The Chemistry of Gliflozins: Recent Advancements in SGLT-2 Inhibitors.

Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician's perspective.

Cannabinoid Signaling in the Diabetic Proximal Tubule: Of Mice and Men

Pharmacologic Glycemic Management of Type 2 Diabetes in Adults.

Sodium-glucose cotransporter (SGLT)2 inhibitors are a class of novel antidiabetic drugs, which can reduce plasma glucose through inhibiting SGLT2-mediated glucose reabsorption in the proximal tubule of kidney. EMPA-REG OUTCOME trail shows that empagliflozin can reduce the major adverse cardiovascular events of diabetics with high cardiovascular risks. The potential mechanism of cardiovascular protective effects of SGLT2 inhibitors maybe include decrease of blood pressure, reduction of plasma volume, depletion of sodium, beneficial effects on renal hemodynamics, weight loss, improvement of insulin-sensitivity, inhibition on myocardial remodeling, decrease of uric acid, etc, but the exact mechanism still remains unclear. Key words: SGLT2 inhibitors; Cardiovascular risk; Diabetes mellitus; Empagliflozin

Do we need another <scp>SGLT2</scp> inhibitor?

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Background Diabetes is a disaease of Insulin insufficiency or resistance which implications on almost every organ and tissue of human body. It plays a direct or indirect role in causation or progression of many chronic conditions like Coronary Heart disease, Cerebrovascular accidents, Chronic Kidney disaease, limb amputation and so forth. It increases the risk and frequency of infections and delays the recovery as well. Management strategies include dietary management,exercise, Oral Antidiabetic drugs,Insulin formulations, pancreatic transplantation. The goal of these management strategies, usually employed in combination, is good glycemic control so as to avoid development of diabetic complications in the long run. Sodium-glucose co-transporter 2(SGLT2) inhibitors There are various classes of Oral Antidiabetic drugs(OAD) which form the basis of management of Diabetes Mellitus type 2 in particular as Type 1 Diabetes Mellitus invariably needs insulin for glycemic control. Sodium-glucose co-transporter 2(SGLT2) inhibitors are a class of OAD, approved by FDA for management of adults with type 2 diabetes. There are many SGLT2 inhibitors currently which can be used in patients with diabetes notably dapagliflozin, canagliflozin, empagliflozin. These oral antidiabetic drugs act by locking the SGLT2 transporters in proximal tubule of nephron and hence lead to glycosuria. They improve glycemic control, reduce body weight, and improve blood pressure control. Furthermore, evidence suggests that SGLT2 inhibitors have renoprotective, Cardiovascular and hypouricemic benefits among others. These benefits of SGLT2i slow progression of diabetic kidney disease. There is some evidence of increased risk of genitourinary fungal infections, Ketoacidosis and Fournier,s gangrene with use of SGLT2i. Conclusion Considering the added benefits of SGLT2i like renoprotection, weight loss, bP control, decreased CV morbidity and mortality with its use has provided an option of retarding the progression of Diabetic Nephropathy and improved survival of Diabetic patients. As more and more information with the experience of using this drug is published many unanswered questions about mechanism of these benefits and adverse events will be answered.

Type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD) is a common complication that increases the risk of cardiovascular (CV) events and kidney failure. Recent therapies, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase IV (DPP-4) inhibitors, show promise in improving outcomes. However, evidence of their comparative effectiveness in reducing CV and renal outcomes is scarce. We searched electronic databases such as PubMed, Scopus, and clinical trial registries for randomized controlled trials (RCTs) published between 2014 and 2024. A network meta-analysis (NMA) was employed to evaluate the effectiveness of antidiabetic drugs on cardiorenal outcomes. Primary outcomes were (1) major adverse CV events (MACE), (2) composite renal outcomes, (3) all-cause mortality. Other outcomes included heart failure (HF), stroke, macroalbuminuria, and a decline in estimated glomerular filtration rate (eGFR) >40% or renal replacement therapy. Twenty-six studies with 143 296 participants with T2DM and CKD were included. SGLT2 inhibitors were highly effective in reducing the risk of renal outcomes such as composite events (P-score: 0.94), eGFR decline >40% or renal replacement therapy (0.99) and CV outcomes such as MACE (0.93) and HF (1.00) followed by GLP-1 RA. While GLP-1 RA was particularly effective in reducing the risk of MI (0.87), macroalbuminuria (0.86) and stroke (0.83) compared to SGLT2 inhibitors. Both SGLT2 inhibitors and GLP-1 receptor agonists are highly effective (0.83) in reducing all-cause mortality. DPP-4 inhibitors had limited benefits compared to SGLT2 inhibitors and GLP-1 RA. SGLT2 inhibitors followed by GLP-1 RA provide strong benefits for CV and kidney health in patients with T2DM and CKD. SGLT2 inhibitors demonstrate superior benefit over GLP-1 receptor agonists for HF and renal outcomes, highlighting their preferred role in these clinical scenarios.

