Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review

Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.

How Low Can You Go? Safety and Efficacy of Sodium-Glucose Cotransporter Inhibitors in Decreased Renal Function

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of medications primarily used as either monotherapy or add-on therapy in those with type 2 diabetes. Given the mechanism of SGLT2 inhibitors, a renal dose adjustment or glomerular filtration rate cutoff in which it should be avoided due to decreased efficacy is recommended. However, studies have shown that these agents may possess renal benefits through decreasing serum glucose levels as well as decreasing intraglomerular pressure and albuminuria. The safety and benefits of SGLT2 inhibitors in patients with decreased renal function is an area of uncertainty.

Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 Diabetes

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (R_A) and efferent (R_E) arteriolar tone and intraglomerular pressure (P_GLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the R_A/R_E ratio and P_GLO with ESKD incidence in 237 Pima Indian persons with T2D who underwent serial measures of GFR (iothalamate) and RPF (<i>p</i>-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants.<b> </b>Of the 237 participants (mean age 42 years, diabetes duration 11 years, GFR 153 ml/min, median ACR 36 mg/g), 69 progressed to ESKD during median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing R_A/R_E ratio (HR: 4.60, 95% CI 2.55-8.31) or elevated P_GLO followed by a rapid decline (HR: 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. P_GLO(R²=21%, <i>p</i><0.0001) and R_A/R_E (R²=15%, <i>p</i><0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression.<b> </b>In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.

Intraglomerular Dysfunction Predicts Kidney Failure in Type 2 Diabetes

No longitudinal data link intraglomerular hemodynamic dysfunction with end-stage kidney disease (ESKD) in people with type 2 diabetes (T2D). Afferent (R_A) and efferent (R_E) arteriolar tone and intraglomerular pressure (P_GLO) are not directly measurable in humans but are estimable from glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure, hematocrit, and plasma oncotic pressure. We examined the association of the R_A/R_E ratio and P_GLO with ESKD incidence in 237 Pima Indian persons with T2D who underwent serial measures of GFR (iothalamate) and RPF (<i>p</i>-aminohippurate). Their association with kidney structural lesions was also examined in a subset of 111 participants.<b> </b>Of the 237 participants (mean age 42 years, diabetes duration 11 years, GFR 153 ml/min, median ACR 36 mg/g), 69 progressed to ESKD during median follow-up of 17.5 years. In latent class analysis, distinct trajectories characterized by increasing R_A/R_E ratio (HR: 4.60, 95% CI 2.55-8.31) or elevated P_GLO followed by a rapid decline (HR: 2.96, 95% CI 1.45-6.02) strongly predicted incident ESKD. P_GLO(R²=21%, <i>p</i><0.0001) and R_A/R_E (R²=15%, <i>p</i><0.0001) also correlated with mesangial fractional volume, a structural predictor of DKD progression.<b> </b>In conclusion, intraglomerular hemodynamic parameters associated strongly with incident ESKD and correlated with structural lesions of DKD.

Effects of SGLT2 inhibitor and dietary NaCl on glomerular hemodynamics assessed by micropuncture in diabetic rats

It has been theorized that Na-glucose cotransporter (SGLT2) blockade slows progression of diabetic kidney disease by reducing physical strain on the glomerulus. This is the first direct measurement of intraglomerular pressure during SGLT2 blockade. Findings confirmed that SGLT2 blockade does reduce glomerular capillary pressure, that this is mediated through tubuloglomerular feedback, and that the tubuloglomerular feedback response to SGLT2 blockade involves preglomerular vasoconstriction and postglomerular vasorelaxation.

