properties of SGLT2 inhibitors evaluating the intra-patient difference in major adverse arrhythmic cardiac events (MAACE) over a six-month period in patients with chronic heart failure who were undergoing continuous monitoring using a cardiac implantable electronic device. RESULTS: From January 2022 to January 2023, 82 patients [median age 63 years (IQR 15), male 87 %] were enrolled in the study, with a median follow-up of 28 weeks (IQR 5). The rate of MAACE at baseline was 11 %, without relevant differences in the follow up in terms of major and minor arrhythmic events. In patients with an arrhythmic phenotype at baseline, a mild but non statistically significant reduction of MAACE (from 36 % to 28 %, p = 0.727) was observed and a significant decrease of non-sustained ventricular tachycardia (from 68 % to 32 %, p = 0.022). CONCLUSIONS: Our findings suggest potential anti-arrhythmic properties of SGLT2 inhibitors, evident in patients with arrhythmic events before the initiation of the drug.

Sodium-glucose cotransporter 2 inhibitors and the risk of Parkinson disease in real-world patients with type 2 diabetes.

IMPORTANCE: Diabetes increases the risk of Parkinson disease (PD). Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new glucose-lowering therapeutic class, have shown neuroprotective effects in mechanistic studies. However, the association between SGLT2 inhibitors and PD risk in real-world populations with type 2 diabetes (T2D) remains unclear. OBJECTIVE: The aim was to assess the association between SGLT2 inhibitors and the risk of PD in older populations with T2D. DESIGN, SETTING AND PARTICIPANTS: This retrospective cohort analysis used Medicare claims data from 2016 to 2020 to identify fee-for-service beneficiaries ≥65 years diagnosed with T2D and without pre-existing PD. EXPOSURES: The initiation of an SGLT2 inhibitor was compared with that of a dipeptidyl peptidase-4 (DPP4) inhibitor. MAIN OUTCOMES AND MEASURES: The outcome was the first incident PD ever since the date initiating either an SGLT2 inhibitor or a DPP4 inhibitor. We employed a 1:1 propensity score matching to balance the baseline covariates between treatment groups, including sociodemographics, comorbidities and co-medications. We applied Cox regression models to assess the effect of SGLT2 inhibitors versus DPP4 inhibitors on incident PD. RESULTS: Of 89 330 eligible Medicare beneficiaries (mean age: 75 ± 7 years, 52% women), 0.6% (n = 537) had incident PD over the follow-up. After 1:1 propensity matching, the PD incidence was 2.5 and 3.5 events per 1000 person-years in the SGLT2 inhibitor group and DPP4 inhibitor group, respectively. The SGLT2 inhibitor group was associated with a significantly lower risk of incident PD than the DPP4 inhibitor group (hazard ratio: 0.70 [95% confidence interval: 0.55-0.89]). There is a potential trend that the risk reduction in incident PD was profound in non-Hispanic Black individuals and insulin users. CONCLUSION AND RELEVANCE: Compared to DPP4 inhibitors, SGLT2 inhibitors were associated with a significantly lower risk of incident PD in older populations with T2D.

Options for patients with out-of-control blood pressure: after all avenues have been exhausted.

INTRODUCTION: Uncontrolled hypertension is the leading risk factor for global mortality. Most hypertensive patients can be controlled with standard medication combinations, but some may not respond adequately to ≥3 or even to ≥5 antihypertensive agents. AREAS COVERED: In this review, we summarize the recent literature on difficult-to-treat hypertension identified by a Medline search, and we discuss the options for fourth line and subsequent therapy. EXPERT OPINION: It is essential to confirm resistant hypertension with out-of-office blood pressure measurements and to consider lifestyle factors, adherence to medication and secondary causes of hypertension. When true resistant hypertension is confirmed and blood pressure is not controlled with an optimal triple combination, preferably as a fixed dose combination tablet, spironolactone is usually recommended as the fourth medication. Comorbid conditions should be treated as appropriate with sodium-glucose-cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, sacubitril-valsartan or finerenone. Renal denervation appears to be a useful addition to overcome some of the problems of medication adherence. The endothelin antagonist aprocitentan may be a final option in some countries. Of the drugs in development, the RNA based therapeutics that inhibit angiotensinogen synthesis appear to be some of the most promising.

Sodium-glucose cotransporter 2 inhibitors and renal cancer in the US FDA adverse event reporting system.

