Sodium-glucose Cotransporter Type 2 Inhibitors Research Articles

Amelioration of pancreatic fat accumulation in Japanese type 2 diabetes patients treated with sodium-glucose cotransporter 2 inhibitors: a retrospective study.

BackgroundPrior reports have suggested that pancreatic fat is related to type 2 diabetes. Sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors are expected to reduce ectopic fat accumulation.AimThis study assessed the effect of SGLT‐2 inhibitors on pancreatic and liver fat accumulations in patients with type 2 diabetes.Materials and MethodsRetrospective analyses of indices of pancreatic and liver fat accumulations were conducted in 22 type 2 diabetes outpatients who were receiving SGLT‐2 inhibitors for more than 12 weeks. The differences between the pancreatic (P) or liver (L) and splenic (S) computed tomography values were evaluated.ResultsFatty pancreas was defined as P−S < −8 Hounsfield Unit (HU), and the number of patients with fatty pancreas was 11 (50%). Fatty pancreas significantly improved after SGLT‐2 inhibitor use (median, −20.8; IQR, −34.8 to −14.3 HU vs. median, −14.6; IQR, −29.5 to −7.8 HU; p = 0.041). Fatty liver was defined as L−S ≤ 3.9 HU, and the number of patients with fatty liver was 11 (50%). Fatty liver significantly improved after SGLT‐2 inhibitor use (median, −4.3; IQR, −23.0 to 3.0 HU vs. median, −0.7; IQR, −5.2 to 6.3 HU; p = 0.016).ConclusionPancreatic fat and liver fat accumulations might be reduced after treatment with SGLT‐2 inhibitors in type 2 diabetes patients with intense cumulative fat depositions in these organs.

Association of type 2 diabetes mellitus with the development of new-onset atrial fibrillation in patients with non-ischemic dilated cardiomyopathy: impact of SGLT2 inhibitors.

The aim of this study was to investigate the association of type 2 diabetes mellitus (T2DM) with the development of new-onset atrial fibrillation (AF) for non-ischemic dilated cardiomyopathy (DCM) patients. We also tested the hypothesis that sodium glucose cotransporter type 2 (SGLT2) inhibitors reduce the risk of development of new-onset AF for non-ischemic DCM patients.We retrospectively studied 210 patients with non-ischemic DCM and sinus rhythm, mean age of 59.0 ± 16.7years and left ventricular ejection fraction of 31.0 ± 8.2% (all < 45%). T2DM was identified in 60 patients (28.6%), and the remaining 150 patients (71.4%) were classified as non-T2DM patients.New-onset AF occurred in 21 patients (10.0%) over a median follow-up of 6.1years. Kaplan-Meier curve analysis showed that non-ischemic DCM patients without T2DM experienced fewer occurrences of the development of new-onset AF compared with those with T2DM (log-rank p = 0.0003). Furthermore, global longitudinal strain in patients who showed development of new-onset AF was significantly lower than that in those whose sinus rhythm was preserved (6.4 ± 1.4% vs. 7.7 ± 2.2%, p = 0.01). Of the 60 non-ischemic DCM patients with T2DM, those treated with SGLT2 inhibitors experienced fewer occurrences of the development of new-onset AF than did those not treated with SGLT2 inhibitors (log-rank p = 0.040).T2DM is associated with the development of new-onset AF in non-ischemic DCM patients, and treatment with SGLT2 inhibitors can significantly reduce the development of new-onset AF. Our findings may thus offer a new insight into the management of non-ischemic DCM patients with T2DM.

Ингибиторы натрий-глюкозного котранспортера 2-го типа у пациентов с сердечной недостаточностью. Что нового? какие перспективы?

