Management of diabetic dyslipidemia in Indians: Expert consensus statement from the lipid association of India

An estimated 537 million adults aged 20–79 years worldwide have diabetes mellitus, almost all type 2 diabetes.1 In India, the burden of diabetes has been increasing steadily since 1990 but the pace accelerated after the year 2000, resulting in an increase in the prevalence of diabetes from 7.1% to 8.9% between 2009 and 2019. It is estimated that the number of individuals with diabetes in India will increase from 74 million in 2021 to more than 125 million in 2045,1 primarily driven by increasing rates of elevated body mass index (BMI) and the metabolic syndrome in association with visceral adiposity.2, 3, 4 It is estimated that more than half of patients with diabetes in India are undiagnosed.

The Indian Council of Medical Research-INdiaDIABetes (ICMR–INDIAB) study, the largest nationally representative study of diabetes, provided cumulative data from 15 states representing a total adult population of 363.7 million people (51% of India's adult population). The prevalence of diabetes varied nearly 3-fold across the country, with higher prevalence in urban areas and in states with higher per capita income.5

The objective of our recommendations is to reduce cardiovascular morbidity and mortality in patients of Indian origin with diabetes. The major cause of mortality among patients with type 2 diabetes is cardiovascular disease. Delays in diagnosis of type 2 diabetes and undertreatment of dyslipidemia contribute to high rates of cardiovascular disease among patients with type 2 diabetes. Although there are excellent recommendations from societies globally for the management of dyslipidemia in diabetes6, 7, 8, 9, 10, 11, 12, there are unique features of type 2 diabetes and cardiovascular risk in India that warrant development of specific guidelines for the Indian population. Among the estimated 74 million adult patients with diabetes in India (1 in 12), more than 90% are anticipated to have atherogenic dyslipidemia, and another 70 million with prediabetes may have dyslipidemia.13 This indicates that a sizable population of more than 140 million individuals with type 2 diabetes or prediabetes have atherogenic dyslipidemia that warrants early diagnosis and targeted treatment.

The Lipid Association of India (LAI) was founded in 2012 with the goal of promoting evidence-based management of lipid disorders and improving cardiovascular outcomes among Indians, resulting numerous published expert recommendations.14, 15, 16, 17, 18, 19 With the goal of developing an expert consensus statement on management of dyslipidemia in diabetes, the LAI conducted a series of 165 webinars across the country from May 2020 to July 2021, involving 155 experts in endocrinology and cardiology and an additional 2880 physicians.

There are notable differences in the epidemiological pattern of diabetes amongst Indian persons compared to White and other ethnic groups.

An epidemiological survey involving 4,600 newly diagnosed patients with diabetes across India found that nearly half (46.7%) of the subjects were under the age of 40 years and 40% were between the ages of 41–50 years.20 Despite nearly 90% of individuals being younger than 50 years old, hypertension, obesity, dyslipidemia and ischemic heart disease were observed in 23.3%, 26%, and 27% and 6% of patients respectively.20 In another multinational study, Asian Indians were found to have the highest prevalence of diabetes mellitus among 24,335 subjects from 11 countries, and the age of peak prevalence of diabetes mellitus occurred about 10 years earlier among Asian Indians in comparison with Chinese and Japanese individuals.21 According to the ICMR-INDIAB study, the typical age of onset of type 2 diabetes among Asian Indians occurs between 25 and 34 years of age, which is a decade or two earlier than for Western populations.22

Asian Indians have a much higher prevalence of metabolic abnormalities including glycemic impairment and diabetes compared to non-South Asian cohorts as demonstrated in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study.23 The prevalence of prediabetes and diabetes in US South Asians was 33% and 23%, respectively, both of which were much higher than the prevalence among Whites, Chinese Americans, Blacks, and Hispanics. The Chennai Urban Rural Epidemiology Study (CURES) study reported that 19.4% of those with normoglycemia converted to diabetes and 25.7% converted to prediabetes (overall conversion rate to dysglycemia of 45.1%) and 58.9% of those with prediabetes converted to diabetes during a median follow-up period of 9.1 years.4

Asian Indians also have a high prevalence of metabolic syndrome, estimated at 20–32%,24 commonly with BMI <30 kg/m2. Individuals with metabolic syndrome have a 30–40% probability of developing diabetes and/or atherosclerotic cardiovascular disease (ASCVD) within 20 years, depending on the number of components of metabolic syndrome present.25 There is a stepwise gradient in risk of mortality from coronary heart disease, CVD and all-causes from those who are disease free to metabolic syndrome, DM, and prior CVD; those with both DM and CVD having the highest risk, indicating this combination is a very high or extreme risk condition.26

Asian Indian persons have a distinct phenotype, influenced by specific clinical and biochemical characteristics that distinguish them from people of other major ethnic groups in relation to risk of type 2 diabetes. The South Asian or Indian phenotype is commonly described as elevated body fat mass, often with normal body weight and BMI, but with insulin resistance, dyslipidemia, and heightened risk of type 2 diabetes.27 Asian Indians have higher waist circumference, higher waist-to-hip ratio, more visceral fat, and lower insulin sensitivity compared to Euro-Americans for a given BMI.28

The subcutaneous layer of abdominal adipose tissue is thicker in South Asians and is associated with metabolic syndrome, independent of intraabdominal and total body fat.29 Among Indians with type 2 diabetes, additional physical characteristics include a higher waist-to-hip ratio, higher subscapular skinfold thickness, higher body fat percentage, higher abdominal and ectopic fat and a lower lean body mass compared to BMI-matched individuals without diabetes.