Background: Heart failure (HF) and chronic kidney disease (CKD) are responsible for substantial morbidity and mortality in individuals with type 2 diabetes (T2D).Methods: This review discusses the significance of these comorbidities of T2D and current options for managing them, with a focus on sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Based on a focused literature search of cardiovascular outcomes trials (CVOTs), this review assessed the effects of SGLT-2 inhibitors in individuals with T2D with or without established cardiovascular disease (CVD).Results: In addition to effective glycemic control and weight loss, SGLT-2 inhibitor treatment of T2D prevents adverse cardiovascular and renal outcomes in individuals with and without these comorbidities. Reduced rate of hospitalization due to HF (HHF) and improved renal outcomes appear to be class effects of SGLT-2 inhibitors. Reduction in CV events may be more significant in individuals with established cardiovascular disease.Conclusions: CVOTs and other studies confirm that the SGLT-2 inhibitors, mostly used in combination with other glucose-lowering drugs, offer several clinical benefits beyond improved glycemic control. These include reducing HHF risk and improving renal outcomes. HF and renal benefits are observed in individuals with and without established CVD, which may simplify therapeutic selection. Ongoing SGLT-2 inhibitor CVOTs will help clarify the potential of these drugs to treat T2D comorbid with different forms of HF (HF with preserved vs reduced ejection fraction) and different degrees of renal dysfunction, and in individuals with T2D vs pre-diabetes or normal glucose metabolism.

INTRODUCTIONRandomised controlled trials show that SGLT2 inhibitors provide metabolic benefits, and cardiovascular and renal protection in patients with Type 2 Diabetes Mellitus(T2DM). Little is known in terms of real-world evidence for the use and persistence, metabolic benefits, durability in glucose control and adverse events related to SGLT2 inhibitors, particularly in South East Asia. The aim was to determine the metabolic, renal and cardiovascular outcomes and adverse events amongst T2DM patients commenced on SGLT2 inhibitors. METHODOLOGYWe retrospectively analysed the demographics, clinical characteristics, metabolic, renal and cardiovascular outcomes, as well as adverse events, of patients commenced on SGLT2 inhibitors. Data were extracted from electronic medical records in a tertiary care hospital and followed up for 24 months. RESULTSA total of 504 participants were analysed (male: 53.1%, mean age: 68.2 ± 7.1 years). The participants had a baseline HbA1c of 8.5%, 46.5% were insulin users, 49% with established ASCVD and 19.8% with CKD stage 3 and above. The SGLT2 inhibitors used were empagliflozin (81.4%) and dapagliflozin (18.6%). A significant reduction was seen in all metabolic parameters from baseline to 24 months: HbA1c: 0.6 ± 1.8% (p &lt;0.001), fasting plasma glucose (FPG): 0.7 ± 3.9 mmol/l (p &lt;0.001), weight: 2.6 ± 6.5 kg (p &lt;0.001), systolic blood pressure (SBP): 3.8 ± 20.6 mmHg (p = 0.001) and low-density lipoprotein (LDL): 0.25 ± 1.29 mmol/l (p &lt;0.001). The eGFR declined by 2.8 ± 10.6 ml/min/1.73 m2 from baseline (p &lt;0.001) and the urine albumin-creatinine ratio (UACR) showed no significant change of 4.4 ± 73.5 mg/ mmol (p = 0.996) over 24 months. There was no difference in terms of metabolic or renal outcomes amongst those with and without atherosclerotic cardiovascular disease (ASCVD) except those without ASCVD had greater weight loss compared to those without (3.1 vs 0.6 kg, p=0.04). We reported eighteen cardiovascular (CV) events of the acute coronary syndrome and nine events of hospitalisation for heart failure. Fifteen participants discontinued therapy due to adverse events and the causes were: genitourinary infections (0.8%), excessive polyuria (0.8%), and worsening eGFR of more than 40% from baseline (0.8%) were among the commonest. We observed only two events of diabetic ketoacidosis. Our findings were similar to other real-world studies done in other parts of the world. CONCLUSIONIn this real-world study, SGLT2 inhibitors effectively improved HbA1c, FPG, weight, SBP and LDL amongst multi-ethnic Malaysians with T2DM, similar to the magnitude reported in randomised clinical trials. Adverse events reported were lower than observed in randomised trials. This data compliments the current available literature on the efficacy and safety of SGLT2 inhibitors.

