In 2015, 8.5% individuals had diabetes globally and estimates for 2016 suggest that 7.8% of >1 billion population of India have diabetes. This unprecedented rise in the prevalence of diabetes reflects a parallel increase in the prevalence of contributing risk factors such as obesity and diabetes-related microvascular and macrovascular complications that have detrimental cardiovascular, renal, and ocular manifestations. Several epidemiological studies from Asia and India have suggested a strong interplay between rising rates of obesity and the uptrend in diabetes. India along with China accounted for 15% of the 671 million obese (body mass index ≥30 kg/mg2) adults worldwide in 2013 highlighting the substantial risk of diabetes in these populations.
Results from meta-analysis and population-based studies attribute a 2-fold increase in the occurrence of coronary heart disease, multiple types of stroke, and related deaths (relative risk, 1.67–1.75) to diabetes. In Asian patients, prediabetes has been associated with an increased risk of chronic kidney disease (CKD, overall relative risk, 1.12 [95% confidence interval (CI) 1.02–1.21]). A cumulative analysis involving 54 countries indicated that in half of these countries, diabetes was the primary cause of end-stage renal disease (ESRD), accountable for 31% new ESRD. Other complications such as vision impairments because of retinopathy (7%–11% patients with diabetes have vision-threatening retinopathy) and ischemic events (10%–20% higher in patients with diabetes) have also been closely associated with the pathogenesis of diabetes.
Assessments of utility scores for individual complications indicate that ischemic events, stroke, blindness, renal failure, heart failure, and myocardial ischemia result in largest reductions in health-related quality of life (QoL). Further, the catastrophic impact of diabetes and related complications on health-related QoL accrues enormous economic burden on the patient, their families, and national health-care networks. Thus, prevention of diabetes-related complications is a key component in the management of diabetes that can positively impact the declining QoL and lower the overall disease burden.
The MEDLINE/PubMed and Cochrane databases were searched on April 11, 2016. Other data sources included trial registers (http://www.clinicaltrials.gov/) for data on ongoing trials, Google, and Google Scholar for treatment guidelines and prescribing information. Medical Subject Headings and free-text keywords were used and combined using “OR” and “AND” (diabetes mellitus, type 2 diabetes mellitus [T2DM], sodium-glucose cotransporter type 2 inhibitors [SGLT2i], canagliflozin, dapagliflozin, and empagliflozin). Inclusion of articles was based on screening of titles and abstracts. Articles reporting clinical trials, reviews, systematic reviews, and meta-analysis were included and no other filters were used. The search was strengthened by screening reference lists of retrieved articles manually for additional relevant sources.
CHANGING TREATMENT NEEDS
Raised glycated hemoglobin (HbA1c) has been regarded as a reliable marker of diabetes-related complications, and most accepted guidelines on control of T2DM recommend lowering of HbA1c (≤7.0%) as an obligatory therapeutic goal. Among currently prescribed antihyperglycemic agents (AHAs), metformin is the most preferred first-line drug and is generally well tolerated; however, gastrointestinal disturbances and risk of fatal lactic acidosis restrict its use in patients with compromised hepatic functioning. Other common AHAs (sulfonylureas, glinides, thiazolidinediones, gliptins, or DPP-IV inhibitors) have been associated with frequent incidences of hypoglycemia, weight gain, cardiovascular sequelae, and other metabolic derailments either as mono or add-on therapies that deter their favorable glycemic effects. Insulin therapies for T2DM have also been associated with significant weight gain that is nearly proportional to the lowering of glucose.
Findings from large landmark clinical studies such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), and the Veterans Affairs Diabetes Trial (VADT) underscore the limitations of exclusively glycemia-targeted strategies, emphasizing the need for simultaneous control of multiple metabolic defects [Table 1]. In addition, the benefits of a structured multidrug intervention (combination of glucose-lowering, antihypertensive, lipid-lowering treatments, aspirin, and vitamin supplementation) are supported by results from the Steno-2 study that reported a 50% reduction in cardiovascular risks in patients with T2DM and microalbuminuria. Durability of favorable cardiovascular outcome following the long-term (mean, 7.8 years) multifactorial approach was observed in a subsequent 5.5-year follow-up study.
REVISED GUIDELINES FOR DIABETES CARE
Critical observations from the ACCORD, ADVANCE, and VADT studies involving over 23,000 patients have been pivotal in transforming the dogma of diabetes care and refining treatment to attain a more holistic outcome. Recent amendments of the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) guidelines provide distinct treatment goals for coexisting metabolic conditions along with targets for glycemic control (ADA: HbA1c <7.0%, AACE: HbA1c ≤6.5%, if achievable in a safe manner). Both recommendations emphasize on minimizing weight gain and advocate comprehensive assessments of body weight and appropriate and timely adoption of medical or surgical interventions. Targets have also been included for systolic (SBP; ADA:<140 mmHg, AACE: <130 mm Hg) and diastolic blood pressure (DBP; ADA: <90 mm Hg, AACE:<80 mmHg) and both groups endorse monitoring and managing dyslipidemia (AACE: low-density lipoprotein cholesterol [LDL-C], <100 mg/dL or <70 mg/dL; triglyceride, <150 mg/dL). The ADA recommends pharmacological intervention in patients with T2DM having elevated urinary albumin excretion (modest elevation, 30–299 mg/dL; severe elevation, >300 mg/dL) and with eGFR <60 mL/min/1.73 m2.
