Risk Amplifiers for Vascular Disease and CKD in South Asians

Abstract

South Asians, comprising almost one fourth of the world population, are at higher risk of type 2 diabetes mellitus, hypertension, cardiovascular disease, and CKD compared with other ethnic groups. This has major public health implications in South Asia and in other parts of the world to where South Asians have immigrated. The interplay of various modifiable and nonmodifiable risk factors confers this risk. Traditional models of cardiometabolic disease progression and CKD evaluation may not be applicable in this population with a unique genetic predisposition and phenotype. A wider understanding of dietary and lifestyle influences, genetic and metabolic risk factors, and the pitfalls of conventional equations estimating kidney function in this population are required in providing care for kidney diseases. Targeted screening of this population for metabolic and vascular risk factors and individualized management plan for disease management may be necessary. Addressing unhealthy dietary patterns, promoting physical activity, and medication management that adheres to cultural factors are crucial steps to mitigate the risk of cardiovascular disease and CKD in this population. In South Asian countries, a large rural and urban community-based multipronged approach using polypills and community health workers to decrease the incidence of these diseases may be cost-effective.

Introduction

South Asia (including Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka), home to 1.9 billion people, represents one of the most populous and fastest-growing regions of the world.¹ Since health care spending in South Asia is only 3.1% of the gross domestic product, chronic diseases such as cardiovascular disease and CKD strain these developing economies.² Several challenges exist in delivering health care services in these countries, including lack of access to quality health care, regional inequality, and lack of financial risk protection from catastrophic health care expenditures.³ Prolonged life expectancy, sedentary lifestyles, unhealthy dietary habits, air pollution, and chronic infections may lead to a higher prevalence of chronic diseases. In this review, we summarize the existing literature on why South Asians may experience a higher risk for metabolic and vascular diseases and consequent CKD. We also aim to address how measures of kidney function and management of CKD need to be tailored to this population.

What Drives Vascular Disease and CKD in South Asians?

Vascular disease, which contributes to both cardiovascular disease and CKD, is a leading cause of mortality in South Asians and is mediated through diabetes mellitus and hypertension.^4,5 South Asians tend to develop type 2 diabetes mellitus on an average 5–10 years earlier than White Europeans.^6,7 South Asians living in the United Kingdom, the United States, and Canada have been shown to have a higher prevalence of diabetes mellitus than the local population living in these countries.^8–11 The immigrant Bangladeshi population living in England and Wales has a four-fold greater risk of type 2 diabetes mellitus compared with the local population (Table 1).¹² Interestingly, in an observational cohort study of 3444 patients with CKD in British Columbia, South Asians had a faster rate of progression to kidney failure but better survival than White patients.¹³ Although the reason for this was not clear, the South Asian cohort was significantly younger than the White patient cohort, which may have contributed to lower mortality. There have also been reports of a higher prevalence of diabetes and cardiovascular disease in people of South Asian ethnicity in Singapore, Fiji, and Guyana, although the number of studies has been fewer.^14–18 Elevated diabetes and cardiovascular risks in South Asians are derived from several nonmodifiable and modifiable risk factors (Figure 1).

Table 1.

Crude and age-standardized incidence of type 2 diabetes mellitus per 1000 person-years by ethnicity and sex in England and Wales¹²

Ethnicity	Women			Men
	Person-Yr	Crude Rate	Age-Standardized Rate (95% CI)	Person-Yr	Crude Rate	Age-Standardized Rate (95% CI)
White/not recorded	8,176,581	4.16	4.13 (4.08 to 4.17)	7,900,533	5.33	5.31 (5.26 to 5.36)
Indian	31,535	6.41	7.90 (6.73 to 9.08)	28,127	8.64	9.60 (8.35 to 10.85)
Pakistani	18,735	8.49	11.19 (9.16 to 13.21)	19,634	9.88	13.22 (11.24 to 15.21)
Bangladeshi	6683	11.37	18.20 (12.93 to 23.47)	6944	12.82	19.34 (14.28 to 24.4)
Other Asian (excluding Chinese)	13,056	3.45	6.08 (2.73 to 9.44)	9588	7.09	8.09 (6.03 to 10.15)

CI, confidence interval.

Figure 1.

Overview of modifiable and nonmodifiable risk factors for vascular disease and CKD in South Asians.

