SGLT2 Inhibitors and the Diabetic Kidney

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addition to their glycemic and blood pressure benefits, may provide nephroprotective effects

Meta‐analysis of the association between sodium‐glucose co‐transporter‐2 inhibitors and risk of skin cancer among patients with type 2 diabetes

A slight increase in melanoma risk was observed among sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitor users in the regular reports. However, the association remains uncertain. To address this issue, we performed a systematic search of electronic databases up to May 2, 2018 and a meta‐analysis of 21 randomized controlled trials (RCTs) involving 20 308 patients. We did not find a significant increase in risk of melanoma among SGLT‐2 inhibitor users (Peto odds ratio [OR], 2.17; 95% confidence interval [CI], 0.80‐5.89; I2, 0%). Similar results were observed in the subgroup analyses according to the type of SGLT‐2 inhibitor, type of control, ages of patients, race/ethnicity, and trial durations. For non‐melanoma skin cancer risk, no significant difference was observed when all trials were combined (Peto OR, 0.70; 95% CI, 0.47‐1.07; I2, 0%), while a significantly decreased risk was observed among trials with duration <52 weeks (Peto OR, 0.12; 95% CI, 0.02‐0.59; I2, 0%). No evidence of publication bias was detected in the analyses. Current evidence from RCTs did not support a significantly increased risk of skin cancer associated with SGLT‐2 inhibitors

An emerging protagonist: Sodium Glucose Co-transporters (SGLTs) as a burgeoning target for the treatment of diabetes mellitus

Contemporary therapies to rationalize the hyperglycaemia in type 2 diabetes mellitus (T2DM) generally involve insulin-dependent mechanisms and lose their effectiveness as pancreatic b-cell function decreases to a greater extent. The kidney emerges out as a novel and potential target to trim down the T2DM. The filtered glucose is reabsorbed principally through the sodium glucose co-transporter-2 (SGLT2), a low affinity transport system, which is present at the luminal surface cells that cover the first segment of proximal tubules. Competitive inhibition of SGLT2 therefore represents an innovative therapeutic strategy for the treatment of hyperglycaemia and/or obesity in patients with type 1 or type 2 diabetes by enhancing glucose and energy loss through the urine. Selective inhibitors of SGLT2 reduce glucose reabsorption, causing excess glucose to be eliminated in the urine; this decreases plasma glucose. SGLT2 inhibitors are coupled with osmotic dieresis and loss of weight which aid in reducing blood pressure. The observation that individuals with familial renal glycosuria maintain normal long-term kidney function provides some encouragement that this mode of action will not adversely affect renal function. This novel mechanism of targeting the kidney for the treatment of T2DM is reasonably valuable and is independent of insulin and clutch with the low risk of hypoglycemia

Novel diabetes drugs and the cardiovascular specialist

Recently, treatment with 2 newer classes of type 2 diabetes drugs were found to reduce events in patients with diabetes and cardiovascular (CV) disease, a group common in cardiology clinics. The sodium-glucose cotransporter 2 inhibitor, empagliflozin, markedly and rapidly reduced CV death and heart failure hospitalization, likely with hemodynamic/metabolic-driven mechanisms of action. More recently, the glucagon-like peptide–1 receptor agonists liraglutide and semaglutide also reduced CV death and/or major adverse CV events, but did so more slowly and did not influence heart failure risks, suggesting alternative mechanisms of benefit. We will discuss drug therapy for diabetes relative to CV risk, briefly summarize key findings of CV benefit from recent trials, discuss potential mechanisms for benefits of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide–1 agonists, and suggest how such drugs might be embraced by CV specialists to reduce CV events and mortality in their patients

Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes

Background Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents. Objective To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. Data sources MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers. Inclusion criteria Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy. Methods Systematic review. Quality assessment used the Cochrane risk of bias score. Results Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by −0.54% (weighted mean differences (WMD), 95% CI −0.67 to −0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to −0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD −1.81 kg (95% CI −2.04 to −1.57), canagliflozin up to −2.3 kg compared to placebo). Limitations Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers. Conclusions Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed

Kidney and heart failure outcomes associated with SGLT2 inhibitor use

Chronic kidney disease (CKD) and heart failure affect many people worldwide. Despite the availability of pharmacological treatments, both diseases remain associated with considerable morbidity and mortality. After observations that sodium-glucose co-transporter 2 (SGLT2) inhibitors - originally developed as glucose-lowering agents - improved cardiovascular and renal outcomes in patients with type 2 diabetes, dedicated trials were initiated to evaluate the cardiovascular and kidney protective effects in patients with CKD or heart failure. The results of these clinical trials and subsequent detailed analyses have shown that the benefits of SGLT2 inhibitors are consistent across many patient subgroups, including those with and without type 2 diabetes, at different stages of CKD, and in patients with heart failure with preserved or reduced ejection fraction. In addition, post-hoc analyses revealed that SGLT2 inhibitors reduce the risk of anaemia and hyperkalaemia in patients with CKD. With respect to their safety, SGLT2 inhibitors are generally well tolerated. More specifically, no increased risk of hypoglycaemia has been observed in patients with CKD or heart failure without diabetes and they do not increase the risk of acute kidney injury. SGLT2 inhibitors therefore provide clinicians with an exciting new treatment option for patients with CKD and heart failure. Clinical trials have demonstrated sodium-glucose co-transporter 2 (SGLT2) inhibitors to be safe and effective drugs that improve kidney outcomes in patients with and without diabetes. SGLT2 inhibitors also improve heart failure outcomes for patients with preserved or reduced ejection fraction. This Review summarizes findings from clinical trials of SGLT2 inhibitors, focusing on the effects of these agents in patients with chronic kidney disease and heart failure, and describes how potential mechanisms of action may translate into clinical benefit