This review presents the main results of recently (in 2020) published clinical studies investigating additional properties of drugs of the family of sodium-glucose co-transporter type 2 (SGLT2) inhibitors in patients with heart failure (HF). Of these, the most important is the EMPEROR-Reduced study which demonstrates the superiority of empagliflozin over placebo in preventing cardiovascular death and hospitalization for HF in patients with chronic HE with reduced left ventricular ejection fraction (LVEF). An important finding of this study is that, as in a recent study with a similar design with dapagliflozin – DAPA-HF, the benefit of SGLT2 inhibitors was independent on the presence or absence of diabetes mellitus in patients. The use of empagliflozin in patients with acute HF was studied in the EMPA-RESPONSE-AHF pilot study, in which, although there was no difference between placebo and the drug in the effect on the primary endpoint events, there was a clear trend towards improvement in clinical outcomes under the treatment with empagliflozin after 1 and 2 months of follow up. Administration of another member of the SGLT2 inhibitors family – sotagliflozin – in the SOLOIST-WHF study in patients with diabetes and recent worsening HF (with any LVEF) was associated with a significant decrease in adverse events. In the VERIT CV study, another SGLT2 inhibitor, ertugliflozin, although it had no effect on long-term outcomes in patients with diabetes and cardiovascular disease, was better than placebo in preventing hospitalization for heart failure. Overall, the recently completed studies of SGLT2 inhibitors show that drugs of this family, which already play an important role in the treatment of patients with HF with reduced LVEF, may in the future become an important component of therapy in a wider range of patients with various types of HF. Keywords: heart failure, sodium-glucose co-transporter type 2 inhibitors, empagliflozin, dapagliflozin, sotagliflozin, cardiovascular death For citation: Erlikh AD, Riabova DV. Sodium-glucose co-transporter-2 inhibitors in patients with heart failure. What's new? What are the prospects? Consilium Medicum. 2021; 23 (1): 48–51. DOI: 10.26442/20751753.2021.1.200681

The dawn of the four-drug era? SGLT2 inhibition in heart failure with reduced ejection fraction.

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are a relatively new class of antihyperglycemic drug with salutary effects on glucose control, body weight, and blood pressure. Emerging evidence now indicates that these drugs may have a beneficial effect on outcomes in heart failure with reduced ejection fraction (HFrEF). Post-approval cardiovascular outcomes data for three of these agents (canagliflozin, empagliflozin, and dapagliflozin) showed an unexpected improvement in cardiovascular endpoints, including heart failure hospitalization and mortality, among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease or risk factors. These studies were followed by a placebo controlled trial of dapagliflozin in patients with HFrEF both with and without T2DM, showing a reduction in all-cause mortality comparable to current guideline-directed HFrEF medical therapies such as angiotensin-converting enzyme inhibitors and beta-blockers. In this review, we discuss the current landscape of evidence, safety and adverse effects, and proposed mechanisms of action for use of these agents for patients with HFrEF. The United States (US) and European guidelines are reviewed, as are the current US federally approved indications for each SGLT2 inhibitor. Use of these agents in clinical practice may be limited by an uncertain insurance environment, especially in patients without T2DM. Finally, we discuss practical considerations for the cardiovascular clinician, including within-class differences of the SGLT2 inhibitors currently available on the US market (217/300).

Sodium-Glucose Co-Transporter 2 Inhibitors and the Risk of Venous Thromboembolism in Patients with Type 2 Diabetes: A Cohort Study

PurposeWe assessed whether sodium-glucose co-transporter type 2 (SGLT2) inhibitors are associated with a higher incidence rate of venous thromboembolism in patients with type 2 diabetes. MethodsWe conducted a population-based cohort study using the InGef database including patients with type 2 diabetes newly treated with noninsulin antidiabetic drugs between 2012 and 2018. Cases of venous thromboembolism identified during follow-up were matched to 40 controls on age, sex, cohort entry date, and duration of follow-up. Using a nested case-control approach, conditional logistic regression estimated incidence rate ratios (RRs) with 95% confidence intervals (CIs) of venous thromboembolism adjusted for sociodemographic and clinical variables, comparing current use of SGLT2 inhibitors with current use of dipeptidyl peptidase-4 (DPP-4) inhibitors. ResultsIn a cohort of 219,538 patients, we identified 2152 cases of venous thromboembolism and matched them to 85,104 controls. Compared with DPP-4 inhibitors, current use of SGLT2 inhibitors was associated with a lower rate of venous thromboembolism (RR, 0.75; 95% CI, 0.59-0.94). Effect estimates were similar for dapagliflozin (RR, 0.77; 95% CI, 0.57-1.03) and empagliflozin (RR, 0.71; 95% CI, 0.52-0.98). ConclusionsCompared with DPP-4 inhibitors, SGLT2 inhibitors were not associated with a higher rate of venous thromboembolism, providing reassurance regarding their thromboembolic safety.