Nonmodifiable Risk Factors: A Unique Phenotype of Dysglycemia

The interplay of several nonmodifiable factors such as genetic predisposition for dysglycemia, low birth weight, and predisposition to central adiposity is associated with an elevated risk of cardiovascular disease and CKD.¹⁹ The adipose tissue overflow hypothesis speculates that there is a lower capacity for storing subcutaneous fat in South Asians, which results in a larger proportion of visceral fat storage.^20,21 Visceral fat is more likely to undergo lipolysis, which can result in excess lipid accumulation in the liver, causing impaired insulin signaling and proinflammatory changes.²² South Asians living in the United States have higher levels of insulin resistance at a given body mass and can have rapid β-cell failure, which elevates their vascular risk independent of visceral adiposity.^23–25 Normal-weight South Asians have higher levels of cardiometabolic abnormalities compared with other ethnic groups, after adjusting for the mean visceral fat area.²⁶ Other factors that may mediate insulin resistance in South Asians include lower lean body mass, lower genetically determined β-cell capacity, and increased intrahepatic fat deposition.^27–29 A higher fat-to-muscle ratio for a given body mass index (BMI) may result in greater levels of insulin resistance.³⁰ Genetically lower β-cell function likely contributes more than insulin resistance to impaired fasting glucose and impaired glucose tolerance, as shown in the Diabetes Community Lifestyle Improvement Program in Chennai, India.³¹ Normal-weight people of Indian origin may have increased hepatic insulin resistance, which can lead to increased gluconeogenesis, impaired fasting glucose, and hepatic steatosis.³² These factors influenced the American Diabetes Association to recommend lowering the threshold for diabetes mellitus type 2 screening to a BMI of 23 kg/m² in Asian Americans.³³

About one third of live births in the South Asian region were reported to be low birth weight by the World Health Organization (WHO), resulting in lower nephron mass and a higher lifetime risk of kidney failure.^34–36 The risk factors for low birth weight include genetic factors, maternal malnutrition, pregnancy complications, place of residence (urban versus rural), level of education, and other socioeconomic factors.³⁷ Low birth weight may be considered as a modifiable or nonmodifiable risk factor, depending on the etiology.

There is a paucity of research investigating genetic risk factors for insulin resistance and CKD in South Asians. In a recent genome-wide association study, 21 genetic loci were identified and were significantly associated with type 2 diabetes mellitus in people of South Asian ancestry (n=50,533) compared with European ancestry (n=231,420).³⁸ The authors also developed a South Asian–specific polygenic risk score for type 2 diabetes mellitus, which risk stratifies South Asians into quartiles based on diabetes risk, with the top quartile having a risk of 4.03 (95% confidence interval [CI], 3.36 to 4.85; P<0.001) relative to the bottom quartile, and they report that this risk stratification has greater predictive power for diabetes in South Asians than Europeans.³⁸ The authors performed cross-ancestry comparisons of these 21 genetic loci with East Asian (n=135,780), African (n=32,037), and Hispanic (n=20,499) populations and discovered that many genetic loci may represent risk factors unique to the South Asian population.³⁸ More genetic studies will be needed to ascertain the utility of targeted screening of South Asian populations with elevated genetic risk.

Modifiable Risk Factors: High Carbohydrate-to-Protein Intake Ratio

Metabolic and vascular diseases are also influenced by modifiable risk factors such as level of activity, smoking, and diet. The effect of behavioral factors and diet on diabetes mellitus and cardiovascular risk in South Asians who immigrated (and their progeny) to the United States from India is being evaluated in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort.³⁹ The MASALA study is the only prospective, longitudinal, community-based study consisting of 1164 participants (aged 40–84 years and without cardiovascular disease at enrollment) of South Asian ethnicity living in San Francisco and Chicago. MASALA was designed for cross-ethnic comparison with the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, which included White Americans, Black Americans, Hispanic Americans, and Chinese Americans without cardiovascular disease.⁴⁰

