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

Byline: Syed Abbas Raza, A. H. Aamir, Ali Jawa, Faisal Masood Qureshi, Ibrar Ahmad, Khalid Mahmud Khan, Khursheed Khan, Nauman Naseer, Najmul Islam, Osama Ishtiaq and Saeed Ahmed Mahar

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 in end-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 a calorie restricted and ketogenic state, SGLT-1 inhibition, and optimization of insulin:glucagon ratio, can lead to glycaemic benefits with SGLT-2 inhibitors.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. 24 SGLT-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 at age 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.

Table-1: Efficacy and safety of monotherapy with SGLT-2 inhibitors.

###Key efficacy parameters###Key safety parameters

Reference###Pharmacotherapy###Baseline###Baseline###IHbA1c from###IFBG from###Hypoglycemic###Genital tract###Urinary tract

(Sample, duration)###HbA1c(%)###FBG(mg/dl)###baseline(%)###baseline(%)###events(%)###infections(%)###infections(%)

Kaku 2013###D: 1, 2.5, 5 or 10mg###8.1###162###D: 0.11 to -0.44###D: 15.6 to -31.9 0-2vs.2###0-2vs.0###0-4vs.2

(n=279;12W)###or P###P: 0.37###P: 11.2

Roden 2013###Em: 10 or 25mg or S###7.9###151.6###Em: -0.66, -0.78###Em: -19.4, -24.5

(n=899;24W)###or P###S: 0.66###S: -6.8###<1vs.<1###5-12vs.0###14-17vs.9

###P: 0.08###P: 11.7

Terra 2017####Er: 5 or 15mg or P###8.2###183###Er: -0.79, -0.96###2, 2vs.4###14, 19vs.5###13, 11vs.6

(n=461;26+26W*)###P: 0.20

C: Canagliflozin; D: Dapagliflozin; Em: Empagliflozin; Er: Ertugliflozin; HbA1c: Glycosylated hemoglobin; M: Metformin; OD: Once daily; P: Placebo; S: Sitagliptin; SGLT-2:

Sodium-glucose co transporter type 2; W: weeks. All studies were in treatment-native patients of T2DM; #Washout allowed; *26 weeks of placebo control followed by

26 weeks of active control (Metformin). All SGLT-2 inhibitors were administered in once daily dosing.

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 glycaemic targets in T2DM.

Table-2: Efficacy and safety of SGLT-2 inhibitors as add-on treatment with oral hypoglycemic agents.

###Key efficacy parameters###Key safety parameters

Reference###Pharmacotherapy###Baseline###Baseline###IHbA1c from###IFBG from###Hypoglycemic###Genital tract###Urinary tract

(Sample, duration###HbA1c###FBG(mg/dl)###baseline(%)###baseline(%)###events(%)###infections(%)###infections(%)

Lavalle Gonzalez 2013###Add-on to M###7.9###169.2###C: -0.73, -0.88###C: -26.2, -35.2###NR###12-16 vs. 1###5-8 vs. 7

(n=1020; 52W)###C: 100 or 300mg or P###P: -0.6###P: -17.8

###S: -17.7###S: -17.7

Wilding 2013###Add-on to M+SU###8.1###170###C: -0.85, -1.06###C: -18.0, -30.6###33.8, 36.5 vs. 17.9###5.7-18.8 vs. 1.3-###8.3 vs. 7.7

(n=469; 26W)###C: 100 or 300mg or P###P: -0.13###P: 3.6###5.0

Forst 2014###Add-on to M+PIO###7.9###165.8###C: -0.89, -1.03###C: 26.8, -33.2###4.4, 6.1 vs. 6.1**###3.9-16.7, 4.8-21.6###5.3, 7.9 vs. 7.8**

(n=342; 26+26W*)###C: 300mg or S###P: -0.26###P: 2.5###vs. 7.7**

Schernthaner 2013###Add-on to M+SU###8.1###167.4###C: -1.03###C: -30.6###43 vs. 41###12 vs. 2###4 vs. 6

(n=755; 52W)###C: 300mg or S###S: -0.66###S: -5.4

Haring 2014###Add-on to M###7.9###155###Em: -0.70, -0.77###Em: -20, -22###1.8, 1.4 vs. 0.5###3.7, 4.7 vs. 0###5.1, 5.6 vs. 4.9

(n=637; 24W)###Em: 10 or 25mg or P###P: -0.13###P: 5.0

Rosenstock 2018###Add-on to M###8.1###167###Er: -0.7, -1.0###Er: -1.5, -2.2###3.4, 3.4 vs. 1.9###3.1-5.5, 3.2-6.3 vs.###2.9, 3.4 vs. 1.0

(n=621; 26W)###Er: 5 or 15mg or P###P: -0.2###P: -0.1###0.9

Prately 2018^###Add-on to M vs. S or Er+S###8.6###180###E5: -1.0###E5: -35.7###E5: 2.4###E5: 4.9###E5: 5.2

(n=1233; 26+26W)###Er: 5 or 15mg###E15: -1.1###E15: -36.9###E15: 2.4###E15: 7###E15: 5.6

