SGLT2-inhibitors in the Management of Type 2 DiabetesMellitus among East Asians-A Review

1. Introduction

According to International Diabetes Federation (IDF) the prevalence of Diabetes has increased by 4 fold, since the 1980s, 578 million in 2019 and 642 million people projected worldwide by the year 2040 (1). Type 2 Diabetes mellitus (T2DM) is increasing at an alarmingly high rate in east Asian population, China being highest with 116.4 million and second highest 77 million in India (1). Its understood that there is a sudden trend in massive urbanization and upgradation in the East Asian countries. The outcome of which is attributed to significant change in lifestyle which has a direct impact on diabetes mellitus (2) . As compared to the Caucaceans, according to Lim et al, 2017, the major factors that contribute to the outgrowth of T2DM in this subcontinent includes, juvenile T2DM, a reduced body mass index, increased visceral adiposity and ultimately the malfunctioning of pancreatic beta cells (2).

Hence, considering such a crisis it is pertinent to control the disease with drugs which could potentially control the blood glucose levels simultaneously controlling the associated complications. In this regard, a group of Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors have been regarded of remarkable significance. The different drug names include canagliflozin, dapaglifozin, empagliflozin, etc (3). The major functioning of these inhibitors is to control the glucose reabsorption in kidney which has a direct positive impact on the stabilization of blood pressure alongwith weight control and hence the blood sugar levels (4). In this article, we are going to review the role of this group of drugs in diabetes management on the East Asian population.

1. Diabetes mellitus in East Asian population-an overview

2.1 Prevalance and Epidemiology in East Asia- According to the International Diabetes Federation (IDF), https://www.diabetesatlas.org, the prevalence rate of diabetes mellitus globally is 9.3% for 2019 while it may dramatically increase by 10.2% by the year 2030 (5). It has been reported that due to sedentary lifestyle, lowered body mass index, juvenile diabetes and economic outgrowth, the East Asian countries including China (1), (6), India, Japan, Korea and Pakistan have an increasing trend of the disease (7). In Korea, over a period of 40 years, an estimated 9.9% increase in its incidence has been reported (1) (8). Interestingly, in the south east Asia itself, the IDF has mentioned that there were more than a million deaths in 2019 itself.

2.2 Factors responsible for the increased rates in East Asians

As compared to the rest of the world, the East Asians are suffering more due to several clinical phenotypes. In this context, scientists have elaborately classified the various factors attributed to this population (9), (2),(5). Such factors have been discussed in this section-

2.2.1 Poor body mass index (BMI)- In China, the biggest risk factor attributed to central obesity (5). A Bone Mass Index of ≥28 kg/m2 and ≥50 years in female populations are the second highest risk factors compared to males. In Japan and Korea, the risk factors were also found out to be ageing and targeting male populations. Visceral adiposity is considered a major contributor and indicator (10). Visceral fats release a large amounts of adipokines and cytokineswhich targets organs and hence complications.

2.2.2 Insufficient beta-cell response- To counter insulin resistance , insufficient Beta cells of Pancreas in Asian population have been understood to be a major factor (11). Ohn et al., 2016, has shown through genomic studies in Korean population that reduced beta cell functioning affects insulin sensitivity and hence thereby the glucose tolerance (12). According to the Joint Asia Diabetes Evaluation (JADE) cohort study, almost every 1 in 5 adult Diabetic had a history of young age Diabetes (13).

2.2.3 Urbanization- In China the development of Diabetes is a big threat hence, considered as an uncontrolled epidemic. The vital factors which include advanced economic growth, demographic transitions, urbanizations, change in food habits and lifestyles (2). Interestingly, a recent report by Pradeepa in 2017, stated that a speedy socioeconomic transition with an increase in urbanization and industrialization are the main reasons for the high incidence rate in India (14).

2.2.4 Vascular complications- An early onset of T2DM in the younger generation of the East Asians have potentially affected the micro and macro vascular constitutions in the form of increased inflammatory markers, chronic inflammation cardiovascular manifestations and acute renal injury (15).

2.2.4 Vascular complications- An early onset of T2DM in the younger generation of the East Asians have potentially affected the micro and macro vascular constitutions in the form of increased inflammatory markers, chronic inflammation cardiovascular manifestations and acute renal injury (15).

3. Therapy with the SGLT2 inhibitors

Regardless of the availability of a considerable number of antiglycemic medications, the control of blood glucose with complications have not yet been successful (16). However, recent advances on SGLT2 inhibitors have been widely accepted as they are considered to act in an insulin independent manner with no involvement in insulin secretion or action (16). Dapagliflozin, empagliflozin, tofogliflozin, the generic names of such drugs been orally given to reduce blood glucose levels in T2DM patients (17).

3.1Pharmacology and mode of action- Canagliflozin competitively inhibits SGLT1 and SGLT2 proteins, with high potency and selectivity for SGLT2. Inhibition constant (Ki) values for SGLT1 and SGLT2 were 770.5 and 4.0 nM, respectively (18).

3.2 Drug efficacy and safety

The safety and efficacy of SGLT2 inhibitors has been explained pictorially in Figure 2. Due to the safe use of SGLT2 inhibitors on Diabetic patients in Asia, JADE has recommended SGLT2 inhibitor be a preferred add on therapy for T2DM patients suffering from Cardiovascular or chronic kidney complications (19).