The South Asians in the MASALA cohort are less physically active than all the ethnic groups in the MESA cohort. In the MASALA study, the researchers found three predominant dietary patterns among the population of South Asian descent: an animal protein–rich dietary pattern, a high-fat vegetarian pattern, and a low-fat vegetarian pattern.⁴¹ The diet rich in animal protein was associated with higher BMI, waist-to-hip ratio, total cholesterol, and low-density lipoprotein cholesterol. A predominantly vegetarian diet but with fried snacks, sweets, and high-fat dairy led to greater insulin resistance and lower high-density cholesterol. A low-fat vegetarian diet consisting of ample fruits, vegetables, nuts, and legumes had the most favorable metabolic profile and a decreased association with hypertension. Sodium intake is another modifiable aspect in the South Asian diet (mean sodium intake of South Asian countries is about 10 g/d, whereas the WHO's recommended intake is <5 g/d).⁴² The prevalence of smoking is significantly higher in South Asian men (31.6%–60%) than women (2.2%–4.02%).⁴³ Communities with higher smoking rates had more poverty, lower educational background, and were often located in rural areas.⁴³

In addition to risk factor modification, evaluating vascular sites (such as carotid intimal thickness, pulse wave reflections, and coronary artery calcification measurements) may help detect subclinical atherosclerotic cardiovascular disease.^44,45 Ethnic differences between South Asians, White patients, and Black patients living in the United States showed higher pulse wave reflections in South Asians, a marker of arterial stiffness.⁴⁶ Further investigation is needed to determine the optimal medical management in patients with subclinical atherosclerotic disease and its effect on long-term cardiovascular outcomes.

Prevalence of Hypertension, Cardiovascular Disease, and CKD in the South Asian Population

Several studies have attempted to assess the burden of hypertension and the development of subsequent CKD and/or proteinuria in ethnic South Asians. A cross-sectional study performed in both urban and rural areas of Delhi, India, showed an increase in the prevalence of hypertension from 23% to 42% in the past 20 years.⁴⁷ A meta-analysis showed that the overall prevalence of hypertension in the South Asian subcontinent is approximately 27%.⁴⁸ The Cardiometabolic Risk Reduction in South Asia (CARRS) cohort, which had over 17,000 individuals in Karachi, Chennai, and Delhi, found that the prevalence of hypertension was the highest in Delhi (37%) and the lowest in Karachi (24%).⁴⁹ They also found that awareness about hypertension was very low, and its occurrence was associated with older age, lower socioeconomic status, obesity, and dysglycemia.

A United Kingdom–based study showed earlier onset and higher prevalence of hypertension in South Asian (11.3%) and Black (11.1%) patients compared with White patients (8.2%).⁵⁰ The study also found that severe CKD (stages 4–5) occurred at higher rates in South Asian patients after adjustment for age and other clinical markers.⁵⁰ Earlier onset of hypertension despite lower BMI has been reported in foreign-born South Asians living in a major US city (as compared with non-Hispanic White patients).⁵¹ The ADDITION-Leicester study, a United Kingdom–based multiethnic study, found among a population of 6749 patients, one third of them (1894 patients of which 372 were South Asians) had undiagnosed hypertension.⁵² In this population, South Asians had a higher likelihood of microalbuminuria and a trend toward a lower eGFR as compared with White Europeans. The authors concluded that dedicated efforts are needed to screen for hypertension in South Asians given the high risk of microalbuminuria and CKD.

The prevalence of CKD, mainly due to diabetes and hypertension (as reported by the Indian CKD registry), in South Asia is estimated to be between 10.2% and 21.2 %.^53,54 Per the Indian CKD registry, chronic glomerulonephritis occurred in approximately 14% of patients.⁵⁴ In Sri Lanka and the Andhra Pradesh region of India, CKD of unknown etiology (CKDu) with a predominantly interstitial pattern of kidney injury has been increasingly reported (with prevalence as high as 13% in some districts of Andhra Pradesh).⁵⁵ Possible risk factors include contaminated drinking water, exposure to agrochemicals, heat stress, and air pollution, but none have been proven to be causative.⁵⁵ One study showed that Indians were at a higher risk of developing AKI after cardiac surgery as compared with Chinese patients.⁵⁶ The authors hypothesized that underlying atherosclerosis of the renal vasculature predisposed South Asians to develop postoperative AKI.