Estimation of Intraglomerular Pressure Using Invasive Renal Arterial Pressure and Flow Velocity Measurements in Humans

BackgroundGlomerular hyperfiltration resulting from an elevated intraglomerular pressure (Pglom) is an important cause of CKD, but there is no feasible method to directly assess Pglom in humans. We developed a model to estimate Pglom in patients from combined renal arterial pressure and flow measurements.MethodsWe performed hemodynamic measurements in 34 patients undergoing renal or cardiac angiography under baseline conditions and during hyperemia induced by intrarenal dopamine infusion (30 μg/kg). For each participant during baseline and hyperemia, we fitted an adapted three-element Windkessel model that consisted of characteristic impedance, compliance, afferent resistance, and Pglom.ResultsWe successfully analyzed data from 28 (82%) patients. Median age was 58 years (IQR, 52–65), median eGFR was 95 ml/min per 1.73 m2 (IQR, 74–100) using the CKD-EPI formula, 30% had microalbuminuria, and 32% had diabetes. The model showed a mean Pglom of 48.0 mm Hg (SD=10.1) at baseline. Under hyperemia, flow increased by 88% (95% CI, 68% to 111%). This resulted in a 165% (95% CI, 79% to 294%) increase in afferent compliance and a 13.1-mm Hg (95% CI, 10.0 to 16.3) decrease in Pglom. In multiple linear regression analysis, diabetes (coefficient, 10.1; 95% CI, 5.1 to 15.1), BMI (0.99 per kg/m2; 95% CI, 0.38 to 1.59), and renal perfusion pressure (0.42 per mm Hg; 95% CI, 0.25 to 0.59) were significantly positively associated with baseline Pglom.ConclusionsWe constructed a model on the basis of proximal renal arterial pressure and flow velocity measurements that provides an overall estimate of glomerular pressure and afferent and efferent resistance in humans. The model provides a novel research technique to evaluate the hemodynamics of CKD on the basis of direct pressure and flow measurements.Clinical Trial registry name and registration numberFunctional HEmodynamics in patients with and without Renal Artery stenosis (HERA), NL40795.018.12 at the Dutch national trial registry (toetsingonline.nl).

Why Are SGLT2 Inhibitors Nephroprotective? Mechanisms of Action And Possible Benefits A Review

Recent researches have demonstrated that SGLT2i (Sodium-Glucose Linked Transporter 2 inhibitors) play a role in preventing the development and progression of chronic kidney disease (CKD). However, these studies have not to look into the mechanisms that justify this progress. In this document, we will approach the physiologic causes of the kidney response to SGLT2i treatment. SGLT2i were firstly designed as physiologic antidiabetic drugs due to its glucose anti-absorptive action in kidneys. Nevertheless, the effect on glucose levels has proved to be modest, so other different ways have to be involved in their renal benefits. After the commercialization of these drugs, their hypouricemic action, antihypertensive effects, and weight loss have been noticed. Although those actions are positive for the kidney, they are mild and hardly could induce a reduction of proteinuria and a kidney function stabilization effect. Other actions such as anti-inflammatory and metabolic could have more importance in the role of SGLT2i. SGLT2i have been shown to reduce hypoxia and fibrosis in the kidney by changing energetic balance and by reducing inflammatory activity. These two mechanisms are closely related to the settlement and progression of CKD. In addition, SGLT2i reduce proteinuria, which is probably the leading contribution of these drugs for renal function stabilization, due in part to its hemodynamic action by reducing intraglomerular pressure (tubule glomerular balance). In conclusion, SGLT2i kidney benefits could hardly be explained by a single effect. In fact, SGLT2i trigger several effects, that taken together explain the kidney improvements that have been described.