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

We systematically reviewed the anti-atherosclerotic effects beyond glucose lowering of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes, and found that SGLT-2 inhibitors are proved to be significantly associated with weight loss and reduction of blood pressure, in addition to lowering plasma glucose, by a relatively large number of studies [1]. However, the studies investigating effects of SGLT2 inhibitors on visceral fat, insulin sensitivity, serum lipids, inflammation and adipocytokines were very limited [1]. Recently, we reported the effects of SGLT2 inhibitors on metabolic parameters in patients with type 2 diabetes [2]. Our study demonstrated that SGLT2 inhibitors significantly reduced HbA1c and body weight and improved liver functions [2]. SGLT2 is expressed in the proximal tubule of kidney and mediates reabsorption of approximately 90% of the filtered glucose [3]. SGLT2 inhibitors block reabsorption of filtered glucose by inhibiting SGLT2, and promote the renal excretion of glucose [4]. Currently, several SGLT2 inhibitors with various degrees of selectivity toward SGLT2 versus SGLT1 selectivity are being tested in clinical trials [5]. I raised the issue of a significance of SGLT1 inhibition by SGLT2 inhibitors as my expert opinion [6]. Canagliflozin has a low potency to inhibit SGLT1 [7], which is highly distributed in intestine, and may improve postprandial hyperglycemia due to blocking intestinal absorption of glucose by inhibiting SGLT1. Tofogliflozin was identified as a potent and highly selective SGLT2 inhibitor [8]. I found a significant difference in hypoglycemic effect between canagliflozin and tofogliflozin [6], and suggested that a significance of SGLT1 inhibition and selectivity for SGLT2 are the issues that cannot be ignored. I also recommended that we should study how SGLT1 inhibition and selectivity for SGLT2 have an influence on glucose control, and we should elucidate whether such influence is different depending on the patients or not. As the key to resolve these issues, a different distribution between SGLT1 (intestine) and SGLT2 (kidney) came to my mind. SGLT2 inhibitors with potency to inhibit SGLT1 may be more effective to lower glucose as compared with highly selective SGLT2 inhibitors, in patients with renal insufficiency. To understand an influence of the estimated glomerular filtration rate (eGFR) on improvement in metabolic parameters by SGLT2 inhibitors, we sub-analyzed our previous study [2]. We studied 48 patients with type 2 diabetes. Baseline characteristics of subjects who had taken SGLT2 inhibitors and SGLT2 inhibitors prescribed to subjects at baseline are shown in Tables 1 and 2, respectively. The mean value of eGFR in subjects was 93.1 mL/min/1.73 m2. We divided patients into the high eGFR group (mean ± SD of eGFR, 117 ± 36 mL/ min/1.73m2; n = 22) and the low eGFR group (72 ± 14 mL/ min/1.73 m2; n = 26) by the mean value of eGFR. The changes in HbA1c, body weight and alanine aminotransferase (ALT) at 1, 2, 3 and 6 months after the start of SGLT2 inhibitors are shown in Figure 1. HbA1c significantly decreased in the high eGFR group as compared with the low eGFR group at 1, 2, 3 and 6 months after the SGLT2 inhibitors started. The changes in HbA1c at 2 months (r = -0.361, P = 0.059, by the Pearson’s

Type 2 diabetes mellitus affects over 537 million adults globally and represents the leading cause of cardiovascular morbidity and mortality, with diabetic patients experiencing a 2- to 4-fold increased risk of major adverse cardiovascular events compared to non-diabetic populations. This narrative review compared the cardiovascular protective mechanisms and clinical efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors versus metformin in type 2 diabetes management. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science databases from 2008 to 2024, focusing on cardiovascular outcome trials, mechanistic studies, and comparative effectiveness research. SGLT2 inhibitors demonstrated superior cardiovascular protection through multiple mechanisms, including osmotic diuresis, cardiac energy metabolism optimization, and direct myocardial protective effects, with major trials showing a 13-17% reduction in cardiovascular death compared to placebo. Metformin provided cardiovascular benefits primarily through AMP-activated protein kinase activation and improved insulin sensitivity, though evidence derives predominantly from observational studies rather than dedicated cardiovascular outcome trials. Head-to-head comparisons revealed that SGLT2 inhibitors confer greater cardiovascular risk reduction, particularly for heart failure hospitalization (35-39% reduction) and cardiovascular mortality, while metformin demonstrates superior glycemic control and metabolic benefits. Both drug classes exhibited complementary mechanisms that support combination therapy approaches. The evidence strongly supported SGLT2 inhibitors as first-line therapy for diabetic patients with established cardiovascular disease or high cardiovascular risk, while metformin remains optimal for metabolic control in lower-risk populations. Keywords: SGLT2 inhibitors, Metformin, Cardiovascular protection, Type 2 diabetes, Heart failure.

Choosing the Best Therapy for Your Patients in Today's Diabetes World.

Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes. Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term. The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58-0.94] and 0.70 [0.37-1.30], respectively), expanded MACEs (0.77 [0.62-0.96] and 0.87 [0.51-1.48]), renal composite (0.70 [0.59-0.83] and 0.52 [0.33-0.83]), and MACEs or death (0.74 [0.59-0.93] and 0.65 [0.36-1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use. The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298.