CKD prevalence in the MASALA cohort (South Asians living in US cities, n=748) was compared with the CARRS cohort (South Asians living in Chennai and Delhi, India, n=5294).⁵⁷ CKD was defined in both studies as a single urine albumin-to-creatinine ratio ≥30 mg/g or a single calculation of estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (eGFR_CKD-EPI) of <60 ml/min per 1.73 m². The age-adjusted prevalence of CKD in the MASALA cohort was 14% versus 10.8% in the CARRS cohort (P<0.05), and the prevalence of albuminuria was 13.8% in MASALA versus 8.7% in CARRS.⁵⁷ Although age-adjusted prevalence rates of albuminuria in men were comparable, the prevalence of albuminuria in women in the MASALA cohort was significantly higher. However, the CARRS cohort, which was younger and had a lower level of education, had more severe CKD and a higher likelihood of uncontrolled diabetes mellitus and hypertension. Only 9% of patients in the CARRS group were prescribed angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) as compared with 29% in the MASALA cohort. This difference may be due to poor access to health care, especially subspecialty care, as well as lower health literacy among the CARRS population, and it highlights the need for better screening and management of vascular disease risk factors. Microalbuminuria is also more common in the South Asian population in Newcastle, United Kingdom, compared with the European origin population, which is a strong risk factor for the progression of CKD and cardiovascular disease.⁵⁸ Given the higher risk of CKD in the South Asian population, it becomes essential to accurately estimate kidney function.

Estimation of GFR in the South Asian Population

Correctly identifying CKD in South Asian patients is paramount to help slow down its progression. Clinical laboratories in South Asia do not routinely report on eGFR, although the practice may be improving. The existing Modification of Diet in Renal Disease (eGFR_MDRD) and eGFR_CKD-EPI equations have not been validated in the South Asian population.

A cross-sectional study of 581 adults from Pakistan aged 40 years and older was conducted to compare the performances of the eGFR_MDRD and eGFR_CKD-EPI equations against body surface area–adjusted inulin clearance (mGFR).⁵⁹ Twenty percent of the patients were selected from the nephrology clinic with a serum creatinine >2 mg/dl, presumed to have CKD, and the rest were selected from the general population. Median mGFR, eGFR_MDRD, and creatinine-based eGFR_CKD-EPI were 91.0 (interquartile range [IQR], 36.7), 100.5 (IQR, 40.4), and 104.4 (IQR, 25.4) ml/min per 1.73 m², respectively. Both the MDRD and CKD-EPI equations overestimated mGFR in this population. A modified CKD-EPI equation named CKD-EPI Pakistan (eGFR_CKD-EPI(PK)) was derived using linear regression models. The Pakistani correction factor for the CKD-EPI equation can be rendered as eGFR_CKD-EPI(PK)=0.686 × eGFR_CKD-EPI^1.059. This correction factor improved accuracy measured using P₂₀ and P₃₀, which refer to the percentage of eGFR values that differ by <20% and 30% of the mGFR values, respectively. P₂₀ was 65.9% (95% CI, 62.1% to 69.7%) versus 57.8% (95% CI, 53.8% to 61.8%; P<0.001), and P₃₀ was 81.6% (95% CI, 78.4% to 84.8%) versus 76.1% (95% CI, 72.7% to 79.5%; P<0.001) for the CKD-EPI_PK and CKD-EPI equations, respectively. It was common to find variations of the eGFR_CKD-EPI(PK) from mGFR among the extremes of BMI. In a cross-sectional study of 557 participants aged 40 years in Pakistan, the use of cystatin C–based CKD-EPI equations (eGFR_cys and eGFR_cr-cys) did not offer substantial advantages over the eGFR_CKD-EPI(PK) equation.⁶⁰ Although more studies are required to validate the CKD-EPI_PK equation, a wider understanding of subpopulation norms could steer clinicians and patients toward risk mitigation at higher levels of estimated kidney function. For example, a clinician may want to use the CKD-EPI_PK for eGFR estimation in South Asians or may choose to convey alarm for South Asians with eGFR around 75 ml/min per 1.73 m² using MDRD or CKD-EPI equations, rather than awaiting a threshold of eGFR <60 ml/min per 1.73 m², due to their tendency to overestimate GFR.

