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April 2019, Volume 69, Issue 4

Opinion and Debate

Expert Opinion: Use of sodium glucose co-transporter type-2 inhibitors in South Asian population -The Pakistan perspective

Syed Abbas Raza  ( Shaukat Khanum Cancer Hospital and Research Center. Johar Town, Lahore, Punjab. Pakistan )
A. H. Aamir  ( Hayatabad Medical Complex Peshawar. Pakistan )
Ali Jawa  ( Wilshire Cardiovascular and Endocrine Center of Excellence WILCARE Lahore )
Faisal Masood Qureshi  ( Al Khaliq Hospital, Multan )
Ibrar Ahmad  ( Lady Reading Hospital Peshawar )
Khalid Mahmud Khan  ( Allama Iqbal Medical College Lahore )
Khursheed Khan  ( Allama Iqbal Medical College Lahore )
Nauman Naseer  ( Akhtar Saeed Medical College, Lahore )
Najmul Islam  ( AKUH Karachi )
Osama Ishtiaq  ( Shifa International Hospital Islamabad )
Saeed Ahmed Mahar  ( National Institute of Cardiovascular Diseases Karachi, Pakistan )

Abstract


Sodium-glucose co-transporter type 2 inhibitors (SGLT 2- i)are increasingly being used in the management of type 2 diabetes mellitus (T2DM). With the novel insulinindependent glycosuric action, these agents help to attain glycaemic goals by lowering HbA1c and fasting blood glucose. In addition, these agents improve metabolic control in diabetes and ameliorate comorbidities like obesity and hyper tension. Beneficial effec ts on cardiovascular outcomes have been a key attraction for physicians. These agents are used alone or in combination with oral antidiabetic agents and insulin to attain glycaemic and metabolic targets. A major disadvantagewith these agents is the increased risk for genital andurinary infections. When used in appropriate settings, there is no additional increased risk of hypoglycaemia or volume depletion with these agents. Available evidence suggests good efficacy and safety of these agents in diabetes management. The easy and convenient oncedaily dosing should be customized according to patient needs and glycaemic profiles.
Keywords: Diabetes, SGLT-2, dapagliflozin, canagliflozin, empagliflozin, ertugliflozin

