Journal of Diabetology

REVIEW ARTICLE
Year
: 2019  |  Volume : 10  |  Issue : 2  |  Page : 57--61

Implications of CVD-REAL 2 study for Indian diabetic population


Rajeev Chawla1, Shalini Jaggi2,  
1 North Delhi Diabetes Centre, New Delhi, India
2 Dr. Mohan's Diabetes Specialities Centre, New Delhi, India

Correspondence Address:
Dr. Rajeev Chawla
North Delhi Diabetes Centre, 180, Jai Apartment, Rohini, Sector 9, New Delhi - 110 085
India

Abstract

South Asians are reported to have a higher risk of developing macrovascular complications of Diabetes, i.e., coronary artery and cerebrovascular diseases as compared to Caucasians. Literature evidence has shown that among the currently available agents, the sodium/glucose cotransporter 2 inhibitors (SGLT2i) offer a rational approach for management of T2DM over other glucose lowering therapies because of their insulinindependent action, modest weight loss, mild reduction in BP and low risk of hypoglycaemia. Recently, CVDREAL 2 study was conducted across six countries (Israel, Canada, South Korea, Japan, Singapore and Australia) to determine the CV benefits of various SGLT2i in >400,000 T2DM patients in a realworld scenario. Around 75% of the patients in this study were from the AsiaPacific region. Among all the available SGLT2i, most of the study population was exposed to dapagliflozin, contributing to 75% of the total exposure time. The CVDREAL 2 study favoured SGLT2i over other glucose lowering drugs for lower risk of death, HHF, MI and stroke. All these points suggest that the results of CVDREAL 2 study can be incorporated in the high CVD risk Indian population who need much more aggressive treatment for diabetes than other patient populations.



How to cite this article:
Chawla R, Jaggi S. Implications of CVD-REAL 2 study for Indian diabetic population.J Diabetol 2019;10:57-61


How to cite this URL:
Chawla R, Jaggi S. Implications of CVD-REAL 2 study for Indian diabetic population. J Diabetol [serial online] 2019 [cited 2019 Aug 18 ];10:57-61
Available from: http://www.journalofdiabetology.org/text.asp?2019/10/2/57/257209


Full Text



The global rise in diabetes epidemic comes as no surprise in current times with the International Diabetes Federation (2017) estimating 425 million people worldwide as already having diabetes, and a further projected increase to 629 million by the year 2045.[1] What's worse is that 5%–10% of people with pre-diabetes also tend to convert to diabetes every year, a fact endorsed by the American Diabetes Association (ADA) expert panel which reported that about 70% of the pre-diabetic population can go on to develop diabetes in the long run, further adding to the burden.[2] This mammoth increase in the prevalence of diabetes is a major health concern, more so closer home for us in India, with a rapidly urbanising population increasing at a drastic rate due to unhealthy eating patterns and sedentary lifestyle. This has brought us face-to-face with the growing epidemic of obesity, type 2 diabetes mellitus (T2DM) and associated cardiovascular (CV) risks.[3],[4]

The Indian Council of Medical Research (ICMR)-India DIABetes (INDIAB) (2017) study, the largest nationwide study looking at diabetes numbers in different parts of India, reported an overall diabetes prevalence of 7.3% along with an increasing pre-diabetes prevalence of 10.3% or 24.7% as per the World Health Organisation or the ADA criteria, respectively.[5] Not only that, it has also been suggested that Indians progress faster from pre-diabetes to diabetes compared to other ethnic groups.[6] This can be a grave cause of concern considering that increased incidence of pre-diabetes is not only a high-risk state predisposing to diabetes but also carries the inherent risk of CV diseases (CVDs).[7]

