The latest emerging drugs for the treatment of diabetic cardiomyopathy.

INTRODUCTION: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus involving multiple pathophysiologic mechanisms. In addition to hypoglycemic agents commonly used in diabetes, metabolism-related drugs, natural plant extracts, melatonin, exosomes, and rennin-angiotensin-aldosterone system are cardioprotective in DCM. However, there is a lack of systematic summarization of drugs for DCM. AREAS COVERED: In this review, the authors systematically summarize the most recent drugs used for the treatment of DCM and discusses them from the perspective of DCM pathophysiological mechanisms. EXPERT OPINION: We discuss DCM drugs from the perspective of the pathophysiological mechanisms of DCM, mainly including inflammation and metabolism. As a disease with multiple pathophysiological mechanisms, the combination of drugs may be more advantageous, and we have discussed some of the current studies on the combination of drugs.

SGLT2 inhibitor improves kidney function and morphology by regulating renal metabolism in mice with diabetic kidney disease.

BACKGROUND: Diabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease. AIM: To investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism. METHODS: DKD model was established using high-fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low-dose of canagliflozin, 4) high-dose of canagliflozin and 5) ß-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed. RESULTS: Canagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. ß-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice. CONCLUSION: Canagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.

Care Gaps in Sodium-Glucose Cotransporter-2 Inhibitor and Renin Angiotensin System Inhibitor Prescriptions for Patients with Diabetic Kidney Disease.

BACKGROUND: Renin and angiotensin system inhibitors (RAASi) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended for patients with diabetic kidney disease (DKD) to reduce the progression to end-stage kidney disease; however, they are under-prescribed. OBJECTIVE: To evaluate the frequency of care gaps in RAASi and SGLT2i prescription by patient demographic, health system, and clinical factors in patients with DKD. DESIGN: Retrospective cohort study. PARTICIPANTS: Adult primary care patients with DKD at an integrated health system in Bronx, NY, with 23 primary care sites in 2021. MAIN MEASURES: The odds of having a care gap for (1) SGLT2i or (2) RAASi prescription. Multivariate logistic regression models were performed for each outcome measure to evaluate associations with patient demographic, health system, and clinical factors. KEY RESULTS: Of 7199 patients with DKD, 80.3% had a care gap in SGLT2i prescription and 42.0% had a care gap in RAASi prescription. For SGLT2i, patients with A1C at goal (aOR 2.32, 95% CI 1.96-2.73), Black non-Hispanic race/ethnicity (aOR 1.46, 95% CI 1.15-1.87), and Hispanic race/ethnicity (aOR 1.46, 95% CI 1.11-1.92) were more likely to experience a care gap. For RAASi, patients with blood pressure at goal (aOR 1.34, 95% CI 1.21-1.49) were more likely to experience a care gap. CONCLUSIONS: The care gaps for SGLT2i and RAASi for patients with DKD with well-controlled diabetes and blood pressure suggest failure to recognize DKD as an independent indication for these medications. Racial/ethnic disparities for SGLT2i, but not for RAASi, suggest systemic racism exacerbates care gaps for novel medications. These factors can be targets for interventions to improve patient care.

Real-World Safety and Effectiveness of Canagliflozin Treatment for Type 2 Diabetes Mellitus in Japan: SAPPHIRE, a Long-Term, Large-Scale Post-Marketing Surveillance.

INTRODUCTION: This long-term post-marketing surveillance (SAPPHIRE) collected information on the safety and effectiveness of canagliflozin (approved dose 100 mg) prescribed to patients with type 2 diabetes mellitus (T2DM) in real-world practice in Japan. METHODS: Patients with T2DM who were prescribed canagliflozin between December 2014 and September 2016 were registered and observed for up to 3 years. Safety was evaluated in terms of adverse drug reactions (ADRs). Effectiveness was assessed in terms of glycaemic control. Data were also analysed across age subgroups (< 65, ≥ 65 to < 75, and ≥ 75 years old) and the estimated glomerular filtration rate (eGFR) categories for chronic kidney disease (G1-G5 based on eGFR) at baseline. RESULTS: A total of 12,227 patients were included in the safety analyses and 11,675 in effectiveness analyses. Overall, 7104 patients were treated with canagliflozin for ≥ 3 years. The mean age, haemoglobin A1c (HbA1c), and eGFR at baseline were 58.4 ± 12.5 years, 8.01 ± 1.49%, and 80.04 ± 21.85 mL/min/1.73 m2, respectively. There were 1836 ADRs in 1312 patients (10.73%) and 268 serious ADRs in 225 patients (1.84%). The most common ADRs were those related to volume depletion (1.39%), genital infection (1.34%), polyuria/pollakiuria (1.23%), and urinary tract infection (1.19%). The frequencies of ADRs tended to increase with age and stage of chronic kidney disease. The reductions in mean HbA1c after starting canagliflozin were maintained for up to 3 years with a mean change of - 0.68% (n = 6345 at 3 years). Maintained reductions in mean HbA1c were observed in each age subgroup and in patients with G1-G3b renal function. CONCLUSION: This surveillance in real-world clinical practice showed that canagliflozin provides sustained glucose-lowering effects in patients with T2DM, including elderly patients and patients with moderate renal impairment, without new safety concerns beyond those already described in the Japanese package insert. TRIAL REGISTRATION: JapicCTI-153048.