Abnormalities in maternal health and nutrition can have deleterious effects on offspring mediated in part through intrauterine and postnatal programming as well as epigenetic effects. In a New Delhi Birth Cohort of 1492 individuals, the presence of hyperglycemia at mean age of 29 years was associated with a low birthweight and poor growth during the first 2 years of life, but rapid growth and weight gain during childhood and adolescence.30 The high prevalence of maternal malnutrition and low birth weight compared to Western populations may in part be responsible for increased prevalence of diabetes.

One of the earliest studies demonstrating the predilection for early coronary artery disease (CAD) among Asian Indians was published more than 60 years ago by Shaper and Jones in their study of migrant Indians in Uganda.31 This finding was confirmed among migrant Indians in multiple regions of the world, demonstrating that migrant Indians have much higher prevalence of fatal and nonfatal CAD compared to the host populations of those countries, but also develop CAD at least a decade earlier.32,33 The same pattern is seen in India in comparison to the Western World.

The rise in prevalence of CAD among Asian Indian individuals has paralleled the increasing prevalence of diabetes. In the 1970s, the prevalence of CAD was only 1.0% in urban India,34 but over the subsequent two decades, the prevalence of CAD and cardiovascular risk factors increased exponentially. A meta-analysis of CAD prevalence in India during this time interval suggested that the prevalence of CAD increased nine-fold and two-fold in urban and rural populations, respectively.35 As of 2020 the prevalence of CAD in India was estimated at 11% among individuals without diabetes and 21.4% among those with diabetes.36

The prevalence of risk factors for coronary artery disease including dyslipidemia among South Asian individuals is very high. The prevalence of hypertension (p =0.003), total cholesterol ≥200 mg/dl (p <0.0001) and family history of diabetes (p <0.0001) was significantly higher in diabetic South Asian individuals compared to non-diabetic individuals. Also 45% of diabetic individuals without known history of CAD had positive exercise tolerance test. Two-thirds of South Asian individuals with diabetes and about half of those without diabetes had subclinical CAD as determined by carotid intima-media thickness (CIMT).37

Data from the Chronic complications in newly diagnosed patients with Type 2 Diabetes Mellitus in India (CINDI) 2 trial demonstrated that ASCVD risk factors are highly prevalent in young patients (≤40 years) with type 2 diabetes, with almost 25% being smokers, 27.6% with hypertension, 62.4% with dyslipidemia, and 83.2% overweight or obese with BMI >23 kg/m2.38

Asian Indian persons with type 2 diabetes have a 3–4 fold higher risk of cardiovascular disease compared to Whites, even after adjusting for sex, age, smoking status, hypertension, and obesity.39 This may be attributable to the atherogenic milieu in Asian Indian individuals that is associated with higher prevalence of visceral adiposity, insulin resistance, hypertriglyceridemia, and low HDL-C.20

The prevalence of dyslipidemia in patients with diabetes is very high and was 85.5% among males and 97.8% among females at baseline in one Indian study.40 In another study, subjects belonging to low socio-economic strata and residing in the urban slums also showed substantial prevalence of hypercholesterolemia (27%) and hypertriglyceridemia (12–17%).41 In a population-based study, 47.3% of those without diabetes with a mean BMI of 25.83 ± 4.62 (obese as per South-Asian cut-off) had dyslipidemia, 20.6% had hypercholesterolemia, 19.6% had hypertriglyceridemia, and 17.5% had low HDL-C levels. The prevalence of increased LDL-C and non-HDL-C levels was similar in those with and without diabetes: 23.0% vs 25.9% and 23.5% vs 22.6%, respectively.42

The prevalence of atherogenic small, dense LDL (sdLDL- 18.0 to 20.5 nm in size on NMR spectroscopy) was significantly higher in Asian Indians compared with White in the USA (44% vs 21%; p <0.05).43

Among Asian Indians the risk of CAD is three to four times higher than Americans, six times higher than Chinese and 20 times higher than Japanese.44 In addition, in the US and Europe rates of cardiovascular mortality among adults aged between 25 and 64 years have decreased by about 70% since 1968, but early onset heart disease still accounted for almost 20% of all deaths among this age group in 2017.45

The opposite trend has occurred in India, with increasing rates of coronary artery disease during the last three decades. The earlier onset of diabetes and prediabetes in Indians, as well as the high prevalence of atherogenic dyslipidemia and subclinical atherosclerosis at diagnosis, along with the greater prevalence of ASCVD risk factors at a younger age, warrants aggressive interventions aimed at reducing ASCVD risk factors and treating dyslipidemia to achieve LDL-C and non-HDL-C goals established by expert consensus from the Lipid Association of India.14, 15, 16, 17, 18, 19