3.2.1 Glycemic control-

Its reported that the risk of hypoglycemia is lower with SGLT2 inhibitors, as compared to sulfonylureas (20, 21) . 5 mg and 10 mg of Dapagliflozin have been found to reduce HbA1c significantly as a monotherapy (22) and a dual therapy with metformin (23, 24). Despite of its association with genito- urinatory SGLT2 inhibitor based therapy is considered ideal anti-hypoglycemic (24).

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Table 1- The Glycemic efficacy of SGLT2 inhibitors in East Asian population (31264765)

Study

Design and population

Intervention

Glycemic effects

Inagaki N, et al. 2014

Phase III, 24-week double-blind randomized study; Japanese T2DM (N=272)

Canagliflozin (100, 200 mg); placebo

−0.74% (100 mg); −0.76% (200 mg); +0.29% (placebo)

Ji L, et al. 2014

Phase III, 24-week double-blind randomized study; drug-naïve Asian T2DM (N=393)

Dapagliflozin (5 or 10 mg); placebo

−1.04% (5 mg); −1.11% (10 mg); −0.29% (placebo)

Kaku K, et al. 2014

Phase III, 24-week double-blind randomized study; Japanese T2DM (N=261)

Dapagliflozin (5 or 10 mg); placebo

−0.41% (5 mg); −0.45% (10 mg); −0.06% (placebo)

3.2.2 Cardiovascular outcomes-Hayashi et al., 2017 have reported an increase in High Density Lipoproteins and suppression of the atherogenic marker soluble Low Density Lipoprotein on 80 Japanese T2DM patients under Dapagliflozin administration (25, 26). As per our knowledge, till date there has been almost no report on the direct consequence of SGLT2 inhibitors on the Asian patients. Over the past decade, several clinical trials have been undergoing as listed in Table 2. Once they are being approved then the regionwise analysis would begin.

3.2.3 Diabetic Kidney manifestations- As compared to the rest of the world, there has been critical thinking on the function of SGLT2 inhibitors in Asian T2DM patients suffering from Kidney ailments. Treatment with SGLT2 inhibitor, ipragliflozin on Japanese patients in an Long‐Term ASP1941 Safety Evaluation in Patients with Type 2 Diabetes with Renal Impairment (LANTERN) study, described the potential use of the drug’s safety and efficacy on moderately impaired renal patients (27). Such results support the potential use of SGLT2-inhibitors in addition to RAAS inhibitors on Diabetic patient suffering from kidney ailment. Hence, such positive data on East Asians, are crucial to perform long term studies in validating the renoprotective effects of these drugs (19).

3. 3 Clinical trial studies with SGLT2 inhibitors- The details of the clinical Trial on Cardiovascular manifestations with SGLT2 inhibitors have been provided in Table 2 and the associated renal outcomes have been provided in Table 3.

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Table 2- The cardiovascular outcome trial of the SGLT2 inhibitor-based studies as adapted from Deerochanawong et al, 2019 (28). Abbtns: MACE - Major Adverse Cardiac Events, HR- Hazard Ratio

TRIAL NAME

ESTIMATED DATE OF COMPLETION

REPORTS

MultiCentric and evaluating the effect of Dapagliflozin on Cardiovascular Events(DECLARE TIMI58)

(Dapagliflozin vs placebo), N = 17 160

April 2019

3 point MACE-pvalue 0.17

CV Death –HR 0.83

CV Death- pvalue 0.005

CANagliflozin cardioVascular Assessment Study

(CANVAS)

(canagliflozin vs placebo), N = 10 142

Feb 2017

3 point MACE-pvalue 0.02

CV Death-HR 0.87

CV Death-Pvalue (0.18)

EMPA‐REG OUTCOME (empagliflozin vs placebo), N = 7020

-

3 pont MACE-pvalue 0.04

CVDeath –HR 0.62

CV Death-Pvalue <0.001

Ertugliflozin Treatment in T2D with Vascular Disease (VERTIS CV Study)

June 2020

Ongoing

Table 3- The clinical outcomes of SGLT2 inhibitors on Diabetic Renal functions (29) and (30)

TRIAL NAME

ESTIMATED YEAR OF COMPLETION

REPORTED OUTCOMES

Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy (CREDENCE)

April 2019

The result outcomes are highly satisfactory, best over 20 yrs period time.

Renal and CV outcome-HR 0.7

End stage Kidney disease; Doubling of Serum Creatinine or renal death –HR 0.66

(30)

EMPA (empagliflozin)‐KIDNEY

SEPT 2017

Renal and CV outcome-p value 0.18

Albumin Creatinin Ratio pvalue 0.51

(31)

Canagliflozin on Renal Endpoints in Adult Participants with T2D (CANVAS-R)

FEB 2017

-

4. Concluding remarks

The SGLT2 inhibitors are considered well tolerated due to their safe functions, have already been treated as next line of treatment after Metformin in T2DM patients. They are effective as monotherapy or in combination with other drugs. Researchers have suggested that they should be administered to patients with a number of complications including cardiorenal manifestations. These are found to considerably normalize the BMI and weight gains in East Asian patients. Although clinical trials are providing very positive results about the safety and efficacy of these drugs thay still have adverse effects which need to be monitored appropriately.

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