Evaluating the antiproteinuric efficacy of cilnidipine in diabetic kidney disease

Background: Diabetic kidney disease is a life threatening and disabling complication of uncontrolled diabetes mellitus. Clinical proteinuria is a well-established marker of renal dysfunction. A dual L/N-type calcium channel blocker cilnidipine dilates the afferent and efferent arterioles of the glomerulus decreasing the intraglomerular pressure and showing antiproteinuric effects. The present study was conducted to assess the antiproteinuric efficacy of cilnidipine in patients of diabetic kidney disease.Methods: This interventional study was conducted on 50 patients of both genders aged 18 years and above with diabetic nephropathy (stage-2 to stage 4) visiting the medicine OPD at HIMS, Dehradun over a period of six months, the patients were given tablet cilnidipine (5-20 mg) once or twice a day. Baseline urine protein creatinine ratio (UPCR), serum creatinine and the estimated glomerular filtration rate (eGFR) was recorded at baseline and repeated after a period of 12 weeks. The end point was the decrease in UPCR after a period of 12 weeks. Students-paired T test was used for analysing the intragroup data.Results: After 12 weeks of treatment with cilnidipine, a significant reduction was observed in the urinary protein creatine ratio (mean±SD) from 3.2±1.23 at baseline to 3.09±1.09 respectively (p<0.05). Along with this there was also a reduction in the in serum creatinine which was significant (p<0.05) as well as an increase in the eGFR value which was also statistically significant (p<0.001).Conclusions: Cilnidipine reduces the UPCR as well as improves the kidney function in patients with diabetic kidney disease.

Significant polar vasculosis in a patient with a 30-year history of type 2 diabetes

Summary We report the renal histology of a 66-year-old man with hypertension, cardiovascular disease, and a 30-year history of type 2 diabetes mellitus with proliferative diabetic retinopathy, diabetic neuropathy, and diabetic foot status post toe amputation. Urinary protein excretion was 1.4 g/gCr, serum creatinine level 0.86 mg/dL, estimated glomerular filtration rate 69 mL/min/1.73 m2, and HbA1c 13–15%, despite using insulin. Light microscopy showed global glomerulosclerosis in 37% of the glomeruli, but the remaining glomeruli were intact. Significant polar vasculosis was present, while arteriolar sclerosis was mild. Electron microscopy revealed a thickened glomerular basement membrane, which is compatible with the early stage of diabetic glomerulopathy. The presented case was unique because glomerular changes seen typically in diabetes were not seen in the patient, despite the long-standing history of diabetes and diabetic comorbidities, while prominent polar vasculosis was found. Polar vascular formation helps preserve the glomeruli by allowing hyperosmotic blood bypass the glomeruli; this decreases intraglomerular pressure and minimizes glomerular endothelial damage. Learning points: A 66-year-old man with a 30-year history of type 2 diabetes mellitus with poor glycemic control underwent renal biopsy, which showed scarce glomerular changes typically seen in diabetic kidney disease and instead revealed significant polar vasculosis. Past studies demonstrated that the increased small vessels around the vascular hilus in diabetic patients originated from the afferent arterioles and drained into the peritubular capillaries. Polar vascular formation may preserve glomerular function by allowing the blood flow to bypass the glomeruli and decreasing the intraglomerular pressure, which minimizes endothelial damage of the glomerular tufts.

Antihyperglycemic agents as novel natriuretic therapies in diabetic kidney disease

While sodium-glucose cotransporter-2 (SGLT2) inhibitors have been used for the routine management of type 2 diabetes for several years, it is perhaps their natriuretic effects that are most important clinically. This natriuresis activates tubuloglomerular feedback, resulting in reduced glomerular hypertension and proteinuria, leading to renal protective effects in the EMPA-REG OUTCOME and CANVAS Program trials. In the cardiovascular system, it is likely that plasma volume contraction due to natriuresis in response to SGLT2 inhibition is at least in part responsible for the reduction in the risk of heart failure observed in these trials. We compare this mechanism of action with other antidiabetics. Importantly, other diuretic classes, including thiazide and loop diuretics, have not resulted in such robust clinical benefits in patients with type 2 diabetes, possibly because these older agents do not influence intraglomerular pressure directly. In contrast, SGLT2 inhibitors do have important physiological similarities with carbonic anhydrase inhibitors, which also act proximally, and have been shown to activate tubuloglomerular feedback.