Introduction

Diabetes is a global public health problem. The burden of diabetes is specifically high in the South East-Asia (SEA) region. The region is currently home to more than 72 million patients with diabetes and the numbers are projected to increase to 123 million in 2035. This can be explained by the changing lifestyle in this region given the evolution towards urbanization. T2DM is the predominant type (>95%) of diabetes in this region. 1 T2DM characterized by high plasma glucose levels, has a chronic and progressive course which can culminate inend-organ damage. Novel therapies are continuously being evaluated to help attain glycaemic targets with ease and convenience. Sodium-glucose co-transporter type 2 (SGLT-2) is an emerging target in the management of diabetes. Located at the proximal convoluted tubules, SGLT-2 has an important physiological role in renal glucose reabsorption. Pharmacological inhibition of SGLT-2 increases urinary glucose excretion and decreases plasma glucose levels. Additional metabolic effects including development of acalorie restricted and ketogenic state, SGLT-1 inhibition, and optimization of insulin:glucagon ratio, can lead to glycaemic benefits with SGLT-2 in hibitors . 2 The action of SGLT-2 inhibitors is independent of insulin and these agents can be used as monotherapy or in addition to oral antidiabetic drugs (OADs) or insulin to control hyperglycaemia. 24SGLT-2 inhibitors have been used in both the initiation and intensification of therapy of T2DM. The approved drugs in this class include dapagliflozin (2012), canagliflozin (2013), empagliflozin (2014), and ertugliflozin (2017). SGLT-2 inhibitors are indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. Another agent, ipragliflozin has been approved in Japan. The available SGLT-2 inhibitors differ in their relative selectivity for SGLT- 2 versus SGLT-1. Empagliflozin is the most selective for SGLT-2 (42500:1), followed by dapagliflozin (41200:1) and canagliflozin (4250:1). 3 In SEA, experience with SGLT-2 inhibitors is limited. Many of the key trials for SGLT-2 have Asian centers but there are no reports for the comparison of outcomes in the Asian and rest of the population. Real-world experience with SGLT-2 has been reported for SEA. In a post-hoc analysis, canagliflozin 100 and 300 mg provided clinically meaningful reductions in glycohaemoglobin (HbA1c) in Indian patients (124) and in overall population (n=2313) from four pooled Phase 3 studies (-0.74% and -0.88% vs. -0.81% and -1.00%). The reductions in fasting blood glucose (FBG), body weight, and blood pressure (BP) in the Indian subgroup were consistent with findings in the overall population. 4 In a prospective experience from clinical practice in India (n=100), SGLT-2 inhibitors lead to significant reductions in HbA1c(1.02±0.24%) and body weight (2.64±1.27 kg) irrespective of the background treatment regimen for T2DM. 5 In a retrospective review of a clinical database in India (n=9; follow up: 16 weeks), canagliflozin reduced HbA1c from 9.0% at baseline to 6.8% at follow up (P <0.005). There was reduction in body weight and requirement or dose of OADs during follow up.6 The treatment with SGLT2-inhibitors in T2DM patients is associated with improved glycaemic control and other non-glycaemic outcome including relative risk reduction in cardiovascular death and in all-cause mortality among those with T2DM and cardiovascular disease.The survival benefit in the EMPREG OUTCOME trial was greater for younger patients and diminished compared with placebo as the study patients aged: The mean differences between patients taking empagliflozin and those taking placebo were 4.5 years at age 45, 3.1 years at age 50, 2.5 years atage 60, 2.0 years at age 70, and 1 year at age 80.7 In this paper, we review the existing evidence for the efficacy and safety of SGLT-2 inhibitors to guide the adoption of these agents in Pakistan. Monotherapy with SGLT-2 inhibitors Monotherapy with SGLT-2 inhibitors has helped to improve glycaemic control in T2DM (Table 1).



Dapagliflozin has shown good efficacy in both placebo and active controlled trials in treatment-naive patients with T2DM. When compared to placebo, significant reductions in HbA1c are reported with dapaglifozinin patients with poorly controlled T2DM. 8 In a placebo-controlled, phase 3 trial, patients of T2DM who had not received pharmacological treatment in the last 12 weeks were randomized to receive once daily dose of placebo (n=228), empagliflozin10 mg (n=224), empagliflozin 25 mg (n=224), or sitagliptin 100 mg (n=223). At week 24, adjusted mean differences in change  from baseline HbA1c when compared to placebo were - 0·74% (95% CI -0·88 to -0·59; p<0·0001) for empagliflozin 10 mg, -0·85% (-0·99 to -0·71; p<0·0001) for empagliflozin 25 mg, and -0·73% (-0·88 to -0·59; p<0·0001) for sitagliptin. 9 In a 26-week, placebo controlled, phase 3 study, 461 patients with T2DM were randomized to receive ertugliflozin 5 or 15 mg, or placebo. For the two doses of ertugliflozin, the placebo-adjusted least squares (LS) mean HbA1c changes from baseline were -0.99% and -1.16%, respectively (P<0.001 for both).10

Add-on therapy with SGLT-2 inhibitors

SGLT-2 inhibitors have been used with OADs (Table 2)



as well as insulin (Table 3) for the achievement of glycaemia targets in T2DM.