The ADA and AACE also recommended initiation of combination therapy in patients not achieving desired HbA1c level after 3 months of initial treatment or if the HbA1c is >9.0%, for rapid attainment of target levels. In addition, for patients with multiple comorbidities, adequate treatments with hypolipidemic, antihypertensives, or weight loss medications are regarded imperative for comprehensive management of diabetes and associated complications. Thus, taking into account the need for a multifactorial approach, AHAs that provide sustained glycemic control along with additional metabolic benefits would be optimal treatment choices.
SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS: MOVING BEYOND THE GLYCEMIC TREATMENT GOAL
SGLT2i are a novel class of AHA that lower blood glucose levels by increasing renal glucose excretion. SGLT2 is the active cotransporter of glucose along the proximal renal tubules (S1 and S2 segments) that ensures reabsorption of approximately 90% glucose from the tubular lumen into the cells under normal physiological conditions. Under conditions of hyperglycemia, high tubular concentration of glucose triggers an increase in tubular reabsorption until the transport mechanism reaches its maximum capacity. SGLT2i lower the threshold for glucose excretion by reducing the affinity of SGLT2 for glucose and increase urinary excretion of glucose, which subsequently results in reduction of blood glucose levels.
The efficacy of SGLT2i in achieving standard glycemic targets either as a single agent or as an add-on to standard ongoing therapies has been evidenced by several clinical studies. A pooled analyses of results for SGLT2i (canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, sergliflozin etabonate, remogliflozin etabonate, and tofogliflozin) across multiple doses revealed attainment of glycemic target of HbA1c <7.0% in a significant number of patients that was 2 folds greater than that observed for placebo groups (odds ratio = 2.09, 95% CI, 1.77–2.46). Significant reductions in fasting plasma glucose, mean body weight and blood pressure (SBP and DBP) was also demonstrated following treatment with these SGLT2i. Clinical studies have also revealed persistent glycemic control over long durations of up to 2 years with canagliflozin and empagliflozin and up to 4 years with dapagliflozin. These findings are suggestive of sustained clinical efficacy, fundamental for the management of the chronic manifestations of T2DM. Thus, SGLT2i may have effects in slowing down the progressive deterioration of beta cell function, a common pathogenic feature of T2DM regarded to be the primary cause of diminishing efficacy of metformin, insulin, and sulfonylurea therapies over time.
Unlike most conventional AHAs, SGLT2i do not trigger insulin release while lowering plasma glucose levels owing to their insulin-independent mechanism of action and hence are not associated with the adverse event (AE) of hypoglycemia (except when used in addition to sulfonylurea or insulin where there is an increased risk of hypoglycemia). Multiple physiological actions of SGLT2i have been associated with the lower risk of hypoglycemia that include an increase in glucose production possibly via gluconeogenesis, carbohydrate-sparing increase in lipid utilization (ketogenesis) and a compensatory renal effect of SGLT1 mediated glucose reabsorption. Further, the counter regulatory responses triggered by hypoglycemia have been associated with increased risk of cardiovascular events via modulations in sympathetic activity, inflammatory cytokine release and changes in endothelial function, blood coagulation and fibrinolysis. Thus, the absence of clinically significant hypoglycemia may be regarded as a potential cardiovascular benefit of SGLT2i. Other favorable metabolic effects of SGLT2i include lowering of the insulin: glucagon ratio (IGR) by increasing glucagon levels and reducing insulin levels. This effect on IGR is thought to be useful in rectifying the disrupted metabolism (maladaptive anabolism) and associated complications in hyperinsulinemic individuals. Further, the 'calorie restriction mimetic' action of SGLT2i by the virtue of increased glycosuria and supplemented by their effects on IGR and ketogenesis has been postulated to have additional metabolic benefits that include body weight reductions. Taking into the account the relation of T2DM with cardiovascular risk and the alarming rise in incidences of risk factors, the ADA and Canadian Diabetes Association Clinical Practice Guidelines Expert Committee recommend initiation of SGLT2i therapy in patients not meeting the therapeutic glycemic requirements with conventional treatment strategies for a more comprehensive management of T2DM and its complications. The following sections of this review will discuss the nonglycemic benefits of SGLT2 inhibitors currently approved in India (canagliflozin, dapagliflozin and empagliflozin) and highlight their role in the changing treatment strategies for T2DM that focus on achieving targets beyond the standard glycemic goals.
Effects on body weight
Clinically relevant reductions in body weight associated with SGLT2i have been attributed to the increase in glycosuria resulting in a negative energy balance and calorie loss. SGLT2i as monotherapy and add-on to current treatments have shown favorable effects on weight loss [Table 2]. Findings of weight reduction following use of SGLT2i in conjunction with drugs such as sulfonylureas (glipizide, glyburide, glibenclamide) and pioglitazone that are known to trigger weight gain highlight the usefulness of SGLT2i in maximizing the effects of current treatments. Reductions in body weight have also been reported with the use of SGLT2i as add-on to insulin therapy thus offering an additional advantage for patients receiving insulin. Further, canagliflozin, dapagliflozin and empagliflozin have also demonstrated steady and sustained reductions in body weight similar to observations for glycemic control following treatment for 2–4 years. Clinically, modest weight reductions associated with SGLT2i treatment have been accompanied with favorable effects on blood pressure, lipids and inflammatory markers that positively impact the cardiovascular profile of patients at risk.