Canagliflozin is a sodium­glucose cotransporter 2 (SGLT2) inhibitor that lowers blood glucose levels by increasing urinary glucose excretion. It was approved for the management of blood glucose levels in patients with type 2 diabetes mellitus following clinical trials. However, clinical trials may not fully represent the safety or effectiveness of a drug in real-world clinical practice. Therefore, a 3-year post-marketing surveillance was performed in Japan to obtain safety and effectiveness data for a large group of 12,227 patients with type 2 diabetes mellitus and various demographic/clinical characteristics. Safety and effectiveness data were collected for up to 3 years while patients were treated with canagliflozin. Adverse drug reactions occurred in 10.73% of patients. The most common types of adverse drug reactions were those related to volume depletion (body fluid decreased), followed by genital infection, polyuria/pollakiuria (increased urination), and urinary tract infection. Adverse drug reactions tended to be more common in elderly patients and in patients with renal impairment. As expected, canagliflozin was associated with improvements in haemoglobin A1c, a marker of blood glucose control, in patients with type 2 diabetes, including in elderly patients and patients with moderate renal impairment. In this surveillance in real-world clinical practice, long-term treatment with canagliflozin raised no new safety concerns beyond the information already included in the Japanese package insert. Canagliflozin provides sustained glucose-lowering effects.

Canagliflozin Suppresses Atrial Remodeling in a Canine Atrial Fibrillation Model.

Background Recent clinical trials have demonstrated the possible pleiotropic effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors in clinical cardiovascular diseases. Atrial electrical and structural remodeling is important as an atrial fibrillation (AF) substrate. Methods and Results The present study assessed the effect of canagliflozin (CAN), an SGLT2 inhibitor, on atrial remodeling in a canine AF model. The study included 12 beagle dogs, with 10 receiving continuous rapid atrial pacing and 2 acting as the nonpacing group. The 10 dogs that received continuous rapid atrial pacing for 3 weeks were subdivided as follows: pacing control group (n=5) and pacing+CAN (3 mg/kg per day) group (n=5). The atrial effective refractory period, conduction velocity, and AF inducibility were evaluated weekly through atrial epicardial wires. After the protocol, atrial tissues were sampled for histological examination. The degree of reactive oxygen species expression was evaluated by dihydroethidium staining. The atrial effective refractory period reduction was smaller (P=0.06) and the degree of conduction velocity decrease was smaller in the pacing+CAN group compared with the pacing control group (P=0.009). The AF inducibility gradually increased in the pacing control group, but such an increase was suppressed in the pacing+CAN group (P=0.011). The pacing control group exhibited interstitial fibrosis and enhanced oxidative stress, which were suppressed in the pacing+CAN group. Conclusions CAN and possibly other SGLT2 inhibitors might be useful for preventing AF and suppressing the promotion of atrial remodeling as an AF substrate.

Decision Algorithm for Prescribing SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease.

Diabetic kidney disease and its comorbid conditions, including atherosclerotic cardiovascular disease, heart failure, diabetes, and obesity, are interconnected conditions that compound the risk of kidney failure and cardiovascular mortality, and exponentiate health care costs. Sodium glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide 1 receptor agonist (GLP-1 RA) are novel diabetes medications that prevent cardiovascular events and kidney failure. Clinical trials exploring the cardiovascular and kidney outcomes of SGLT2i and GLP-1 RA have fundamentally shifted the treatment paradigm of diabetes. Clinical guidelines for diabetes management recommend a more holistic approach beyond glycemic control and emphasize heart and kidney protection of SGLT2i and GLP-1 RA. However, the adoption of prescribing SGLT2i and GLP-1 RA for patients with diabetes and high cardiovascular and kidney risk has been slow. In this review, we provide a decision-making tool to help clinicians determine when to consider SGLT2i and GLP-1 RA for heart and kidney protection. First, we discuss a comprehensive risk assessment for patients with diabetic kidney disease. We compare the effectiveness of SGLT2i and GLP-1 RA for different risk categories. Then, we present a decision algorithm using cardiovascular and kidney failure risk stratification and the strength of current evidence for the use of SGLT2i and GLP-1 RA. Lastly, we review the adverse effects of SGLT2i and GLP-1 RA and propose mitigation strategies.

Canagliflozin, a sodium glucose cotransporter 2 inhibitor, attenuates obesity-induced inflammation in the nodose ganglion, hypothalamus, and skeletal muscle of mice.

Chronic inflammation in systemic organs, such as adipose tissue, nodose ganglion, hypothalamus, and skeletal muscles, is closely associated with obesity and diabetes mellitus. Because sodium glucose cotransporter 2 (SGLT2) inhibitors exert both anti-diabetic and anti-obesity effects by promoting urinary excretion of glucose and subsequent caloric loss, we investigated the effect of canagliflozin, an SGLT2 inhibitor, on obesity-induced inflammation in neural tissues and skeletal muscles of mice. High-fat diet (HFD)-fed male C57BL/6J mice were treated with canagliflozin for 8 weeks. Canagliflozin attenuated the HFD-mediated increases in body weight, liver weight, and visceral and subcutaneous fat weight. Additionally, canagliflozin decreased blood glucose as well as the fat, triglyceride, and glycogen contents of the liver. Along with these metabolic corrections, canagliflozin attenuated the increases in the mRNA levels of the proinflammatory biomarkers Iba1 and Il6 and the number of macrophages/microglia in the nodose ganglion and hypothalamus. In the skeletal muscle of HFD-fed obese mice, canagliflozin decreased inflammatory cytokine levels, macrophage accumulation, and the mRNA level of the specific atrophic factor atrogin-1. Canagliflozin also increased the mRNA level of insulin-like growth factor 1, protected against muscle mass loss, and restored the contractile force of muscle. These findings suggested that SGLT2 inhibition disrupts the vicious cycle of obesity and inflammation, not only by promoting caloric loss, but also by suppression of obesity-related inflammation in both the nervous system and skeletal muscle.