Management of CKD in a South Asian Patient

A multipronged approach that includes lifestyle, medication, and close monitoring is crucial to mitigating vascular risk factors (Table 2). The dietary practices in South Asia have a strong historical, cultural, and religious basis. Recommendations on lifestyle modifications (including healthier cooking and exercise) need to be sensitive to religious observances in South Asians (i.e. prolonged fasting and glycemic control in diabetic Muslim and Jain patients).^72,73 Because the South Asian diet is rich in refined carbohydrates, some authors have proposed nutrition counseling and the reintroduction of whole-grain carbohydrates such as amaranth, barley, pearl millet, finger millet, sorghum, and other ancient grains.⁶¹ These whole grains have lower carbohydrate content and may have protective effects against central adiposity and insulin resistance.⁶¹ Consumption of Western foods rich in animal protein may also be detrimental to South Asians, as shown in the MASALA study.⁴¹ Prospective cohort studies have shown that red meat consumption may be associated with a 40% higher risk of CKD, whereas consumption of legumes, nuts, and low-fat dairy is associated with approximately 17-28% lower risk of CKD.^74,75

Table 2.

Management of vascular risk in the South Asian patient

Prompt diagnosis	Screening for albuminuria57
	Consider using correction factors to improve accuracy of eGFR59
Lifestyle modification	Healthier cooking—less fried, bready snacks/sweets, and high-fat dairy41 Use of culturally acceptable whole grains in diet61
	Exercise (∼230 min of moderate physical activity)62
	Smoking cessation
Medications to reduce complications of diabetes mellitus	Sulfonylureas—cost effective, but effect may be short lived63
	Thiazolidinediones—increase insulin sensitivity in South Asians64
	Metformin—lowers glucose and enhances β cell function in South Asians65,66
	DPP-4 inhibitors—although studied in East Asians (not South Asians), this class may lower insulin resistance and enhance first-phase insulin secretion67,68
	GLP-1 agonists—lowers blood glucose similarly to Western European and White patients69
	SGLT-2 inhibitors—can effectively reduce glucose, body weight, and cardiovascular risk69,70
	ACEIs/ARBs—hypertension management and reduction in CKD progression and cardiovascular events, although more data are needed specifically in South Asians71

DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose cotransporter-2; ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers.

The subgroups that are at the highest risk of physical inactivity include South Asians who are female, skilled workers/professionals, and those with a higher level of education.⁷⁶ In the MASALA study, having network members who were friends or family who exercised along with the study participants increased the moderate-to-vigorous leisure time physical activity for South Asian men.⁷⁷ South Asians may need to undertake more physical activity (approximately 230 minutes of moderate physical activity per week) compared with White Europeans (approximately 150 minutes of moderate physical activity per week) to confer a similar cardiometabolic risk profile.⁶²

In addition to increasing patient awareness, further training of health care workers in South Asian countries is critical to improving health outcomes. The WHO has estimated that South Asia has one of the lowest densities of skilled health care workers in the world.⁷⁸ Table 3 shows the number of doctors and nurses or midwives per 10,000 population in South Asian countries, as estimated by the WHO Global Health Workforce Statistics.⁷⁹ Owing to the skilled health care worker shortage, some studies have been conducted using community health care workers in rural settings. The Control of Blood Pressure and Risk Attenuation—Bangladesh, Pakistan, and Sri Lanka (COBRA-BPS) study evaluated the role of community health workers in the rural setting specifically trained in hypertension management.⁸⁰ The group of patients randomized to community health workers had significant reductions in both systolic and diastolic BP, after referral to a physician. This study's findings show that proactive multicomponent interventions can lead to major cardiovascular risk reduction in these populations and thus can have major public health implications.

Table 3.

Estimated number of doctors and nurses/midwives per 10,000 population in South Asian countries

Country	Doctors per 10,000 Population	Nurses/Midwives per 10,000 Population
Afghanistan	2.54	4.46
Bangladesh	6.67	4.89
Bhutan	4.99	20.78
India	7.34	17.48
Maldives	20.53	46.61
Nepal	8.52	33.42
Pakistan	11.18	4.83
Sri Lanka	12.29	24.95

Source: World Health Organization Global Health Workforce statistics database. Last updated Jan 24, 2022.