Glucose-lowering pharmacotherapies in Chinese adults with type 2 diabetes and cardiovascular disease or chronic kidney disease. An expert consensus reported by the Chinese Diabetes Society and the Chinese Society of Endocrinology.

Patients with type 2 diabetes mellitus (T2DM) are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease (CKD), which are important causes of disabling and death in patients with T2DM. For the prevention and management of ASCVD or CKD, cardiovascular risk factors should be systematically evaluated, and ASCVD and CKD should be screened in patients with T2DM. In this consensus, we recommended that metformin should be used as the first-line therapy for patients with T2DM and ASCVD or very high cardiovascular risk, heart failure (HF) or CKD, and should be retained in the treatment regimen unless contraindicated or not tolerated. In patients with T2DM and established ASCVD or very high cardiovascular risk, addition of a glucagon-like peptide 1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter type 2 (SGLT2) inhibitor with proven cardiovascular benefits should be considered independent of individualised glycated haemoglobin (HbA1C ) targets. In patients with T2DM and HF, an SGLT2 inhibitor should be preferably added regardless of HbA1C levels. In patients with T2DM and CKD, SGLT2 inhibitors should be preferred for the combination therapy independent of individualised HbA1C targets, and GLP-1RAs with proven renal benefits would be alternative if SGLT2 inhibitors are contraindicated. Moreover, the prevention of hypoglycaemia and management of multiple risk factors by comprehensive regimen, including lifestyle intervention, antihypertensive therapies, lipid-lowering treatment and antiplatelet therapies, should be kept in mind in treating patients with T2DM and ASCVD, HF or CKD.

The association of amputations and peripheral artery disease in patients with type 2 diabetes mellitus receiving sodium-glucose cotransporter type-2 inhibitors: real-world study.

The aim of this study was to evaluate the temporal pattern of amputations in patients with type 2 diabetes mellitus (T2DM), the risk of amputations by new and older anti-diabetic drugs (ADDs), and the interplay of peripheral artery disease (PAD) with therapy and amputation risk. Using Centricity Electronic Medical Records from USA, 3293983 patients with T2DM were identified: 169739 received sodium-glucose cotransporter type-2 inhibitors (SGLT-2i; no exposure to incretins); 149826 received glucagon-like peptide 1 receptor agonists [GLP-1RA, no SGLT-2i or dipeptidyl peptidase-4 inhibitor (DPP-4i) exposure]; 448225 received DPP-4i (no exposure to GLP-1RA or SGLT-2i); and 1954353 received other ADDs. The proportion of incident amputations per 10000 adults ranged between 4.7 and 6.8 during 2000-08 and significantly increased to 12.3 in 2017. Over 17211719 person-years follow-up post T2DM diagnosis, the rates per 1000 person-years of any and lower limb amputations (LLAs) were similar between SGLT-2i and incretins [95% confidence interval (CI) range: 1.06-1.67], and significantly higher in other groups (95% CI range: 1.96-2.29). In propensity score-adjusted pairwise analyses, the risk of LLA was not higher in SGLT-2i vs. GLP1-RA [hazard ratio (HR) (95% CI): 0.88 (0.73, 1.05)], and lower in SGLT-2i vs. DPP-4i/other ADD [HR (95% CI): 0.65 (0.56, 0.75)/0.43 (0.37, 0.49)]. The rate of LLA was similar in patients treated with canagliflozin, empagliflozin, or dapagliflozin. Patients with PAD had more than four-fold higher LLA risk (range of 95% CI of HR: 3.6-6.0). The risk of amputation in patients treated with SGLT-2i and incretins was not higher compared with other ADDs. Pre-existing PAD was the greatest driver of amputation risk.

Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure

Abstract Background Type 2 diabetes mellitus (T2DM) has come to be considered an independent predictor of mortality, and also a contributor to the development of heart failure (HF) with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Left ventricular (LV) longitudinal myocardial dysfunction as assessed in terms of lower global longitudinal strain (GLS), has been identified even in T2DM patients with preserved LV ejection fraction (LVEF), and should be considered the first marker of a preclinical form of DM-related cardiac dysfunction, leading to HFpEF. Sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a new class of anti-hyperglycemic agents for T2DM, but the effect of SGLT2 inhibitors on LV longitudinal myocardial function in T2DM patients with HF remains uncertain. To examine this effect, as well as the association of LV longitudinal myocardial function with LV diastolic function after administration of SGLT2 inhibitor in T2DM patients with stable HF, we analyzed data from our previous prospective multicenter study, in which we investigated the effect of SGLT2 inhibitor on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Methods Our previous trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e' annular velocities (E/e'). LV longitudinal myocardial function was assessed as GLS based on the current guidelines. Results E/e' significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p=0.020) as previously described, while GLS showed significant improvement from 15.5±3.5% to 16.9±4.1% (p&amp;lt;0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HFpEF patients was more significant from 17.0±1.9% to 18.7±2.0% (p&amp;lt;0.001), compared to that in HFrEF patients from 11.3±3.8% to 11.8±4.6% (p=0.13). It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameter for the change in E/e' after administration of dapagliflozin. Conclusion Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF. Representative case Funding Acknowledgement Type of funding source: None

SGLT2 Inhibitors: A Novel Player in the Treatment and Prevention of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) characterized by diastolic and systolic dysfunction independently of hypertension and coronary heart disease, eventually develops into heart failure, which is strongly linked to a high prevalence of mortality in people with diabetes mellitus (DM). Sodium–glucose cotransporter type2 inhibitors (SGLT2Is) are a novel type of hypoglycemic agent in increasing urinary glucose and sodium excretion. Excitingly, the EMPA-REG clinical trial proved that empagliflozin significantly reduced the relative risk of cardiovascular (CV) death and hospitalization for heart failure (HHF) in patients with type 2 DM (T2DM) plus CV disease (CVD). The EMPRISE trial showed that empagliflozin decreased the risk of HHF in T2DM patients with and without a CVD history in routine care. These beneficial effects of SGLT2Is could not be entirely attributed to glucose-lowering or natriuretic action. There could be potential direct mechanisms of SGLT2Is in cardioprotection. Recent studies have shown the effects of SGLT2Is on cardiac iron homeostasis, mitochondrial function, anti-inflammation, anti-fibrosis, antioxidative stress, and renin–angiotensin–aldosterone system activity, as well as GlcNAcylation in the heart. This article reviews the current literature on the effects of SGLT2Is on DCM in preclinical studies. Possible molecular mechanisms regarding potential benefits of SGLT2Is for DCM are highlighted, with the purpose of providing a novel strategy for preventing DCM.

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio >300 mg/g, and estimated glomerular filtration rate of 30 to <90 mL/min/1.73 m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions in order to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

SGLT2 Inhibitors: Emerging Roles in the Protection Against Cardiovascular and Kidney Disease Among Diabetic Patients.