SGLT-2 inhibitors with OADs

Dapagliflozin has been studied as add-on therapy to metformin, glimiperide, pioglitazone, and sitagliptin. As add-on therapy to metformin, canaglifozin has been compared to placebo, sitagliptin, and glimepiride.11  In a52-week phase 3 trial, 1020 patients with T2DM inadequately controlled with metformin were randomized to receive canagliflozin 100 mg, 300 mg, sitagliptin 100 mg, or placebo. At 26 weeks, canagliflozin (100 mg and 300 mg/day) significantly reduced HbA1c relative to placebo (-0.62% and -0.77%, respectively). At 52 weeks, both doses of canagliflozin were non-inferior and canagliflozin 300 mg was superior to sitagliptin in lowering HbA1c (-0.73%, -0.88%, and -0.73%, respectively) .11 Benefits are also reported for add-on therapy with canagliflozin in patients of T2DM who are being treated with one or more sulphonylureas. In a phase 3 study, 469 patients of T2DM inadequately controlled with metformin and sulphonylurea, received canaglifozin 100 or 300 mg or placebo in once daily dosing. At week 26, HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo (-0.85%, -1.06%, and -0.13%; p <0.001). These reductions were sustained at week 52 (-0.74%, -0.96%, and 0.01%).12 Schernthaner et al. (2013) compared canagliflozin 300 mg/day with sitagliptin 100 mg/day in patients of T2DM inadequately controlled with metformin plus sulfonylurea. At 52 weeks, canagliflozin 300 mg was superior to sitagliptin 100 mg in reducing HbA1C (-1.03% and -0.66%, respectively; least squares mean difference between groups, -0.37% [95% CI, -0.50 to -0.25]) .13 In another phase 3 study in patients with T2DM inadequately controlled with metformin and pioglitazone (n=342), canagliflozin 100 or 300 mg significantly lowered HbA1c compared with placebo at week 26 (-0.89%, -1.03% and -0.26%; p <0.001) .14 In a 24-week trial, subjects with T2DM and HbA1c levels 7% to 10% while on treatment with metformin (1,500 mg/day) were randomized to receive once-daily treatment with empagliflozin 10 mg (n=217), empagliflozin 25 mg (n=213), or placebo (n=207) for 24 weeks. The mean (SE) changes from baseline in HbA1c with placebo, empagliflozin 10 mg, and empagliflozin 25 mg were - 0.13% (0.05), -0.70% (0.05), and -0.77% (0.05) respectively (P <0.001 for both doses) .15 In the 26-week VERTIS MET trial, add-on therapy with ertugliflozin 5 or 15 mg or placebo was studied in 621 patients with T2DM receiving metformin (1,500 mg/d for 8 weeks). In this study, the placebo-adjusted LS mean change from baseline HbA1c was -0.7% and -0.9% for the two doses of ertugliflozin, respectively (both P<0.001) .16 In the 52-week VERTIS FACTORIAL trial (n=1233), patientsreceiving metformin were randomized to add-on therapy with ertugliflozin 5 (E5) or 15 (E15) mg/d, sitagliptin 100 mg/d (S100), E5/S100 or E15/S100. At 26 weeks, the least square mean HbA1c reductions from baseline were -1.0%, -1.1%, -1.1%, -1.5%, and -1.55, respectively for the dosing groups (P <0.001 for all comparisons). .17 In another trial (VERTIS SITA 2) for add-on ertugliflozin in patients receiving metformin 1,500 mg/day and sitagliptin 100 mg/day, ertugliflozin 5 and 15 mg reduced HbA1c at 26 weeks by -0.7%, and -0.8%, respectively (both P<0.001) compared with placebo. 18In the 26-week VERTIS SITA study, the least squares mean HbA1c change (95% confidence intervals) from baseline was - 0.4% (- 0.7, - 0.2), - 1.6% (- 1.8, - 1.4), and - 1.7% (- 1.9, - 1.5) with ertugliflozin 5 mg+ sitagliptin 100 mg, ertugliflozin 15 mg+ sitagliptin 100 mg, and placebo, respectively.19 In the VERTIS SU study, 1326 patients inadequately controlled on metformin (1500 mg/day) were randomized (1:1:1) to ertugliflozin receive 5 or 15 mg once-daily, or glimepiride (titrated from 1 mg/day; Mean daily dose: 3 mg). At week 52, the least squares mean change (95% CI) from baseline in HbA1c was - 0.6% (- 0.6, - 0.5), - 0.6% (-0.7, -0.5), and - 0.7% (-0.8, -0.7) in the three groups, respectively. 20