The high prevalence rate of diabetes in the Indian population has been attributed to the South Asian phenotype that distinguishes Indian population from Caucasians.[8] A typical South Asian phenotype is characterised by increased levels of body fat, insulin resistance, triglycerides, small dense low-density lipoprotein and high-sensitivity C-reactive protein; and decreased levels of adiponectin, high-density lipoprotein (HDL), beta-cell mass and body mass index (BMI).[9] To add fuel to the fire, several studies have shown a much younger age of onset of T2DM among the South Asians as compared to that of Caucasians.[9],[10] An ICMR-INDIAB national survey in 2011 resulted in a grave statistic that more than half of the Indian population had diabetes <50 years of age, much earlier than the Caucasian population who get diabetes at around 58 years.[7],[11] Similar results were reported by Gujral et al. with the lowest mean age at diagnosis of diabetes found in South Asians at 49 years when compared with the African Americans (57 years) and the Caucasians (58 years) living in US,[12] clearly suggesting that diabetes in the Asian population occurs at a younger age.[13]

Another major concern associated with diabetes is its microvascular (diabetic nephropathy, neuropathy and retinopathy) and macrovascular complications (coronary artery disease, peripheral arterial disease and stroke).[14] South Asians are reported to have a higher risk of developing macrovascular complications, i.e., coronary artery and cerebrovascular diseases as compared to Caucasians.[15],[16] The ADVANCE study (multicentre, randomised controlled trial, n = 11,140) documented the diabetes-related complications in three regions, namely Asia, Eastern Europe and established market economies (Canada, Australia, New Zealand and several Western European countries) and showed higher rate of ischemic stroke in Asians (n = 576, 14%) than Eastern Europe (n = 172, 8%) and established market economies (n = 275, 6%).[17] Considering the risk of diabetic complications, it is recommended that if HbA1c levels are reduced to <7%, it decreases the microvascular complications but the risk of macrovascular complications remains.[18] This is demonstrated by the ADVANCE trial which showed statistically significant reduction in the risk of microvascular complications (hazard ratio [HR]: 0.86; 95% confidence interval [CI], 0.77–0.97; P = 0.01) with intensive glucose control in T2DM patients whereas no such effect was noted on macrovascular events (HR: 0.94; 95% CI, 0.84–1.06; P = 0.32).[19] Similar results were noted in the UKPDS trial.[20] Some improvement in macrovascular complications was also noted in these trials, which however took a long-term period. Post-trial monitoring (a 10-year follow-up) of UKPDS (n = 3277) showed a significant reduction of 15%–33% in myocardial infarction (MI) and 13%–27% decrease in death from any cause with intensive glucose control treatment.[20] The Steno-2 (randomised trial in T2DM patients with microalbuminuria) showed 70% reduction in the risk of hospitalisation for heart failure (HHF) with intensive multifactorial treatment at 21.2 years of follow-up.[21] All these factors highlight the risk of macrovascular complications in diabetic patients and call for early and stringent control of diabetes.

South Asians are reported to have a higher risk of coronary heart disease (CHD) and stroke as well as higher mortality rates when compared to other ethnic groups. In fact, CHD occurs 5–10 years earlier in Asians and this high CV risk is attributed to lower HDL levels, higher triglyceride and lipoprotein levels and higher blood pressure (BP).[16],[22],[23],[24],[25],[26],[27] Further, diabetes has been found to be strongly associated with higher rates of HHF and all-cause death (ACD) in Asian patients (HR: 1.50; 95% CI: 1.21–1.87) as compared to white patients (HR: 1.29; 95% CI: 1.22–1.36).[28] These higher rates of CVD complications i.e., coronary disease, stroke and HF in the Asian population with T2DM call for aggressive treatment strategies tailored as per the Asian ethnicity to prevent their occurrence.

Literature evidence has shown that among the currently available agents, the sodium/glucose cotransporter 2 inhibitors (SGLT2i) offer a rational approach for management of T2DM over other glucose lowering therapies because of their insulin-independent action, modest weight loss, mild reduction in BP and low risk of hypoglycaemia.[29] Several CV outcome trials such as EMPA-REG (2015) and CANVAS (2018) trials have demonstrated beneficial effects in T2DM patients. The EMPA-REG trial (randomised, double-blind trial; n = 7028; >99% of established CVDs) showed a marked relative risk reduction for CV death (38%), HFF (35%), death from any cause (32%) and 3-point major adverse CV events (14%) in the empagliflozin arm compared to the placebo arm. These results were also found to be consistent in the Asian sub-group, which comprised 21.6% of the overall study population.[13],[30] Similarly, the CANVAS trial (randomised, single-blind trial; n = 4330; around 65% with established CVDs) showed 14% reduction in composite of death from CV causes, non-fatal MI, or non-fatal stroke with canagliflozin in comparison to placebo (HR: 0.86; 95% CI, 0.75–0.97; P < 0.001); however, the results were not found to be consistent in the Asian sub-set (HR: 1.08, 95% CI, 0.72–1.64; P = 0.40), which comprised 12.7% of the study population.[31] So while one trial showed consistent results even in Asians, the other did not, making it little difficult to generalise equal benefits with this class of drugs in the Asian population, and warranting the need for further data in this ethnic group.