Purpose of ReviewType 2 diabetes mellitus (T2DM) is a prevalent disease with the severe clinical implications including myocardial infarction, stroke, and kidney disease. Therapies focusing on glycemic control in T2DM such as biguanides, sulfonylureas, thiazolidinediones, and insulin-based regimens have largely failed to substantially improve cardiovascular and kidney outcomes. We review the recent findings on sodium-glucose co-transporter type 2 (SGLT2) inhibitors which have shown to have beneficial cardiovascular and kidney-related effects.Recent FindingsSGLT2 inhibitors are a new class of diabetic medications that reduce the absorption of glucose in the kidney, decrease proteinuria, control blood pressure, and are associated with weight loss. SGLT2 inhibitors provide complementary therapy independent of insulin secretion or action with proved glucose-lowering effects. Recent placebo-controlled clinical trials have demonstrated that these medications can decrease cardiovascular death, progression of kidney disease, and all-cause mortality in diabetic and non-diabetic patients. Interestingly, SGT2 inhibitors such as dapagliflozin have also proven to decrease heart failure admissions and cardiovascular endpoints in non-diabetic patients, suggesting pleiotropic effects. The exact mechanisms responsible for reductions in atherosclerotic heart disease, need for kidney replacement therapy, and progressive kidney disease remain unknown. While regulation of glomerular hyperfiltration, albuminuria, and natriuresis may be part of the explanation, it is possible that complex cellular effects including energy balance optimization, downregulation of oxidative stress, and modulation of pro-inflammatory signaling pathways are associated with favorable outcomes observed in large clinical studies.ConclusionSGLT2 inhibitors are novel antidiabetic medications with immense utility in the management of patients with T2DM. Furthermore, SGLT2 inhibitors have demonstrated to reduce the progression to advanced forms of kidney disease and its associated complications. These medications should be front and center in the management of patients with diabetic kidney disease with and without chronic kidney disease as they confer protection against cardiovascular/renal death and improve all-cause mortality. Future studies should evaluate the benefits and implications of early initiation of SGLT2 inhibitors, as well as the long-term effects of this therapy.

Sodium-glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus.

The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.

Evidence-Based Clinical Review on Cardiovascular Benefits of SGLT2 (Sodium-Glucose Co-Transporter Type 2) Inhibitors in Type 2 Diabetes Mellitus.

Cardiovascular (CV) diseases are the leading cause of mortality and morbidity in patients with type 2 diabetes mellitus (DM). Therefore, there has been an increasing endorsement from diabetic associations across the globe for the use of anti-diabetic drugs, which not only provide not only glycemic control but also have cardioprotective effects. Sodium-glucose co-transporter type 2 (SGLT2) inhibitors are one class of drugs that have shown evidence of CV benefits in patients with type 2 DM. We reviewed the published literature and found five adequately powered clinical trials that evaluated the CV effects of SGLT2 inhibitors in type 2 DM patients. These trials assessed the CV effect of three SGLT2 inhibitors, namely, empagliflozin, canagliflozin, and dapagliflozin. It was found that all these clinical trials were multi-centric and conducted in and after 2015 across different parts of the World, enrolling type 2 DM patients with varied baseline characteristics in terms of age, BMI, sex, glomerular filtration rate, history of existing renal diseases, etc. In spite of these differences, the SGLT2 drugs were found to be beneficial by significantly reducing all-cause mortality, mortality due to CV causes, and risk of major CV events. All the studies highlighted the cardioprotective effect of SGLT-2 inhibitors, especially empagliflozin, dapagliflozin, and canagliflozin in type 2 DM patients with established CV disease, but the studies could not find significant improvement in 3P-MACE (three-point major adverse CV event) indicators offered by these drugs except empagliflozin. Hence, adequately powered clinical trials with long follow-up durations are the need of the hour to address this issue specifically.

Sodium-glucose cotransporter2 inhibitors represent a paradigm shift in the prevention of heart failure in type2 diabetes patients.

Recent major clinical trials of the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three‐point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as “cardiomyopathy”. Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca2+ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies.

SGLT2 Inhibitors as Add-On Therapy to Metformin for People with Type 2 Diabetes: A Review of Placebo-Controlled Trials in Asian versus Non-Asian Patients.