SGLT-2 inhibitors with insulin

In the double-blind, placebo-controlled CANagliflozin CardioVascular Assessment Study (CANVAS), patients of T2DM who were being treated with insulin were randomized to receive canagliflozin 100 mg (n = 692), canagliflozin 300 mg (n = 690), or placebo (n = 690). Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were -0.62% (95% CI -0.69, -0.54; P <0.001) and -0.73% (95% CI -0.81, -0.65; P <0.001) at 18 weeks and-0.58% (95% CI -0.68, -0.48) and -0.73% (95% CI -0.83) at 52 weeks. 21 In a double-blind, three-arm parallel-group (1:1:1) trial, 71 patients were randomly assigned to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. At 12 weeks, the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and - 0.78% mean differences in A1C change from baseline versus placebo. 22 In a double-blind, four-arm parallelgroup (1:1:1:1) trial, 800 patients were randomly assigned to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily. At 24 weeks, mean HbA1c decreased by 0.79% to 0.96% with dapagliflozin compared with 0.39% with placebo while the daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo. 23In another placebo-controlled, double-blind study, 808 patients with T2DM inadequately controlledwith insulin 30 IU/day with or without up to two OADs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of dapagliflozin. At 104 weeks, mean HbA1c changes from baseline were -0.4% in the placebo group and -0.6 to -0.8% in the dapagliflozin groups.24 In a 78-week phase 3 clinical trial of empagliflozin as addon to basal insulin in adults with T2DM, empagliflozin when compared to placebo, significantly reduced the HbA1c levels at 18 and 78 weeks. The study was designed to include an 18-week constant-dose period for insulin after which the dose was adjusted at investigator's discretion. At 18 and 78 weeks, the placebo-adjusted changes in HbA1c for empagliflozin 10 mg and 25 mg were -0.6% and -0.7% (P <0.001), respectively, and -0.5% and -0.6%, respectively (P <0.001). At week 78, empagliflozin therapy resulted in significant reduction in the required daily insulin dose.25In another randomized, double-blind, placebo-controlled, parallel-group study (n=563) empagliflozin 10 mg and 5 mg reduced insulin doses (-9 to -11 IU/day) at week 52.9 N o n - g l y c e m i c b e n e f i t s o f S G LT- 2 i n h i b i t o r s Besides control of glucose levels, metabolic goals in the management of T2DM include targets for weight, lipids, and blood pressure (BP) and cardiovascular risk reduction. The effect of SGLT-2 inhibitors on these parameters have been reported in various clinical studies.

Effects on weight

Insulin, insulin secretagogues, and other OADs are known to cause an increase in weight. This makes a metabolicparadox for the achievement of therapeutic targets in T2DM. Experience with SGLT-2 inhibitors in clinical studies yields evidence for weight reduction with these agents as monotherapy as well combination therapy with OADs and insulin. Dapagliflozin monotherapy was associated with a significant weight reduction (-1.9 kg) relative to placebo in a 12-week study in Japanese patients [8]. Similarly, canagliflozin 300 mg added to metformin plus sulfonylurea mitigated the increase in weight(-2.3 kg) when compared with sitagliptin (+0.1 kg).13 The reduction in weight is of relevance to plan pharmacotherapy for the management of T2DM as obesity is a common problem in SEA. This is a desirable effect for SGLT-2 inhibitors when used in combination with agents known to increase weight (example, insulin and pioglitazone).2