Another concern is that, though such randomised clinical trials (RCTs) provide sufficient information on the efficacy of the therapeutic intervention, they are conducted under ideal conditions and thus, their external validity varies from low-to-medium due to homogenous nature of the enrolled “selective” population. Therefore, there is a growing interest towards real-world studies which reflect the effectiveness of the treatment precisely in a real-world scenario. Realworld studies also have flexible interventions which represent low-to-high compliance under real-world conditions, unlike the RCTs. Further, real-world studies involve a heterogeneous population, representing the actual set of people the intervention is targeted at, due to which their external validity is very high. Finally, real-world evidences have high generalisability, and have proven to be useful in detecting rare and late side effects, thus helping to evaluate complex therapies.[32] Therefore, real-world studies are deemed essential to substantiate the findings of RCTs. Few such studies conducted recently (CVD-REAL, EASEL and CVDREAL 2) have demonstrated the benefits of sodium-glucose cotransporter 2 inhibitor (SGLT2i) in T2DM patients, strengthening the evidence for their CV benefits in diabetic patients.

CVD-REAL, the first large real-world study with 309,056 patients of T2DM (13% patients with established CVD) across six countries (US, Germany, Sweden, Norway, Denmark and UK), reported that use of SGLT2i versus other glucose lowering agents was associated with lower rates of HHF (39%), death (51%) and composite of HHF and death (46%) (P < 0.001 for each) despite pre-existing CVDs.[33] Furthermore, EASEL, a US-population based high-risk cohort study (111,576 patients having T2DM and established CVDs) demonstrated the benefits of SGLT2i over non-SGLT2i, including lower risk of composite of ACD and HHF (1.73 vs. 3.01 events per 100 person-years) and major adverse CV events (2.31 vs. 3.45 events per 100 person-years).[34] However, it must be noted that data supporting the use of SGLT2i in Asian diabetic population was limited in these studies.[35],[36] In fact, no Asian patients were enrolled in the first part of CVDREAL study (2017) and all T2DM patients (n > 300,000) were from the US and Europe.[33],[37] Recently, CVD-REAL 2 study was conducted across six countries (Israel, Canada, South Korea, Japan, Singapore and Australia) to determine the CV benefits of various SGLT2i in >400,000 T2DM patients in a real-world scenario.[37] Importantly, around 75% of the patients in this study were from the Asia-Pacific region as compared to EASEL that had only 1.7% of Asians. Moreover, the percentage of the patient population with established CVDs was found to be ~27% in CVD-REAL 2, which is more in line with the real-world estimates as shown by a 32.2% worldwide incidence of CVDs in diabetes in a systematic review.[38] A similar scenario has been noted in the Indian population where the Chennai Urban Population Study found a CAD prevalence of 21.4% in diabetic patients.[39] Besides, the CVD-REAL 2 study focused on a broad range of CV outcomes (including ACD, HHF, composite of ACD or HHF, MI and stroke).[37] All these points highlight the fact that the CV risk profile of the CVD-REAL 2 study can be considered much more similar to the Asian population that we have described above.