###S100: -25.6###S100: -25.6###S100: 2.4###S100: 1.1###S100: 3.2

###ES/S100: -44.0###ES/S100: -44.0###ES/S100: 2.5###ES/S100: 5###ES/S100: 3.3

Dagogo lack 2018^^###Add-on to M+S###8.0###169.7###E: -8.9, -9.4###E: -26, -31###3.8, 0.7 vs. 2.6###4.9-8.0, 3.7-12.7###2.6, 4.6 vs. 5.2

(n=463; 26+26W)###Er: 5 or 15mg or P###P: -1.7###P: -2.5###vs. 19

Miller 2018###Add-on to 5###8.9###197.8###E: -1.7, -1.7###E: -48.2, -55.4###3.1, 3.1 vs. 1###5.3-4.9, 1.9-7.0 vs.###8.2, 3.1 vs. 5.2

(n=291; 26W)###Er: 5 or 15mg or P###P: -0.8###P: -6.3###5

Hollander 2018###Add-on to M###7.8###160###E: -0.6, -0.6###E: -20, -24###3.1, 5.2 vs. 19.2###4.4-7.7, 2.1-10.0###6.7, 6.4 vs. 0.7

(n=1326; 52W)###Er: 5 or 15mg or Gm###Gm: -0.7###Gm: -16###vs. 1.4

C: Canagliflozin; D: Dapagliflozin; Em: Empagliflozin; Er: Ertugliflozin; Gm: Glimepiride; Gp: Glipizide; HbA1c: Glycosylated hemoglobin; M: Metformin; NR: Not reported; OD: Once

daily; OHA: Oral hypoglycemic agents; P: Placebo; PIO: Ploglitazone; S: Sitagliptin; SGLT-2: Sodium-glucose co transporter type 2; SU: Sulphonylurea; W: weeks. *26 weeks of

placebo control followed by 26 weeks of active control (Sitaglipin); **Over 52 weeks. All SGLT-2 inhibitors were administrated in OD dosing; ^Genital infections in females;

^^Data reported for 26 weeks.

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 a 52-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 [greater than or equal to]7% to a$?10% while on treatment with metformin ([greater than or equal to]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 ([greater than or equal to]1,500 mg/d for [greater than or equal to]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), patients receiving 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 [greater than or equal to]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. 18 In 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 ([greater than or equal to]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

Table-3: Efficacy and safety of SGLT-2 inhibitors as add-on treatment with insulin.

###Key efficacy parameters###Key Safety parameters###Changes in weight and BP

Reference###Pharmaco-therapy###Baseline###Baseline###IHbA1c from###IFBG from###Hypoglycemic###Genital tract###Urinary tract###Reduction in###Reduction in BP

(Sample, duration)###HbA1c(%)###FBG(mg/dl)###baseline(%)###baseline(%)###events(%)###infections(%)###infections(%)###weight

Neal 2015###C: 100 or###8.3###165###C: -0.55, -0.69###NR###80 vs. 66###15 vs. 3###7 vs. 8

(n=2072; 52W)###300mg or P###P: -0.03

Wilding 2012###D: 2.5, 5 or###8.6###177.5###D: -0.79 to -1.01###D: -12.4 to -16.9###60 vs. 52###11 vs. 3###11 vs. 5###D: Reduced by

(n=800; 48W)###10mg or P###P: 0.47###P: NR###0.92 to 1.61kg

###P: Increased by

###0.43kg

Wilding 2013###D: 2.5, 5 or###8.6###179.0###D: -0.64 to -0.78###D: -20.5 to -23.4###61-70 vs. 62###13-35 vs. 6###17-20 vs. 11###D: Reduced by

(n=808; 104W)###10mg or P###P: -0.43###P: -18.0###0.9 to 1.4kg

###P: Increased by

###1.8kg

Rosenstock 2015###Em: 10 or###8.2###143###E: -0.5, -0.6###E: -18, -20###33-35 vs. 33###10-12 vs. 8###4-8 vs. 4###Em 10mg:###Em 10mg vs. P:

(n=494; 78W)###25mg or P###P: 0###P: 10###-2.2@0.5kg###SBP: -4.1+-1.0mmHg vs.

###Em 25mg:###0.1+-1.0mmHg;

###-2.0@0.5kg###-0.3+-0.6

###P: 0.7@0.5kg###mmHg(p=0.004

###for both).

###No significant changes

###with

###25mg Em.

Bp: Blood pressure; C: Canagliflozin; D: Dapagliflozin; Em: Empagliflozin; HbA1c: Glycosylated hemoglobin; NR: Not reported; OD: Once daily; P: Placebo; S: SGLT-2: Sodium-glucose cotransporter

type-2; W: weeks. All SGLT-2 inhibitors were administered in OD dosing.

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 parallel-group (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. 23 In another placebo-controlled, double-blind study, 808 patients with T2DM inadequately controlled with insulin [greater than or equal to]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 add-on 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 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 urinary tract infections are reported 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 to monitor 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 hypoglycaemia compared to those receiving 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 trends for 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 inhibitors include 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-independent mechanism 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 and insulin, 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 dose of insulin in patients with T2DM. Favourable effects on weight, BP, and lipids explain the benefits of SGLT-2 in T2DM patients with cardiovascular and renal 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, baseline assessments should include vitals, renal function and urine complete analysis. Cangliflozin and Empagliflozin should be discontinued at eGFR <45 mL/min/1.73 m 2 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

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Date:Apr 30, 2019
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