Effects on blood pressure

SGLT-2 inhibitor therapy has shown favourable and sustained improvements in BP in patients with T2DM. The lowering of BP may be attributable to the physiological effects of SGLT-2 inhibitors including osmotic diuresis, natriuresis, reductions in arterial stiffness, and modulations in nitric oxide release.2 Hypertension in a common comorbidity with T2DM in the SE Asian region where benefits of SGLT-2 inhibition can be potentially multifold. Over 52 weeks, canagliflozin (300 mg/day) achieved a significant reduction (-5.1 mmHg) in systolic BP compared to sitagliptin (100 mg/day) (+0.9 mmHg).13 Favourable reductions in systolic BP are also repor ted with empagliflozin when compared to placebo and sitagliptin [9]. In a 24-week study, empagliflozin (10 and 25 mg/day) led to greater reductions in systolic BP (-2.9 and -3.7, respectively) when compared to placebo (-0.3 mmHg). 9

Effects on lipids

Variable and inconsistent effects of SGLT-2 inhibitors are reported for HDL, LDL and total cholesterol levels [2]. Insignificant effects on LDL levels are reported for dapagliflozin in some studies.8,12 Rise in LDL levels was reported with canagliflozin (300 mg) when compared to p l a c e b o ( 4 . 3 a n d 6 . 8 mg / d l ) a n d s i t a gl i p t i n (5.9 mg/dl).12,13 Effects on cardiovascular outcome risk reduction Improved cardiovascular outcomes have been demonstrated with use of SGLT2 inhibitors. Empagliflozin significantlyreduced the risk of cardiovascular death when compared to placebo (3.7 vs 5.9%; HR 0.62, 95% CI 0.49-  0.77).7 In the CANVAS trial (n=10142), cardiovascular deathor hospitalizations for heart failure were reduced in patients treated with canagliflozin compared with placebo (16.3% vs 20.8% per 1000 patient-years; HR: 0.78; 95% CI: 0.67-0.91). 26  In the placebo-controlled, phase III (n=17150) DECLARETIMI 58 cardiovascular outcomes trial (CVOT), dapagliflozinresulted in a lower rate of CV death or hospitalization for heart failure (4.9% vs. 5.8%; HR: 0.83; 95% CI, 0.73-0.95; P=0.005) but not a lower risk of major adverse cardiovascular event (8.8% vs. 9.4%; HR: 0.93; 95% CI, 0.84 -1.03; P=0.17). 27 The ongoing VERTIS CV Study is evaluating the cardiovascular outcomes with ertugliflozin in patients of T2DM having vascular disease (NCT01986881). Suchstudies may find relevance to the SEA populations given the higher risk of cardiovascular complications in these patients.

Effects on NASH/ NAFLD

Dapagliflozinis associated with significant reduction in liver fat content. In the EFFECT-II study, dapagliflozin, either alone or in combination with omega-3 carboxylicacids (OM3CA) reduced liver fat content when compared to baseline values (relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%). The combination treatment reduced total liver fat volume (relative change, -24%, p = 0.037) in comparison with placebo.28 Although these effects are very significant and important for this patient population, but mechanism is poorly understood.