The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure

Concomitant type 2 diabetes and chronic kidney disease increases the risk of heart failure. Recent studies demonstrate beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on chronic kidney disease progression and heart failure hospitalization in patients with and without diabetes. In addition to inhibiting glucose reabsorption, SGLT2 inhibitors decrease proximal tubular sodium reabsorption, possibly leading to transient natriuresis. We review the hypothesis that SGLT2 inhibitor’s natriuretic and osmotic diuretic effects mediate their cardioprotective effects. The degree to which these benefits are related to changes in sodium, independent of the kidney, is currently unknown. Aside from effects on osmotically active sodium, we explore the intriguing possibility that SGLT2 inhibitors could also modulate nonosmotic sodium storage. This alternative hypothesis is based on emerging literature that challenges the traditional 2-compartment model of sodium balance to provide support for a 3-compartment model that includes the binding of sodium to glycosaminoglycans, such as those in muscles and skin. This recent research on nonosmotic sodium storage, as well as direct cardiac effects of SGLT2 inhibitors, provides possibilities for other ways in which SGLT2 inhibitors might mitigate heart failure risk. Overall, we review the effects of SGLT2 inhibitors on sodium balance and sensitivity, cardiac tissue, interstitial fluid and plasma volume, and nonosmotic sodium storage

Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors may reduce cardiovascular and heart failure risk in patients with type 2 diabetes mellitus (T2DM). Objectives: To examine the effects of canagliflozin on cardiovascular biomarkers in older patients with T2DM. Methods: In 666 T2DM patients randomized to receive canagliflozin 100 or 300 mg or placebo, we assessed median percent change in serum N-terminal pro-B type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI) , soluble (s)ST2, and galectin-3 from baseline to 26, 52, and 104 weeks. Results: Both serum NT-proBNP and serum hsTnI levels increased in placebo recipients but remained largely unchanged in those randomized to canagliflozin. Hodges-Lehmann estimates of the difference in median percent change between pooled canagliflozin and placebo were –15.0%, –16.1%, and –26.8% for NT-proBNP, and –8.3%, –11.9%, and –10.0% for hsTnI at weeks 26, 52, and 104, respectively (all P &lt;0.05). Serum sST2 was unchanged with canagliflozin and placebo over 104 weeks. Serum galectin-3 modestly increased from baseline with canagliflozin versus placebo, with significant differences observed at 26 and 52 weeks but not at 104 weeks. These results remained unchanged when only patients with complete samples were assessed. Conclusions: Compared to placebo, treatment with canagliflozin delayed rise in serum NT-proBNP and hsTnI over 2 years in older T2DM patients. These cardiac biomarker data provide support for beneficial cardiovascular effect of SGLT2 inhibitors in T2DM

SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels

学位記番号：医博甲173

Efficacy and Renal Outcomes of SGLT2 Inhibitors in Patients with Type 2 Diabetes and Chronic Kidney Disease

Objective: To review glucose-lowering efficacy and changes in renal function associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Data sources: A literature search of MEDLINE and Cochrane databases was performed from 2000 to August 2018 using search terms: SGLT2 inhibitors, sodium glucose co-transporter 2, canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, and chronic kidney disease. References of identified articles were also reviewed. Study selection and data extraction: English-language studies investigating glucose-lowering endpoints and/or changes in renal function with one of four U.S. approved SGLT2 inhibitors were included. A total of 10 studies met inclusion criteria and are included in this review. Results: In patients with T2DM and CKD, SGLT2 inhibitors are modestly effective in lowering hemoglobin A1C and fasting plasma glucose compared to placebo. Small reductions in eGFR are seen shortly after initiating therapy with SGLT2 inhibitors, but return to baseline levels after discontinuation. SGLT2 inhibitors are associated with a substantial reduction in albuminuria and reduced risk of progression to albuminuria. Conclusions: In patients with T2DM and CKD, SGLT2 inhibitors have a decreased glucose-lowering effect compared to patients without CKD. Renal benefits among patients with CKD are similar to those without CKD and include a significant reduction in albuminuria and reduced incidence of worsening albuminuria. Given that CKD and T2DM are both associated with increased cardiovascular risk, we believe these agents should considered as preferred add-on agents in most patients with uncontrolled T2DM and eGFR \u3e30 ml/min/1.73 m2. Ongoing studies will provide additional information as to whether these agents should be added to the current standard of care for CKD patients, with and without T2DM