SGLT2i have also demonstrated favorable reductions in waist circumference and body fat mass and these effects have been associated with improvements in overall metabolic status. Treatment with canagliflozin has shown reductions in fat mass (in subcutaneous and visceral adipose tissue) that was primarily responsible for the reported weight loss as compared to glimepiride which was associated with an increase in fat mass and body weight. Considerable reduction in body weight was observed in canagliflozin treated patients at the end of 104 weeks; nearly two-thirds of which was from reduction in the fat mass. Decreases in waist circumference (−3.1 to −3.3 cm) were also observed following prolonged treatment with canagliflozin for 52–104 weeks in these studies. Following treatment with dapagliflozin over 102 weeks, reductions in body weight was accompanied by favorable reductions in fat mass and waist circumference (−5.0 cm) versus placebo. Significant reductions in waist circumference (−1.0 to −1.3 cm) have also been reported with use of empagliflozin over a shorter duration of 12 and 24 weeks versus placebo.
Effects on blood pressure
Stable reductions in blood pressure have been associated with the use of SGLT2i. Although the precise mechanism facilitating this effect remains to be determined, weight loss, osmotic diuresis and mild natriuresis have been linked to reductions in blood pressure. Other secondary mechanisms that are hypothesized to be involved include blockade of the renin-angiotensin-aldosterone system owing to the decreased proximal sodium reabsorption and changes in nitric oxide release due to improved glycemic control. Cumulatively, all these effects have been associated with a reduction in arterial stiffness and lowering of blood pressure.
Clinically significant reductions in blood pressure have been observed with the use of SGLT2i either as single agents or as a combination [Table 2]. Observation of reductions in ambulatory blood pressure, a distinctive measure and a sensitive predictor of cardiovascular endpoint, following short-term treatment (6–12 weeks) with canagliflozin and empagliflozin underscores the effectiveness of these agents in rapid lowering of blood pressure in patients with T2DM and comorbid hypertension. Data from pooled analysis of results from phase 2 and 3 clinical studies of SGLT2i involving large patient populations have demonstrated clinically relevant mean reductions in SBP (−0.27 to −4.0 mm Hg) and DBP (−0.24 to −1.6 mm Hg). Further, analysis of each SGLT2i separately demonstrated significant lowering of SBP and DBP relative to the control. It is important to note that the reduction in blood pressure by SGLT2i is not accompanied by an increase in heart rate. Consistent with the findings for glucose control and weight loss, sustained reduction in SBP have also been observed following prolonged use of canagliflozin for 2 years versus sulfonylureas that increased blood pressure marginally.
Hyperglycemia and hypertension are important mediators of diabetic nephropathy that eventually exacerbates to ESRD. Experimental models of diabetes have regarded glomerular hyperfiltration (125–140 mL/min/1.73 m2) and microalbuminuria as early markers of diabetic renal dysregulation.
SGLT2i have shown favorable responses on renal endpoints that are complementary to their glucose control and blood pressure lowering effects, the exact mode of action however is not well-elucidated. Reduction of sodium reabsorption in the proximal nephron by SGLT2i is thought to increase the delivery of sodium to the juxtaglomerular apparatus in the distal nephron thereby activating the tubuloglomerular feedback mechanism. This eventually results in a reduction of glomerular pressure lowering hyperfiltration and inducing a decrease in urinary albumin excretion thus producing ambient physiological changes that may promote renoprotection. Additional postulated mechanisms include reduction in progressive nephron damage through ameliorations in inflammation and restoration of renal microvasculature.
Canagliflozin at both doses successfully achieved glycemic targets (reductions in fasting plasma glucose and higher proportion of patients achieving HbA1c <7.0%) versus placebo in patients with stage 3 CKD without negatively impacting the deteriorating renal function in these patients. Pooled data from long-term studies of dapagliflozin involving patients with T2DM having normal or mildly impaired renal function, did not appear to increase the risk of renal toxicity or decline in nephron function. SGLT2 inhibition by empagliflozin has demonstrated attenuation of hyperfiltration (−33 mL/min/1.73 m2) during clamped euglycemia in patients with type 1 diabetes mellitus along with significant improvement in eGFR and other renal parameters suggestive of restoration of tubuloglomerular feedback. This along with significant reductions in glomerular hydrostatic pressure suggests meaningful impact on hemodynamic abnormalities that are hallmark pathogenic changes in the progression of nephropathy. Empagliflozin treatment in T2DM patients with challenged renal functioning has also demonstrated reductions in HbA1c along with improved albumin to creatinine ratio in T2DM patients with stage 2 CKD and a higher number of patients at stage 3 CKD receiving empagliflozin 25 mg improving from macroalbuminuria to microalbuminuria or microalbuminuria to no albuminuria. Thus, in renal-impaired patients with T2DM, long-term treatment with SGLT2i have been successful in attaining therapeutic targets and facilitating improvements in measures of renal function, in this special patient cohort having limited treatment options among the available AHAs.