Effects on albumin-to-creatinine ratio

Independent of glycaemic control and effects on bodyweight and BP, SGLT2 inhibitors have renoprotective effects. Empagliflozin has shown significant improvement in albumin-to-creatinine ratio (UACR) (-32% and -41%, respectively vs placebo) in T2DM patients with micro albuminuria (UACR: 30-300 mg/g; n = 636) and macroalbuminuria (UACR >300 mg/g; n = 215).29 Safety and Monitoring of use of SGLT-2 inhibitors. Various adverse events (AEs) have been reported with SGLT2 inhibitors. Genital and urinary tracts infections, volume depletion and hypoglycaemia are of key concerns when using SGLT2 inhibitors. Patients taking SGLT2 inhibitors and experiencing symptoms such as dizziness, difficulty in breathing, nausea, vomiting, pain in abdominal and atypical fatigue or sleepiness need to seek medical attention immediately. In case, diagnosis of acidosis/ ketoacidosis is confirmed, SGLT2 inhibitor use should be discontinued and acidosis should be treated. In addition, it is essential to monitor glucose levels. There is no experience for the use of SGLT2 inhibitors in pregnant women and use in this group of special population should always be on the discretion of the treating physician. Clinical symptoms for genital mycotic infection (pain during urination, itching, etc.), hypoglycaemia (abnormal sweat, increased hunger, fainting, unusual fatigue, nausea, vomiting, dryness in mouth, tingling lips, etc.), hypotension (fatigue, dizziness, nausea, loss of consciousness, blurry vision, etc.), impaired renal function (frequent urination, etc.), high lipid levels, UTIs (increased urinating urge, pain with urination, etc.), need to be monitored while using any SGLT2 inhibitor. Genital and urinary tract infections: Higher rates of genital and urinar y trac t infec tions are repor ted with monotherapy (Table 1) and combination therapy (Table 2: OADs; Table 3: Insulin) with SGLT-2 inhibitors when compared to placebo and other active controls. The occurrence of these infections can be explained by the glycosuric action of SGLT-2 inhibitors in T2DM which is a risk factor for the development of infections. This is a class effect with SGLT-2 inhibitors without any significant differences in one agent over another.2 These infections are of relevance to the SE Asian population due to the cultural inhibitions in seeking treatment and the compromise in hygiene in the lower socioeconomic segments. A rare but severe complication is necrotizing fasciitis (Fournier's gangrene). At initiation of the treatment with SGLT2-inhibitors, consider taking history of current or recurrent UTI. Hypoglycaemia- Role of SGLT-2 inhibitors in Ramadan: SGLT- 2 inhibitors have a lower risk of hypoglycaemia when compared to placebo, OADs, or insulin (Tables 1-3). This can be explained by the insulin-independent mechanism of action of these agents. However, it is important tomonitor patients for the risk and occurrence of hypoglycaemia and make adjustments in doses of SGLT-2 inhibitors and/or other treatments for diabetes. Religious and cultural practices of prolonged fasting (for example, Ramadan) may predispose the SE Asian population to a higher risk of hypoglycaemia. Benefits of switching to SGLT-2 inhibitors during fasting are reported SEA population. Hypoglycaemic episodes in patients observing the Ramadan fast were significantly lower (P = 0.002) in those who switched to dapagliflozin plus metformin (6.9%) than in those who continued the earlier prescribed SU plus metformin treatment (28.8%).30  In the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS), fewer people receiving canagliflozin (n=162) experienced hy p o g l yc a emi a c omp a r e d to t h o s e r ec e i vi n g sulphonylurea (n=159) (adjusted odds ratio: 0.273 [95% CI: 0.104, 0.719]).31 Volume depletion: SGLT-2 inhibitors can produce a state of volume depletion due to osmotic diuresis caused by glycosuria. This can lead to a fall in BP, postural dizziness, syncope, dehydration and reduced urinary output. A higher occurrence of these adverse events (AEs) have been reported with SGLT-2 inhibitors when compared to placebo and other active comparators. 