Metformin remains the first pharmacological choice for treating hyperglycemia in type 2 diabetes (T2DM) in most international guidelines. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are increasingly used as add-on therapy. T2DM pathophysiology is different in Asian and non-Asian (mainly Caucasian) patients. The aim of this systematic review is to compare the efficacy of SGLT2is vs placebo added to metformin in randomized controlled trials (RCTs: range 12–52 weeks) in Asian versus non-Asian patients with T2DM. The primary endpoint is the reduction in glycated hemoglobin (HbA1c) from baseline and key secondary endpoints are reductions in fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Systematic literature search collected 7 RCTs (3 with 2 doses) in Asian patients (10 analyses, n=1164, iSGLT2: canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, tofogliflozin)) and 10 RCTs (6 with two doses) in non-Asian patients (16 analyses, n=2482, iSGLT2: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin). Baseline values of HbA1c (7.98±0.19 vs 7.89±0.27%), FPG (8.80 ±0.46 vs 9.11±0.49 mmol/l) and SBP (128.4±1.6 vs 130.2±3.1 mmHg) were not significantly different in Asian vs non-Asian patients, but BW was lower in Asian patients (71.6±4.8 vs 88.0±2.5 kg, p<0.001). The placebo-adjusted weighed mean differences (WMD, 95% CI) were similar in Asian versus non-Asian patients regarding the reductions in HbA1c −0.60 (−0.68, −0.53) % versus −0.54 (−0.59, −0.49) % (p=0.568), FPG −1.37 (−1.53, −1.22) mmol/l vs −1.37 (−1.47, −1.27) mmol/l (p=0.627), BW when expressed in percentage of baseline BW −2.23 (−2.55, −1.90) % vs −2.16 (−2.37, −1.96) % (p=0.324), and SBP −4.53 (−5.53, −3.53) mmHg vs −4.06 (−4.83, −3.29) mmHg) (p=0.223). In conclusion, clinical efficacy of SGLT2i, as an add-on treatment to metformin monotherapy in patients with T2DM, is similar in Asian versus non-Asian patients, despite known ethnic differences in phenotype and pathophysiology of T2DM.

Real-World Clinical Outcomes Associated with Canagliflozin in Patients with Type 2 Diabetes Mellitus in Spain: The Real-Wecan Study.

The aims of this multicentric retrospective study were to assess in a real-world setting the effectiveness and safety of canagliflozin 100 mg/d (CANA100) as an add-on to the background antihyperglycemic therapy, and to evaluate the intensification of prior sodium–glucose co-transporter type 2 inhibitor (SGLT-2i) therapy by switching to canagliflozin 300 mg/d (CANA300) in patients with T2DM. One cohort of SGLT2i-naïve patients with T2DM who were initiated on CANA100 and a second cohort of patients with prior background SGLT-2i therapy who switched to CANA300 were included in the study. The primary outcome of the study was the mean change in HbA1c over the follow-up time. In total, 583 patients were included—279 in the cohort of CANA100 (HbA1c 8.05%, weight 94.9 kg) and 304 in the cohort of CANA300 (HbA1c 7.51%, weight 92.0 kg). Median follow-up periods in both cohorts were 9.1 and 15.4 months respectively. CANA100 was associated to significant reductions in HbA1c (−0.90%) and weight (−4.1 kg) at the end of the follow-up. In those patients with baseline HbA1c > 8% (mean 9.25%), CANA100 lowered HbA1c levels by 1.51%. In the second cohort, patients switching to CANA300 experienced a significant decrease in HbA1c (−0.35%) and weight (−2.1 kg). In those patients with baseline HbA1c > 8% (mean 8.94%), CANA300 lowered HbA1c levels by 1.12%. There were significant improvements in blood pressure in both cohorts. No unexpected adverse events were reported. In summary, CANA100 (as an add-on therapy) and CANA300 (switching from prior SGLT-2i therapy) significantly improved several cardiometabolic parameters in patients with T2DM.

Early biomarkers of diabetic kidney disease. A focus on albuminuria and a new combination of antidiabetic agents.