Because of the large dependence of SGLT2i on renal glucose filtration, assessment of kidney function before initiation of SGLT2i therapy is essential. As per current recommendations, SGLT2i should be used only in patients with eGFR of >60 mL/min/1.73 m2 and not initiated in patients with severely compromised GFR (eGFR, <45 mL/min/1.73 m2). Canagliflozin may be used in patients with moderate renal impairment (45–<60 mL/min/1.73 m2) at a recommended once daily dose of 100 mg. Treatment with dapagliflozin is not recommended in patients with eGFR <60 mL/min/1.73 m2. Empagliflozin can be used without dose adjustments in patients with moderate renal impairment (eGFR ≥45 mL/min/1.73 m2).
Effects on lipid profile
SGLT2i have frequently been associated with mild increase in HDL-C levels and small but undesirable increase in LDL-C levels raising concerns of cardiovascular risk. Overall, fewer studies have reported the variable effects of SGLT2i on the lipid profile [Table 2]. Treatments with canagliflozin and dapagliflozin have shown an increase in HDL-C, decrease in triglycerides and an increase in LDL-C. Meta-analyses of results from clinical studies of SGLT2i indicated a significant increase in HDL-C levels and no meaningful effects on LDL-C and triglyceride levels. In a pooled analysis of four placebo-controlled, phase 3 studies that evaluated the safety and tolerability of canagliflozin, a dose-related increase in total cholesterol and LDL-C from baseline as compared to placebo was reported. Though not significant, comparatively large placebo-subtracted least squares mean percent increase from baseline LDL-C was seen with canagliflozin in the lowest tertile compared with the middle and highest tertiles. Although, an increase in HDL-C and decrease in triglycerides may potentially contribute to the atheroprotective effects of SGLT2i, further studies are needed to illustrate their effects on lipid metabolism.
Effects on serum levels of uric acid
Another favorable, yet minimally explored effect of SGLT2i includes the reduction of serum uric acid levels. Although not causal, findings from a meta-analysis have linked elevations in serum uric acid levels to metabolic disturbances as well as cardiovascular and all-cause mortality. An increase in glycosuria mediated by SGLT2i leading to an increased exchange of uric acid by the SLC2A9 (GLUT9) transporter, in the apical membrane of tubular cells has been hypothesized as the possible mechanism for this uricosuric effect. Pooled data from 4 studies of canagliflozin (26-week trials) as monotherapy or in combination with AHAs in patients with T2DM and a subset of patients with hyperuricemia (serum uric acid ≥8 mg/dL) showed a reduction of 13% in serum uric acid relative to placebo in the overall population. More patients with hyperuricemia achieved the target serum uric acid levels (<6 mg/dL).
Completed/ongoing outcome studies
Studies evaluating SGLT2i for focused cardiovascular and renal outcomes such as myocardial infarction, stroke, ESRD, hospitalizations due to cardiovascular events and cardiovascular death in T2DM patients at increased risk for cardiovascular events are important to validate the available findings for surrogate measures. Effects of empagliflozin on cardiovascular morbidity and mortality have been demonstrated by the large clinical study (EMPA-REG OUTCOME) that reported reduction in deaths due to cardiovascular causes in patients receiving empagliflozin as add-on to standard therapy. The effect was accompanied by meaningful changes in risk factors such as lowering of body weight, waist circumference, serum uric acid, blood pressure and marginal rise in HDL levels. Assessment of long-term renal effects from the EMPA-REG OUTCOME study demonstrated delayed progression of kidney disease and lower risk of renal events with empagliflozin treatment versus placebo. Three large outcome studies to evaluate canagliflozin are currently ongoing. Two of these studies are expected to complete in the next 12 months: the CANagliflozin cardiovascular Assessment Study (CANVAS) and the CANVAS – Renal, which comprise the CANVAS Program. The third, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation study that is independent of the CANVAS program, will determine the effects of canagliflozin on CKD and is scheduled for completion by 2020. The DECLARE-TIMI 58 study for dapagliflozin is currently being carried out to assess effectiveness of treatment in reducing cardiovascular events and related mortality.
Results from these large and longer ongoing clinical studies will be pivotal in providing insights and substantial evidence to support findings of beneficial metabolic associations of SGLT2i and establish the benefit-harm balance for these agents. Interestingly, two recent meta-analyses of results from randomized studies (with noncardiovascular endpoints) of multiple SGLT2i support results of the EMPA-REG OUTCOME study and also provide evidence for association of these cardioprotective effects with inhibition of SGLT2 and hence, specific to these agents. The results from the first study, majorly driven by results of the EMPA-REG OUTCOME study, were suggestive of an overall favorable effect SGLT2i on cardiovascular outcomes in T2DM patients in contrast to findings from glycemia-centered treatments. The more recent pooled analysis evaluating effects on specific cardiovascular events, showed significant reduction in myocardial infarction without increased risk of stroke and included results from two cardiovascular outcome based studies, EMPA-REG OUTCOME and CANVAS studies (interim results).