9,12,14,20 The hot and humid weather in SE Asian countries may cause cutaneous vasodilation and compromise the orthostatic responses in patients with T2DM predisposing them to dehydration with SGLT-2 inhibitors. The cultural trendsfor fasting may also predispose these patients to a higher risk of dehydration. In a pooled analysis (4 randomized placebo-control and 1 active-control studies), 917 patients residing in hot climatic regions and receiving capagliflozin (100 and 300 mg) demonstrated no increased risk for volume-depletion related AEs with reductions in HbA1c, FBG, weight, and BP consistent with the rest of the population. 32 However, patients should be advised for adequate hydration and monitored for potential risk of dehydration with SGLT-2 inhibitors. Others: Other less common AEs with SGLT-2 inhibitorsinclude development of euglycaemic ketoacidosis, ischaemic events, reductions in bone mineral density and potentially increased risk for bladder and breast cancer.2 These complications are very rare but should be taken into account when selecting a patient for the use of this class. Expert Opinion SGLT-2 inhibitors are used alone or in combination with OADs and insulin for the attainment of glycaemic targets in patients with T2DM. The insulin-independentmechanism of action makes these agents suitable for both the initiation and intensification of treatment in T2DM. SGLT-2 inhibitors, alone or in combination with OADs andinsulin, help to achieve glycaemic goals by reducing HbA1c, fasting blood glucose (FBG), body weight, BP and risk of cardiac complications. These agents reduce HbA1c in patients receiving high doses of insulin along with  insulin sensitizers and may also help to stabilize the doseof insulin in patients with T2DM. Favourable effects on weight, BP, and lipids explain the benefits of SGLT-2 in T 2 DM p ati e nts w it h c ard i ova s c ul ar and rena l complications.29,33 The once daily oral dosing and lower risk of hypoglycaemia offer ease and convenience for treatment. Patients should be monitored for the development of genital and urinary tract infections and signs of volume depletion during treatment with SGLT-2 inhibitors. Before initiating treatment with SGLT2 inhibitors, baselineassessments should include vitals, renal function and urine complete analysis. Cangliflozin and Empagliflozin should be discontinued at eGFR <45 mL/min/1.73 m2 and dapagliflozin at <60 mL/min/1.73 m.13 SGLT2 inhibitors should be discontinued in patients experiencing ketoacidosis. In the absence of sufficient data in pregnant population, treatment with SGLT2-ihibitors during pregnancy cannot be advocated, till more scientific information is available for potential benefit and risk to the fetus. SGLT-2 inhibitors can benefit patients with T2DM who are overweight and obese, at higher risk of hypoglycaemia with OADs and insulin, and have contraindications or intolerance to other pharmacological options. Additionally, SGLT-2 inhibitors may benefit patients of T2DM with high risk of cardiovascular and renal complications. Treatment in patients in the SE Asian countries should be customized according to the patterns of diet, weather conditions, and lifestyle.