We aimed to determine the efficacy and safety of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists to preventworsening urinary albumin-to-creatinine ratio as an early biomarker of diabetes kidney disease. A total of 178 patients with type 2 diabetes and obesity received combination treatment with SGLT2i added to GLP1ra (n=76), GLP1ra added to SGLT2i (n=50) or GLP1ra plus SGLT2i from start (n=52), according to investigators´ best clinical judgement. Major outcomes assessed at 26weeks were changes in urine albumintocreatinine-ratio (UACR), estimated glomerular filtration rate (eGFR), glycated haemoglobin, body weight and systolic blood pressure. All patients (58.6% men, mean age 61.9±10.0years) completed the study. Baseline HbA1c, weight and eGFR levels were 8.2±0.9%, 109.9±19kg and 83.3±19.6mL/min/m2 , respectively. At 26weeks, we found significant reductions in HbA1c (1.16%), weight (5.17kg) and systolic blood pressure (8.13mmHg). The reduction in UACR was 15.14mg/g (95% CI 8.50-22.4) (-24.6±64.7%), which was greatest in the group of patients with SGLT2i added on to GLP1ra therapy (116.7mg/g; 95% CI: 54-296.5mg/g; P<.001. Patients with urinary albumin-to-creatinine ratio ≥30mg/g, showed a higher declines (63.18mg/g [95% CI 44.5-104.99]) (-56±65.9%). The greatest reduction in urinary albumin-to-creatinine ratio was obtained when SGLT2i was added to GLP1ra (116.7mg/g). The eGFR did not significantly change along the study period. Our results show the beneficial effect of GLP1ra and SGLT2i combination therapy on early biomarkers of diabetes kidney disease such as albuminuria and in other significant outcomes for diabetes control.

Role of ketogenic starvation sensors in mediating the renal protective effects of SGLT2 inhibitors in type 2 diabetes

Sodium-glucose cotransporter 2 (SGLT2) inhibitors ameliorate the progression of diabetic chronic kidney disease, but the mechanisms underlying this nephroprotective effect have not been fully elucidated. These drugs induce a fasting-like transcriptional paradigm, which includes activation of sirtuin-1 (SIRT1) and its downstream effectors, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and fibroblast growth factor 21 (FGF21). This triad of enzymes and transcription factors serve as master regulators of nutrient and cellular homeostasis, and each acts to enhance gluconeogenesis, fatty acid oxidation and ketogenesis, the hallmarks of treatment with SGLT2 inhibitors. At the same time, SIRT1/PGC-1α/FGF21 signaling also promotes autophagy, a lysosome-dependent degradative pathway that cleanses the cytosol of dysfunctional organelles. This action alleviates cellular stress, ameliorates inflammation, and is strikingly nephroprotective. Interestingly, type 2 diabetes is characterized by both a deficiency of SIRT1/PGC-1α signaling and an impairment of autophagic flux, thus explaining the high levels of oxidative stress in the diabetic kidney. SIRT1 gene polymorphisms have been linked with an increased risk of diabetic nephropathy in several epidemiological studies. Importantly, there is an inverse relationship between the activity of SGLT2 and signaling through the SIRT1/PGC-1α/FGF21 pathway, and SGLT2 inhibition leads to activation of these ketogenic nutrient deprivation sensors. Therefore, activation of SIRT1/PGC-1α/FGF21 may explain the effect of SGLT2 inhibitors not only to promote ketogenesis, but also to preserve renal function in type 2 diabetes.

Novel oral hypoglycemic agents SGLT-2 inhibitors: cardiovascular benefits and potential mechanisms.

Diabetes is an independent risk factor for cardiovascular events, and cardiovascular diseases (CVD) increase the risk of death when combined with diabetes. Diabetes and coronary heart disease are like two sides of a coin, which increase each other's long-term cardiovascular events. Therefore, a glucose-lowering regimen that can change the cardiovascular outcome has become a hot spot in the cardiovascular field in recent years. SGLT-2 (sodium-glucose cotransporter type 2) inhibitors have a novel hypoglycemic mechanism that reduces blood glucose by promoting glucose excretion. Clinical studies have shown that SGLT-2 inhibitors such as dapagliflozin and empagliflozin can reduce major cardiovascular adverse events, CV mortality, all-cause mortality, and hospitalization for heart failure. The pharmacological mechanisms by which SGLT-2 inhibitors achieve cardiovascular benefits have also become hot spots. Possible mechanisms for the cardiovascular benefits of SGLT-2 inhibitors known so far include lowering blood pressure, improving heart function and atherosclerosis, reducing inflammation and oxidative stress. This review discusses the clinical trials and possible pharmacological mechanisms of cardiovascular benefits of SGLT2 inhibitors.