COMMON ADVERSE EVENTS
The frequently reported AEs of SGLT2i are attributable to their effect of increasing urinary glucose excretion and osmotic diuresis. Most AEs have been regarded as moderate or mild and leading to fewer discontinuations. Common AEs associated with SGLT2i based on pooled data from clinical studies of all approved doses include genital mycotic infections in men (5.4%–11.6%) and women (1.6%–4.2%), urinary tract infections (UTIs) (4.3%–9.3%) and increased frequency of urination (2.9%–5.1%). AEs related to volume depletion (0.3%–3.4%) include hypotension, orthostatic hypotension, dehydration, dizziness and electrolyte imbalances. Other labelled AEs of this drug class include diabetic ketoacidosis, acute kidney injury and impairment in renal function, hypoglycemia (when used with insulin and insulin secretagogues), increased LDL-C, increased risk of bone fracture (canagliflozin) and risk of bladder cancer (dapagliflozin). The incidences of AEs in Indian patients based on a post hoc analysis of pooled data from canagliflozin studies (UTIs, 2.3%–14.3%; female genital mycotic infections, 1.8%–10.2%; male genital mycotic infections, 1.2%–4.5%; volume depletion AEs, 0.9%–2.0%), were analogous to those reported in other Asian populations and generally lower than rates in global populations. Overall, the risk of common AEs is reported to be higher in elderly patients, patients with impaired renal function and hence SGLT2i should be used cautiously in these patient groups.
The existing classes of AHAs have been successful in achieving therapeutic glycemic goals, however, there remains a need for therapies that can reduce long-term risk of vascular complications and contribute to a multidimensional approach for the management of T2DM. In addition to robust glucose control, SGLT2i have demonstrated considerable potency for beneficial metabolic changes that include weight loss and attenuation of major cardiovascular risk factors (high blood pressure, dyslipidemia and deteriorating renal function). These nonglycemic benefits of SGLT2i have placed them at unique position in the changing treatment strategies for T2DM and enabled their inclusion in the revised therapeutic algorithms recommended by key decision making groups. Emerging data from outcome studies are promising and are expected to exemplify the distinct cardiometabolic effects of each SGLT2i, supporting the inclusion of these agents in treatment regimens for T2DM.
Financial support and sponsorship
This study was funded by Janssen India, Mumbai, India. The sponsor also provided a formal review of the manuscript.
Conflicts of interest
Dr. Nishant Garodia is an employee of Janssen India. Dr. William Canovatchel is an employee of Janssen Research & Development, LLC, USA, and holds company stocks. Dr. Vishal Gupta has received honoraria as a consultant from Janssen India. Dr. B. N. Lokesh was an employee of Janssen India at the time of conception of this review article. Dr. Ravi Santani was an employee of Janssen India until manuscript submission.
Priya Ganpathy, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd., India) provided medical writing assistance and Dr. Sangita Patil, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd., India) provided additional editorial support for the development of this review manuscript. This support was funded by Janssen India.
1. World Health Organization. Global Report on Diabetes 2016.Last accessed on 2016 Aug 16 Available from: http://www.apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf
2. . NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants Lancet. 2016;387:1513–30
3. . International Diabetes Federation IDF Diabetes Atlas. 2015Last accessed on 2016 Aug 167th ed Brussels, Belgium International Diabetes Federation Available from: http://www.diabetesatlas.org/resources/2015-atlas.html
4. Emerging Risk Factors Collaboration. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies Lancet. 2010;375:2215–22
5. Little M, Humphries S, Patel K, Dodd W, Dewey C. Factors associated with glucose tolerance, pre-diabetes, and type 2 diabetes in a rural community of South India: A cross-sectional study Diabetol Metab Syndr. 2016;8:21
6. Meshram II, Vishnu Vardhana Rao M, Sudershan Rao V, Laxmaiah A, Polasa K. Regional variation in the prevalence of overweight/obesity, hypertension and diabetes and their correlates among the adult rural population in India Br J Nutr. 2016;115:1265–72
7. Misra P, Upadhyay RP, Misra A, Anand K. A review of the epidemiology of diabetes in rural India Diabetes Res Clin Pract. 2011;92:303–11
8. Mohan I, Gupta R, Misra A, Sharma KK, Agrawal A, Vikram NK, et al Disparities in prevalence of cardiometablic risk factors in rural, urban-poor, and urban-middle class women in India PLoS One. 2016;11:e0149437
9. Yoon KH, Lee JH, Kim JW, Cho JH, Choi YH, Ko SH, et al Epidemic obesity and type 2 diabetes in Asia Lancet. 2006;368:1681–8
10. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: A systematic analysis for the Global Burden of Disease Study 2013 Lancet. 2014;384:766–81
11. Barengo NC, Katoh S, Moltchanov V, Tajima N, Tuomilehto J. The diabetes-cardiovascular risk paradox: Results from a Finnish population-based prospective study Eur Heart J. 2008;29:1889–95
12. Echouffo-Tcheugui JB, Narayan KM, Weisman D, Golden SH, Jaar BG. Association between prediabetes and risk of chronic kidney disease: A systematic review and meta-analysis Diabet Med. 2016;33:1615–24
13. . United States Renal Data System. 2014 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States In National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2014 Bethesda, MD
14. Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al Global prevalence and major risk factors of diabetic retinopathy Diabetes Care. 2012;35:556–64
15. Hayes A, Arima H, Woodward M, Chalmers J, Poulter N, Hamet P, et al Changes in quality of life associated with complications of diabetes: Results from the advance study Value Health. 2016;19:36–41
16. Seuring T, Archangelidi O, Suhrcke M. The economic costs of type 2 diabetes: A global systematic review Pharmacoeconomics. 2015;33:811–31
17. Elley CR, Kenealy T, Robinson E, Drury PL. Glycated haemoglobin and cardiovascular outcomes in people with type 2 diabetes: A large prospective cohort study Diabet Med. 2008;25:1295–301
18. Qaseem A, Vijan S, Snow V, Cross JT, Weiss KB, Owens DK. Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Glycemic control and type 2 diabetes mellitus: The optimal hemoglobin A1c targets. A guidance statement from the American College of Physicians Ann Intern Med. 2007;147:417–22
19. Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ, et al Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: Executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD) Eur Heart J. 2007;28:88–136
20. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes Diabetes Care. 2009;32:193–203
21. Zheng J, Woo SL, Hu X, Botchlett R, Chen L, Huo Y, et al Metformin and metabolic diseases: A focus on hepatic aspects Front Med. 2015;9:173–86
22. Simó R, Hernández C. Treatment of diabetes mellitus: General goals, and clinical practice management Rev Esp Cardiol. 2002;55:845–60
23. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS 49).UK Prospective Diabetes Study (UKPDS) Group JAMA. 1999;281:2005–12
24. Huang Y, Abdelmoneim AS, Light P, Qiu W, Simpson SH. Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: A cohort study J Diabetes Complications. 2015;29:196–202
25. Lu CJ, Sun Y, Muo CH, Chen RC, Chen PC, Hsu CY. Risk of stroke with thiazolidinediones: A ten-year nationwide population-based cohort study Cerebrovasc Dis. 2013;36:145–51
26. Filion KB, Joseph L, Boivin JF, Suissa S, Brophy JM. Thiazolidinediones and the risk of incident congestive heart failure among patients with type 2 diabetes mellitus Pharmacoepidemiol Drug Saf. 2011;20:785–96
27. Gallagher AM, Smeeth L, Seabroke S, Leufkens HG, van Staa TP. Risk of death and cardiovascular outcomes with thiazolidinediones: A study with the general practice research database and secondary care data PLoS One. 2011;6:e28157
28. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes N Engl J Med. 2007;356:2457–71
29. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: A meta-analysis JAMA. 2007;298:1189–95
30. Fisman EZ, Tenenbaum A, Boyko V, Benderly M, Adler Y, Friedensohn A, et al Oral antidiabetic treatment in patients with coronary disease: Time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up Clin Cardiol. 2001;24:151–8
31. Olsson J, Lindberg G, Gottsäter M, Lindwall K, Sjöstrand A, Tisell A, et al Increased mortality in type II diabetic patients using sulphonylurea and metformin in combination: A population-based observational study Diabetologia. 2000;43:558–60
32. Kos K, Baker AR, Jernas M, Harte AL, Clapham JC, O'Hare JP, et al DPP-IV inhibition enhances the antilipolytic action of NPY in human adipose tissue Diabetes Obes Metab. 2009;11:285–92
33. Standl E, Schnell O. DPP-4 inhibitors and risk of heart failure EXAMINEd Lancet. 2015;385:2022–4
34. Brown NJ, Byiers S, Carr D, Maldonado M, Warner BA. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema Hypertension. 2009;54:516–23
35. Kutoh E, Hirate M, Ikeno Y. Teneligliptin as an initial therapy for newly diagnosed, drug naive subjects with type 2 diabetes J Clin Med Res. 2014;6:287–94
36. . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type diabetes (UKPDS). UK Prospective Diabetes Study (UKPDS) Group Lancet. 1998;352:837–53
37. Fisman EZ, Tenenbaum A, Benderly M, Goldbourt U, Behar S, Motro M. Antihyperglycemic treatment in diabetics with coronary disease: Increased metformin-associated mortality over a 5-year follow-up Cardiology. 1999;91:195–202
38. Action to Control Cardiovascular Risk in Diabetes Study Group. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, et al Effects of intensive glucose lowering in type 2 diabetes N Engl J Med. 2008;358:2545–59
39. ADVANCE Collaborative Group. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes N Engl J Med. 2008;358:2560–72
40. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al Glucose control and vascular complications in veterans with type 2 diabetes N Engl J Med. 2009;360:129–39
41. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes N Engl J Med. 2003;348:383–93
42. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes N Engl J Med. 2008;358:580–91
43. Brunton S. Beyond glycemic control: Treating the entire type 2 diabetes disorder Postgrad Med. 2009;121:68–81
44. . Standards of Medical Care in Diabetes: Summary of Revisions Diabetes Care. 2016;39(Suppl 1):S4–5
45. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al Consensus statement by the american association of clinical endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2016 executive summary Endocr Pract. 2016;22:84–113
46. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: Rationale and clinical prospects Nat Rev Endocrinol. 2012;8:495–502
47. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters Physiol Rev. 2011;91:733–94
48. Patel AK, Fonseca V. Turning glucosuria into a therapy: Efficacy and safety with SGLT2 inhibitors Curr Diab Rep. 2010;10:101–7
49. Ghosh RK, Ghosh SM, Chawla S, Jasdanwala SA. SGLT2 inhibitors: A new emerging therapeutic class in the treatment of type 2 diabetes mellitus J Clin Pharmacol. 2012;52:457–63
50. Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: Role in diabetes mellitus and potential clinical implications Kidney Int. 2009;75:1272–7
51. Berhan A, Barker A. Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus: A meta-analysis of randomized double-blind controlled trials BMC Endocr Disord. 2013;13:58
52. Leiter LA, Yoon KH, Arias P, Langslet G, Xie J, Balis DA, et al Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: A randomized, double-blind, phase 3 study Diabetes Care. 2015;38:355–64
53. Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S. Dapagliflozin Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: Efficacy and safety over 2 years Diabetes Obes Metab. 2014;16:124–36
54. Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC. EMPA-REG HH-SU trial investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: A 104-week randomised, active-controlled, double-blind, phase 3 trial Lancet Diabetes Endocrinol. 2014;2:691–700
55. Del Prato S, Nauck M, Durán-Garcia S, Maffei L, Rohwedder K, Theuerkauf A, et al Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data Diabetes Obes Metab. 2015;17:581–90
56. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes Diabetologia. 2014;57:891–901
57. Merovci A, Mari A, Solis C, Xiong J, Daniele G, Chavez-Velazquez A, et al Dapagliflozin lowers plasma glucose concentration and improves ß-cell function J Clin Endocrinol Metab. 2015;100:1927–32
58. Katsuno K, Fujimori Y, Ishikawa-Takemura Y, Isaji M. Long-term treatment with sergliflozin etabonate improves disturbed glucose metabolism in KK-A(y) mice Eur J Pharmacol. 2009;618:98–104
59. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus Annu Rev Med. 2015;66:255–70
60. Desouza CV, Bolli GB, Fonseca V. Hypoglycemia, diabetes, and cardiovascular events Diabetes Care. 2010;33:1389–94
61. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients J Clin Invest. 2014;124:499–508
62. Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production J Clin Invest. 2014;124:509–14
63. Kalra S, Gupta Y, Patil S. Sodium-glucose cotransporter-2 inhibition and the insulin: Glucagon ratio: Unexplored dimensions Indian J Endocrinol Metab. 2015;19:426–9
64. Kalra S, Ghosh S, Aamir AH, Ahmed MT, Amin MF, Bajaj S, et al Safe and pragmatic use of sodium-glucose co-transporter 2 inhibitors in type 2 diabetes mellitus: South Asian Federation of Endocrine Societies consensus statement Indian J Endocrinol Metab. 2017;21:210–30
65. . Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Pharmacologic management of type 2 diabetes: 2016 interim update Can J Diabetes. 2016;40:484–6
66. Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin J Clin Endocrinol Metab. 2012;97:1020–31
67. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose cotransporter 2 inhibition Diabetes Care. 2015;38:1730–5
68. Strojek K, Yoon KH, Hruba V, Sugg J, Langkilde AM, Parikh S. Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss
over 48 weeks: A randomized, double-blind, parallel-group, placebo-controlled trial Diabetes Ther. 2014;5:267–83
69. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, et al Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: A 24-week, randomized, placebo-controlled trial Diabetes Obes Metab. 2014;16:147–58
70. Forst T, Guthrie R, Goldenberg R, Yee J, Vijapurkar U, Meininger G, et al Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone Diabetes Obes Metab. 2014;16:467–77
71. Wilding JP, Charpentier G, Hollander P, González-Gálvez G, Mathieu C, Vercruysse F, et al Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: A randomised trial Int J Clin Pract. 2013;67:1267–82
72. Fulcher G, Matthews DR, Perkovic V, de Zeeuw D, Mahaffey KW, Weiss R, et al Efficacy and safety of canagliflozin used in conjunction with sulfonylurea in patients with type 2 diabetes mellitus: A randomized, controlled trial Diabetes Ther. 2015;6:289–302
73. Rosenstock J, Jelaska A, Frappin G, Salsali A, Kim G, Woerle HJ, et al Improved glucose control with weight loss
, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes Diabetes Care. 2014;37:1815–23
74. Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, et al Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin Diabetes Obes Metab. 2012;14:539–45
75. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Ways K, et al Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes Diabetes Care. 2015;38:403–11
76. Klein S, Burke LE, Bray GA, Blair S, Allison DB, Pi-Sunyer X, et al Clinical implications of obesity with specific focus on cardiovascular disease: A statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: Endorsed by the American College of Cardiology Foundation Circulation. 2004;110:2952–67
77. Sjöström CD, Hashemi M, Sugg J, Ptaszynska A, Johnsson E. Dapagliflozin-induced weight loss
affects 24-week glycated haemoglobin and blood pressure levels Diabetes Obes Metab. 2015;17:809–12
78. Blonde L, Stenlöf K, Fung A, Xie J, Canovatchel W, Meininger G. Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks Postgrad Med. 2016;128:371–80
79. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial Lancet. 2013;382:941–50
80. Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin Diabetes Obes Metab. 2014;16:159–69
81. Kadowaki T, Haneda M, Inagaki N, Terauchi Y, Taniguchi A, Koiwai K, et al Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: A randomized, 12-week, double-blind, placebo-controlled, phase II trial Adv Ther. 2014;31:621–38
82. Neeland IJ, McGuire DK, Chilton R, Crowe S, Lund SS, Woerle HJ, et al Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus Diab Vasc Dis Res. 2016;13:119–26
83. Majewski C, Bakris GL. Blood pressure reduction: An added benefit of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes Diabetes Care. 2015;38:429–30
84. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus Circulation. 2014;129:587–97
85. Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus Cardiovasc Diabetol. 2014;13:28
86. Townsend RR, Machin I, Ren J, Trujillo A, Kawaguchi M, Vijapurkar U, et al Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension J Clin Hypertens (Greenwich). 2016;18:43–52
87. Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension Diabetes Care. 2015;38:420–8
88. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: A systematic review and meta-analysis J Am Soc Hypertens. 2014;8:262–75.e9
89. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials Diab Vasc Dis Res. 2015;12:90–100
90. Mora-Fernández C, Domínguez-Pimentel V, de Fuentes MM, Górriz JL, Martínez-Castelao A, Navarro-González JF. Diabetic kidney disease: From physiology to therapeutics J Physiol. 2014;592:3997–4012
91. Maltese G, Abou-Saleh A, Gnudi L, Karalliedde J. Preventing diabetic renal disease: The potential reno-protective effects of SGLT2 inhibitors Br J Diabetes Vasc Dis. 2015;15:114–8
92. Gnudi L, Karalliedde J. Beat it early: Putative renoprotective haemodynamic effects of oral hypoglycaemic agents Nephrol Dial Transplant. 2016;31:1036–43
93. Maliha G, Townsend RR. SGLT2 inhibitors: Their potential reduction in blood pressure J Am Soc Hypertens. 2015;9:48–53
94. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, et al Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease Diabetes Obes Metab. 2013;15:463–73
95. Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes J Nephrol. 2016;29:391–400
96. Skrtic M, Yang GK, Perkins BA, Soleymanlou N, Lytvyn Y, von Eynatten M, et al Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration Diabetologia. 2014;57:2599–602
97. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, et al Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: A randomised, double-blind, placebo-controlled trial Lancet Diabetes Endocrinol. 2014;2:369–84
98. . FARXIGA® (Dapagliflozin) Tablets Highlights of Prescribing Information. 2014Last accessed on 2016 Nov 16 Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s003lbl.pdf
99. . JARDIANCE® (Empagliflozin) Tablets Highlights of Prescribing Information. 2014Last accessed on 2016 Nov 16 Available from: http://www.docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jardiance/jardiance.pdf
100. . INVOKANA® (Canagliflozin) Tablets Highlights of Prescribing Information. 2016Last accessed on 2016 Nov 16 Available from: https://www.icanimagine.com/file-resource/be183ed7-5830-4369-b0c0-35220e3eecdc
101. Halimi S, Vergès B. Adverse effects and safety of SGLT-2 inhibitors Diabetes Metab. 2014;40(6 Suppl 1):S28–34
102. Matthaei S, Bowering K, Rohwedder K, Sugg J, Parikh S, Johnsson E. Study Group. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes Diabetes Obes Metab. 2015;17:1075–84
103. Stenlöf K, Cefalu WT, Kim KA, Jodar E, Alba M, Edwards R, et al Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: Findings from the 52-week CANTATA-M study Curr Med Res Opin. 2014;30:163–75
104. Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials Diabetes Obes Metab. 2014;16:457–66
105. Usiskin K, Kline I, Fung A, Mayer C, Meininger G. Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: Pooled analysis of phase 3 study results Postgrad Med. 2014;126:16–34
106. Zhao G, Huang L, Song M, Song Y. Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: A meta-analysis of prospective studies Atherosclerosis. 2013;231:61–8
107. Davies MJ, Trujillo A, Vijapurkar U, Damaraju CV, Meininger G. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus Diabetes Obes Metab. 2015;17:426–9
108. Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi J, Nakanishi T, et al SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria Biopharm Drug Dispos. 2014;35:391–404
109. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes N Engl J Med. 2015;373:2117–28
110. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al Empagliflozin and progression of kidney disease in type 2 diabetes N Engl J Med. 2016;375:323–34
111. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, et al Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS) – A randomized placebo-controlled trial Am Heart J. 2013;166:217–23.e211
112. Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, et al Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial Diabetes Obes Metab. 2017;19:387–93
113. CREDENCE.Last accessed on 2016 Dec 16 Available from: https://www.clinicaltrials.gov/ct2/show/NCT02065791
114. DECLARE-TIMI 58.Last accessed on 2016 Dec 16 Available from: https://www.clinicaltrials.gov/ct2/show/NCT01730534
115. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, et al Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: A systematic review and meta-analysis Lancet Diabetes Endocrinol. 2016;4:411–9
116. Monami M, Dicembrini I, Mannucci E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: A comprehensive meta-analysis of randomized controlled trials Acta Diabetol. 2017;54:19–36
117. Mosley JF 2nd, Smith L, Everton E, Fellner C. Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors in the management of type-2 diabetes: A drug class overview P T. 2015;40:451–62
118. . U.S. Food and Drug Administration FDA Briefing Document. Dapagliflozin Oral Tablets 5 and 10 mg.Last accessed on 2016 Dec 16 Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf
120. Prasanna Kumar KM, Mohan V, Sethi B, Gandhi P, Bantwal G, Xie J, et al Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from India Indian J Endocrinol Metab. 2016;20:372–80
121. John M, Gopinath D, Jagesh R. Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives Indian J Endocrinol Metab. 2016;20:22–31