Acknowledgments

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work, and have given final approval for the version to be published. Medical writing and editorial support in the preparation of this article was provided by Dr. Punit Srivastava and Dr Tarveen Jandoo of Mediception Science Pvt Ltd. Support for this assistance was funded by CCL Pharma. Special thanks Dr. Atika Shaheer from Medical team of CCL for coordinating edits and incorporating the suggestions from Authors.

Disclaimer: None to declare.
Conflict of interest: The authors declare no conflict of interests
Sources of Funding: The authors received no external financial support

References

1. Ramachandran A, Snehalatha C, Ma RC. Diabetes in South-East Asia: an update. Diabetes Res ClinPract. 2014 ;103:231-7.
2. 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 ;21:210-230. 3. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes ObesMetab. 2012;14: 83-90.
4. 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 EndocrinolMetab 2016;20:372- 80. 5. Sosale B, Sosale AR, Kumar PM, Joshi SR. A prospective analysis of the efficacy and safety of sodium glucose cotransporter 2 inhibitors: Real World Evidence from Clinical Practice in India. J Assoc Physicians India 2016;64:40-4.
6. Baruah MP, Kalra S. Short term outcomes of type 2 diabetes mellitus patients treated with canagliflozin in real world setting. Indian J Endocrinol Metab 2016;20:137-41.
7. Zinman B, Wanner C, Lachin J M, Fitchett D, Bluhmki E, Hantel S, et.al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373:2117-2128.
8. Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebocontrolled trial. Diabetes Obes Metab 2013;5:432-40. 9. Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2013;3:208-19.
10. Terra SG, Focht K, Davies M, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab. 2017;19:721-728.
11. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 2013;12:2582-92.
12. Wilding JP, Charpentier G, Hollander P, Gonzalez-Galvez 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 ClinPract 2013;12:1267-82.
13. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52- week randomized trial. Diabetes Care 2013;9:2508-15.
14. 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. doi: 10.1111/dom.12273.
15. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ; EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2014;37:1650-9. 16. Rosenstock J, Frias J, Páll D, Charbonnel B, Pascu R, Saur D, et al. Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET).
Diabetes Obes Metab 2018;20:520-529. doi: 10.1111/dom.13103.
17. Pratley RE, Eldor R, Raji A, Golm G, Huyck SB, Qiu Y, et al. Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial. Diabetes Obes Metab 2018;20:1111-1120. doi: 10.1111/dom.13194.
18. Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, et al. Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized s t u d y. D i a b e te s O b es M e t a b 2 0 1 8 ; 2 0 : 5 3 0 - 5 4 0. d o i : 10.1111/dom.13116.
19. Miller S, Krumins T, Zhou H, Huyck S, Johnson J, Golm G, et al. Ertugliflozin and sitagliptin co-initiation in patients with type 2 diabetes: The VERTIS SITA randomized study. Diabetes Ther 2 0 1 8 ; 9 : 2 5 3 - 2 6 8 . d o i : 1 0 . 1 0 0 7 / s 1 3 3 0 0 - 0 1 7 - 0 3 5 8 -0 .
20. Hollander P, Liu J, Hill J, Johnson J, Jiang ZW, Golm G, et al. Ertugliflozin compared with glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin: the VERTIS SU randomized study. Diabetes Ther 2018;9:193-207. doi: 10.1007/s13300-017-0354-4.
21. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Ways K, Desai M, Shaw W, Capuano G, Alba M, Jiang J, Vercruysse F, Meininger G, Matthews D; CANVAS Trial Collaborative Group. 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.
22. Wilding JP, Norwood P, T'joen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 2009;9:1656-62. 23. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 2012;6:405-15.
24. Wilding JP. The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors. Metabolism. 2014 ;63:1228-37.
25. Rosenstock J, Jelaska A, Zeller C, Kim G, Broedl UC, Woerle HJ; Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial. Diabetes ObesMetab. 2015 ;17:936-48.
26. Bruce Neal, M.B., Ch.B., Ph.D., VladoPerkovic, M.B., B.S., Ph.D., Kenneth W. Mahaffey, M.D., Dick de Zeeuw, M.D., Ph.D., Greg Fulcher, M.D., NgoziErondu, M.D., Ph.D., Wayne Shaw, D.S.L., Gordon Law, Ph.D., Mehul Desai, M.D., and David R.
Matthews, D.Phil., B.M., B.Ch. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657.
27. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et.al, DECLARE-TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.N Engl J Med.2018.
28. Jan W. Eriksson1, Lundkvist P, Jansson PA, Johansson L, Kvarnström Met.al. Effects of dapagliflozin and n-3 carboxylic acids on nonalcoholic fatty liver disease in people with type 2 diabetes: a doubleblind randomised placebo-controlled study. Diabetologia 2018; 61:1923-1934
29. D Cherney, SS Lund, BA Perkins, PH Groop, ME Cooper, S Kaspers et.al. The Effect of Sodium Glucose Cotransporter 2Inhibition With Empagliflozin on Microalbuminuria and Macroalbuminuria in Patients With Type 2 Diabetes. Diabetologia. 2016 ;59:1860-70.
30. Wan Seman WJ, Kori N, Rajoo S, Othman H, Mohd Noor N, Wahab NA, et al. Switching from sulphonylurea to a sodium glucose
cotransporter2 inhibitor in the fasting month of Ramadan is associated with a reduction in hypoglycaemia. Diabetes Obes Metab 2016;18:628-32.
31. Hassanein M, Echtay A, Hassoun A, et al. Tolerability of canagliflozin in patients with type 2 diabetes mellitus fasting during Ramadan: Results of the Canagliflozin in Ramadan Tolerance Observational Study (CRATOS). Int J ClinPract. 2017;71:e12991.
32. John M, Cerdas S, Violante R, Deerochanawong C, Hassanein M, Slee A, Canovatchel W, Hamilton G. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus living in hot climates. Int J Clin Pract. 2016 ;70:775-85.
33. Ferrannini G, Rydén L. Sodium-glucose transporter 2 inhibition and cardiovascular events in patients with diabetes: information from clinical trials and observational real-world data. Clin Sci (Lond).2018 ; 132:2003-2012.

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