With respect to CV outcomes, the CVD-REAL 2 study favored SGLT2i over other glucose lowering drugs for lower risk of death (HR: 0.51; 95% CI: 0.37–0.70; P < 0.001), HHF (HR: 0.64; 95% CI: 0.50–0.82; P = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47–0.76; P < 0.001), MI (HR: 0.81; 95% CI: 0.74–0.88; P < 0.001) and stroke (HR: 0.68; 95% CI: 0.55–0.84; P < 0.001). Among all the available SGLT2i, the majority of the study population was exposed to dapagliflozin, contributing to 75% of the total exposure time in comparison to other SGLT2i (ranging from 1% to 9%).[37] An important finding of the study was lower reduction of ACD in Asian countries, m i.e., Korea (HR: 0.72 [95% CI: 0.67, 0.77]), Japan (HR: 0.56 [95% CI: 0.47, 0.67]) and Singapore (HR: 0.75 [95% CI: 0.38, 1.47]) as compared to North America, i.e., Canada (HR: 0.51 [95% CI: 0.41, 0.65]), Middle East, i.e., Israel (HR: 0.41 [95% CI: 0.30, 0.55]) and Pacific region, i.e., Australia (HR: 0.32 [95% CI: 0.27, 0.38]). Similarly, lesser reductions were noted for HHF, composite ACD or HHF, MI and stroke (P < 0.001) in Asian countries as compared to other regions.[37]

This lower CV risk reduction in Asian diabetic population may be attributed to the typical Asian phenotype. Asians tend to develop diabetes at a younger age and have more insulin resistance, higher abdominal and visceral fat, elevated CRP levels and less physical activity than Caucasians, which all together might be responsible for lower CV risk reduction seen with any agent in this high CV risk population.[12] Furthermore, the quality of diabetes care is sub-optimal in the Asian population.[40] This underscores the fact that the Asian population needs much more aggressive treatment for diabetes to achieve equivalent CV risk reductions seen in European populations. SGLT2i, which have been shown to reduce the incidence of major adverse cardiac events, MI, HHF and mortality in T2DM patients in a recent meta-analysis (n = 35 studies), thus come across as a preferred valid choice in this high CV risk population.[41]

Overall, the CVD-REAL 2 study showing a favourable CV effect of SGLT2i in Asian diabetic patients may be interpreted to have great implications for the Indian diabetic population due to similar phenotype shared by Indians with other Asian populations.[42] A pooled analysis of 20 prospective cohorts in Asia showed that East Asians (China, Taiwan, Singapore, Japan and Korea) and South Asians (India and Bangladesh) have almost similar mean BMI rates, i.e., 23.1 and 22.0, respectively.[43] Moreover, Asians have similar characteristics in terms of high stroke mortality, high salt consumption, high BP and lower levels of cholesterol than Western countries. Since the majority of the population in CVD-REAL 2 study was from the Asian region, the CV benefits of this study may thus be extrapolated to the Indian population.[44] Furthermore, dapagliflozin was the most common drug used in the study and was found to be helpful in reducing macrovascular complications of T2DM. Another advantage of the CVD-REAL 2 study was its observational study design.[37] All these points suggest that the results of CVD-REAL 2 study can be incorporated in the high CVD risk Indian population who need much more aggressive treatment for diabetes than other patient populations.

 About the Declare-TIMI 58 Study



DECLARE-TIMI 58, a randomised, double-blind, multicentre, placebo-controlled CV outcomes trial, has recently completed and evaluated the effects of dapagliflozin on the incidence of CV events. This trial includes a broad ethnic population of T2DM (79.6% whites, 3.5% blacks, 13.4% of Asians and 3.5% others) and CV risk profile (40% with a history of established CVD and 60% with multiple risk factors). Further, it has a composite of CV death, MI, or ischaemic stroke and the composite of CV death or HHF as a dual primary endpoint which was evaluated as only an exploratory end-point in EMPA-REG and CANVAS trials.[45],[46] The trial has shown a landmark finding that dapagliflozin led to significant reduction in CV death or HHF (HR: 0.83 [95% CI: 0.73–0.95]; P = 0.005) which was consistent in both the primary and secondary prevention cohorts. Dapagliflozin also demonstrated numerically lower numbers of major adverse cardiac events with 11% reduction in non-fatal MI in the broad CV risk type 2 diabetic population.[47] This further strengthens the findings of the CVD-REAL 2 study and suggests that we are on the qui vive for the final verdict on these novel agents that can make a paradigm shift to our approach on managing diabetes patients.

Acknowledgement

The authors would like to acknowledge Turacoz Healthcare Solutions, Gurugram (Haryana) for writing support.

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