BACKGROUND: Recent evidence suggests an association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and a higher risk of renal cancer. OBJECTIVE: We conducted a pharmacovigilance analysis using the US FDA Adverse Event Reporting System (FAERS) to investigate the disproportionate association between SGLT2 inhibitors and renal cancer. METHODS: We used AERSMine to mine data from FAERS, covering the period from 2014 Q1 to 2023 Q3. The control group was treated with other glucose-lowering medications (ATC-A10B). Disproportionality analysis results were performed using a proportional reporting ratio (PRR) with a 95% confidence interval (CI) and an information component (IC) with 95% credible interval. RESULTS: Compared to the control group, the SGLT2 inhibitor group had a higher disproportionate renal cancer reporting frequency (0.92 vs 0.27/1000 reports; PRR 3.38; 95% CI 2.68-4.25; p < 0.001) with an IC of 1.36 (0.60-2.06), comprising dapagliflozin (PRR 4.14; 2.95-5.80; p < 0.001), empagliflozin (PRR 2.74; 1.94-3.89; p < 0.001), and canagliflozin (PRR 3.56; 2.48-5.12; p < 0.001). Consistent results were obtained in the diabetes indication with the primary outcomes only for the SGLT2 inhibitors group (not individual molecule). The results of the sensitivity analysis (excluding hypertension indication or antihypertensive drugs, obesity, smoking, alpha-1 blockers, or anti-renal cancer drugs) were highly consistent with the main outcomes, indicating good robustness of the results. The results from 2004 Q1 to 2023 Q3 were similar to those from 2014 Q1 to 2023 Q3, with the exception of empagliflozin. CONCLUSION: There was a disproportionate association between SGLT2 inhibitors and renal cancer, which supports the current meta-analysis results indicating an increased risk of renal cancer associated with SGLT2 inhibitors.

Translating the 2021 ESC heart failure guideline recommendations in daily practice: Results from a heart failure survey. A scientific statement of the ESC Council for Cardiology Practice and the Heart Failure Association of the ESC.

AIMS: Real-world data show that guidelines are insufficiently implemented, and particularly guideline-directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines. METHODS AND RESULTS: A 22-question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non-cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor (ACEi/ARNi) (91.2%), beta-blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1-3 months by 52%, 3-6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time-to-initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach. CONCLUSION: Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care.

Inpatient initiation of sodium-glucose cotransporter-2 inhibitors: the prescribing learning curve.

We aimed to describe the safety and tolerability of initiation of sodium-glucose cotransporter 2 inhibitors (SGLT2i) during hospitalisation with heart failure, and the frequency of, and reasons for, subsequent discontinuation. In total, 934 patients who were not already prescribed a SGLT2i were hospitalised with heart failure, 77 (8%) were initiated on a SGLT2i a median of five (3-8.5) days after admission and two (0.5-5) days prior to discharge. During a median follow-up of 182 (124-250) days, SGLT2i were discontinued for 10 (13%) patients, most frequently due to deteriorating renal function. We observed reductions in body weight (mean difference 2.0 ± 0.48 kg, p<0.001), systolic blood pressure (mean difference 9.5 ± 1.9 kg, p<0.001) and small, non-significant reductions in estimated glomerular filtration rate (eGFR mean difference 2.0 ± 1.5 ml/min/1.73 m2, p=0.19) prior to initiation, with further modest reductions in weight (mean difference 1.2 ± 0.4 kg, p=0.006) but not systolic blood pressure (2.4 ± 1.5 mmHg, p=0.13) or eGFR following initiation of SGLT2i. At discharge the proportion prescribed a beta blocker (44% to 92%), angiotensin-receptor/neprilysin inhibitor (6% to 44%) and mineralocorticoid-receptor antagonist (35% to 85%) had increased. In conclusion, inpatient initiation of SGLT2i was safe and well tolerated in a real-world cohort of patients hospitalised with worsening HF. We observed a 13% frequency of discontinuation or serious side effects.

Exploring the mortality and cardiovascular outcomes with SGLT-2 inhibitors in patients with T2DM at dialysis commencement: a health global federated network analysis.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have demonstrated associations with lowering cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). However, the impact of SGLT-2is on individuals at dialysis commencement remains unclear. The aim of this real-world study is to study the association between SGLT-2is and outcomes in patients with T2DM at dialysis commencement. METHODS: This is a retrospective cohort study of electronic health records (EHRs) of patients with T2DM from TriNetX Research Network database between January 1, 2012, and January 1, 2024. New-users using intention to treatment design was employed and propensity score matching was utilized to select the cohort. Clinical outcomes included major adverse cardiac events (MACE) and all-cause mortality. Safety outcomes using ICD-10 codes, ketoacidosis, urinary tract infection (UTI) or genital infection, dehydration, bone fracture, below-knee amputation, hypoglycemia, and achieving dialysis-free status at 90 days and 90-day readmission. RESULTS: Of 49,762 patients with T2DM who initiated dialysis for evaluation, a mere 1.57% of patients utilized SGLT-2is within 3 months after dialysis. 771 SGLT-2i users (age 63.3 ± 12.3 years, male 65.1%) were matched with 771 non-users (age 63.1 ± 12.9 years, male 65.8%). After a median follow-up of 2.0 (IQR 0.3-3.9) years, SGLT-2i users were associated with a lower risk of MACE (adjusted Hazard Ratio [aHR] = 0.52, p value < 0.001), all-cause mortality (aHR = 0.49, p < 0.001). SGLT-2i users were more likely to become dialysis-free 90 days after the index date (aHR = 0.49, p < 0.001). No significant differences were observed in the incidence of ketoacidosis, UTI or genital infection, hypoglycemia, dehydration, bone fractures, below-knee amputations, or 90-day readmissions. CONCLUSIONS: Our findings indicated a lower incidence of all-cause mortality and MACE after long-term follow-up, along with a higher likelihood of achieving dialysis-free status at 90 days in SGLT-2i users. Importantly, they underscored the potential cardiovascular protection and safety of SGLT-2is use in T2DM patients at the onset of dialysis.

Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: Lessons from preclinical studies.

Clinical and preclinical studies have elucidated the favorable effects of Inhibitors of Sodium-Glucose Cotransporter-2 (iSGLT2) in patients and animal models with type 2 diabetes. Notably, these inhibitors have shown significant benefits in reducing hospitalizations and mortality among patients with heart failure. However, despite their incorporation into clinical practice for indications beyond diabetes, the decision-making process regarding their use often lacks a systematic approach. The selection of iSGLT2 remains arbitrary, with only a limited number of studies simultaneously exploring the different classes of them. Currently, no unique guideline establishes their application in both clinical and basic research. This review delves into the prevalent use of iSGLT2 in animal models previously subjected to induced cardiac stress. We have compiled key findings related to cardioprotection across various animal models, encompassing diverse dosages and routes of administration. Beyond their established role in diabetes management, iSGLT2 has demonstrated utility as agents for safeguarding heart health and cardioprotection can be class-dependent among the iSGLT2. These findings may serve as valuable references for other researchers. Preclinical studies play a pivotal role in ensuring the safety of novel compounds or treatments for potential human use. By assessing side effects, toxicity, and optimal dosages, these studies offer a robust foundation for informed decisions, identifying interventions with the highest likelihood of success and minimal risk to patients. The insights gleaned from preclinical studies, which play a crucial role in highlighting areas of knowledge deficiency, can guide the exploration of novel mechanisms and strategies involving iSGLT2.

Use of Sodium-glucose cotransporter 2 (SGLT 2) inhibitor is associated with reduced emergency room visits and hospitalizations in patients with Chronic obstructive pulmonary disease (COPD) and type 2 Diabetes Mellitus.

BACKGROUND: The Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i) are a class of anti-diabetic medications that confer cardio-renal-metabolic (CRM) benefits. Emerging evidence also suggests that these agents provide better benefits for chronic pulmonary conditions, especially chronic obstructive pulmonary disease (COPD). RESEARCH QUESTION: We aimed to assess the association between SGLT2i use and outcomes in patients with COPD and concomitant Type 2 Diabetes Mellitus (T2DM). STUDY DESIGN AND METHODS: We conducted a retrospective cohort study on adults with T2DM and COPD in a primary care clinic from January 01, 2019 to 01/01//2023. Patients were categorized into two groups based on SGLT2i use. We collected demographic information and outcomes such as emergency room (ER) visits, hospitalizations secondary to COPD exacerbation over the period of four years and time to hospitalization and ER visits. Chi-square analysis was used for categorical variables, whereas an unpaired t-test was used for continuous variables. Cox regression was performed to identify significant prognostic factors of hospitalization and ER visits. A Kaplan-Meir analysis was used to visualize the probability of non-hospitalization and the probability of not visiting the ER. Statistical significance was set at p-value <0.05. RESULTS: Of the 220 patients screened, 94 met the inclusion criteria, of which 20 patients (21.3 %) had SGLT2i use at admission, and 74 (78.7 %) did not. Baseline demographic information were well-matched between the two groups. SGLT2i use was associated with a significant reduction in ER visits (70 % vs. 97.3 %, p-0.001) and the number of hospitalizations (55 % vs 87.8 %, p-0.001). Further multivariate analysis showed lower hazards of hospitalization (adjusted HR-0.156; CI:0.073 to 0.331) and ER visits (HR)-0.232; CI:0.118 to 0.453) in patients on SGLT2i. INTERPRETATION: In patients with T2DM with COPD, SGLT2i use was associated with reduced ER visits and hospitalizations related to COPD. This protective effect of SGLT2i could be explained by reduced systemic proinflammatory markers and increased anti-inflammatory markers via inhibition of Node like receptor protein 3(NLRP3) inflammasome activation in multiple tissues, including the lungs.

Canagliflozin and iron metabolism in the CREDENCE trial.

BACKGROUND AND HYPOTHESIS: Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post-hoc analysis of the CREDENCE trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency. METHODS: We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT < 20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively. RESULTS: Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared to placebo, increased TIBC by 2.1% (95%CI 0.4-3.8; p = 0.014) and decreased ferritin by 11.5% (95%CI 7.1-15.7; p < 0.001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2-8.5; p < 0.001) and 6.7 g/L (95% CI 5.2- 8.2; p < 0.001) in patients with and without iron deficiency, respectively (p-interaction = 0.38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (HR 0.70, 95%CI 0.56-0.87) was consistent regardless of iron deficiency (p-interaction 0.83), as were effects on other cardiovascular and mortality outcomes (all p-interactions ≥ 0.10). CONCLUSIONS: Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with T2D and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.