Medical management is essential in reducing microvascular and macrovascular complications of diabetes mellitus and hypertension in South Asians.⁸¹ For patients living in South Asia, affordability is a huge factor because of the low percentage of gross domestic product spent on health care and the lack of widespread adoption of private or public health insurance policies. Antihyperglycemic agents such as sulfonylureas and metformin are cost-effective first-line agents in South Asians with type 2 diabetes mellitus, especially in the early stages.⁶³ The effect of sulfonylureas may not be long-lived in South Asians because of accelerated β-cell failure. Moreover, owing to the lack of widespread self-monitoring of blood glucose, the risk of hypoglycemia must be emphasized.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have shown benefits in glycemic control and decreasing cardiovascular risk in patients with diabetes mellitus^82–84. Remogliflozin is an affordable SGLT-2 inhibitor approved for use in India after a phase 3 trial showed comparable glucose-lowering effects and safety profile with dapagliflozin.^85,86 Although it is unclear whether remogliflozin has similar kidney-related benefits seen in other SGLT-2 inhibitors (empagliflozin, dapagliflozin, ertugliflozin, sotagliflozin), it was found to be noninferior to dapagliflozin in control of hemoglobin A1c and had no clinically relevant difference regarding fasting plasma glucose, postprandial plasma glucose, body weight, and safety profile.⁸⁷ The South Asian Federation of Endocrine Societies recommends consideration of SGLT-2 inhibitors as initial therapy in metformin-intolerant individuals, after taking into account their body types, dietary patterns, and lifestyles (particularly because of the possibility of ketoacidosis and dehydration from hot climate and religious fasting).⁷⁰ Oral medications may delay the need for insulin therapy, which has been associated with social stigmas in South Asian communities.⁸⁸

The antiproteinuric and kidney protective effects of ACEIs and ARBs in both diabetic and nondiabetic kidney disease have been well established.⁷¹ These classes of medications should be considered first-line agents to manage hypertension and CKD in South Asians.⁷²

Medication adherence, however, is a challenge in South Asia due to several social determinants including poor health literacy, lack of social support, and adequate housing and fiscal burdens.^89,90 The polypill, which is defined as a fixed-dose combination of medications, was a strategy suggested by the WHO to improve adherence.⁹¹ The polypill can be single-purpose (i.e. fixed-dose combinations of antihypertensives, such as an ACEI, hydrochlorothiazide, and a calcium channel blocker) or multipurpose (i.e. statin, aspirin, β blocker, and ACEI). Recent meta-analyses have demonstrated that fixed-dose polypills lead to better adherence, better BP control, and a reduction in the incidence of myocardial infarction, stroke, and cardiovascular death.^92,93 However, these polypills may be more expensive, leading to problems with affordability.⁹⁴

Prolonged life expectancy, sedentary lifestyles, and unhealthy dietary habits have resulted in a higher prevalence of chronic conditions in people of South Asian origin. In South Asian countries, conditions such as diabetes mellitus, hypertension, and CKD place a tremendous socioeconomic burden on people and health care infrastructure. Prompt assessment of vascular risk, aggressive management of risk factors using lifestyle modification, smoking cessation, and medications can help prevent end-organ damage. Further research is needed to determine methods for disease prevention in South Asians and improve access to health care particularly in the South Asian subcontinent.

Disclosures

S. Anand reports consultancy agreements with GLG group and Vera Therapeutics, honoraria from St. Rose Hospital (CME activity), and advisory or leadership roles for i3C (ISN) & ANIO, unpaid. S. Anand reports that Ascend Clinical Laboratory funded sample assays for S. Anand's COVID-19 seroepidemiology work. S. Anand is supported by National Institute for Diabetes and Digestive and Kidney Health grant #K23 DK101826. P. Deshpande's husband is an allergist and has been a consultant for Sanofi; P. Deshpande's husband has been involved in industry and federally funded research; P. Deshpande's husband received honoraria from the NY Allergy Society; and P. Deshpande's husband participated in an advisory board for Sanofi. M. Vijayan reports ownership interest in Amazon, American Express, AT&T, Cleveland Cliffs Steel, Plug Power, and Warner Bros. M. Vijayan's spouse reports employment with Hennes & Mauritz. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

All authors conceptualized the study; K. Deshpande, P. Deshpande, and M. Vijayan wrote the original draft; and S. Anand, P. Deshpande, and M. Vijayan reviewed and edited the manuscript.