Although LDL-C lowering is an important strategy for ASCVD prevention in type 2 diabetes, the key features of dyslipidemia in type 2 diabetes consist of an atherogenic triad of hypertriglyceridemia, low HDL-C, and small dense LDL particles without significant elevation in the LDL-C concentration, but elevated non-HDL-C. These features may be accentuated in Indian persons with diabetes as a consequence of the high background prevalence of these abnormalities in the general population. Abnormalities in lipoprotein function may also occur in response to non-enzymatic glycation of apolipoproteins, enzymes, and cofactors involved in lipoprotein metabolism. ASCVD risk in diabetes is proportional to the plasma non-HDL-C concentration, which is more predictive of risk than LDL-C. Non-HDL-C is calculated by subtracting HDL-C from total cholesterol and represents the sum of all circulating atherogenic lipoproteins including LDL, remnant lipoproteins, and lipoprotein(a). Treatment of dyslipidemia in type 2 diabetes requires attention to all aspects of atherogenic dyslipidemia in addition to the focus on LDL-C lowering.

Diabetes independently increases the risk of CV events in patients with prior CV disease, at any level of achieved LDL-C. The Heart Protection Study subgroup analysis reported that patients with diabetes achieved greater relative CHD risk reduction as compared to those without diabetes in response to treatment with simvastatin 40 mg per day vs placebo (placebo-corrected 33% vs 24%).46 The same findings were reported in the diabetes subgroup of the Scandinavian Simvastatin Survival Study (4S), in which simvastatin reduced the risk of major coronary events by 42% in patients with diabetes and 38% in patients without diabetes.47 In the Treating to New Targets (TNT) study, among patients with clinically evident CHD and diabetes, intensive therapy with atorvastatin 80 mg (mean LDL-C levels 77 mg/dl) significantly reduced the rate of major cardiovascular events by 25% compared with atorvastatin 10 mg (mean LDL-C levels 98.6 mg/dl) suggesting that intensive LDL-C lowering further reduces adverse events.48

Among the 4933 (27%) patients with diabetes in IMPROVE-IT trial, treatment with simvastatin and ezetimibe reduced the 7-year primary end point absolute event rate by 5.5% (HR 0.85; 95% CI 0.78–0.94) vs 0.7% absolute difference in patients without diabetes (HR 0.98; 95% CI 0.91–1.04; p =0.02) compared with simvastatin alone, indicating a number needed to treat (NNT) of only 18 in those with diabetes. The largest relative reductions in patients with diabetes were in myocardial infarction (24%) and ischemic stroke (39%).49 The above data indicates that high intensity statin therapy in combination with ezetimibe results in further relative risk reduction compared to statin monotherapy in patients with diabetes and established ASCVD.

The atherogenic triad of elevated triglycerides, low HDL-C and normal or mildly raised LDL-C contributes to residual risk of ASCVD events in patients with type 2 diabetes even after achieving LDL-C goals. The residual ASCVD risk is proportional to the plasma non-HDL-C concentration, which is calculated by subtracting HDL-C from total cholesterol. It represents sum of all circulating atherogenic cholesterol including LDL-C, remnant lipoproteins, and lipoprotein(a).

The lowest ASCVD risk was observed in patients with on-treatment triglycerides <150 mg/dl and LDL-C <70 mg/dl (HR 0.72, 95% CI 0.54–0.94; p =0.017) or low on-treatment triglycerides, LDL-C, and C-reactive protein (<2 mg/l) (HR 0.59, 95% CI 0.41–0.83; p =0.002) compared with higher levels of each variable in adjusted analysis.50 In a meta-analysis of data obtained from 62,154 statin-treated patients enrolled in 8 trials, increased non-HDL-C levels were associated with an increased risk of future CV events even if LDL-C levels were at goal.51

The cornerstone of treatment for insulin resistance and diabetes-related atherogenic dyslipidemia is lifestyle modification in combination with statin therapy, supplemented with other therapies if indicated in combination with glycemic control.

Despite achieving a median LDL-C level of 30 mg/dl in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, 14.4% of patients with diabetes still had CV events,52 which highlights the importance of other ASCVD risk factors as contributors to residual risk. SGLT2i have been documented in multiple studies to reduce cardiovascular events in patients with type 2 diabetes, primarily due to a reduction in heart failure events, which is believed to be a class effect. Multiple mechanisms have been hypothesized to explain the cardiovascular benefits of SGLT2i, including decreases in serum levels of total cholesterol, triglycerides and small density LDL-C particles,53,54 but these changes are insufficient to account for the cardiovascular risk reduction. Decreased blood pressure, body weight, and reno-protective effects are also likely to be relevant, as well as possible effects in the arterial wall.

The LAI recommends consideration of treatment with SGLT2i as adjunctive therapy in patients with type 2 diabetes for glucose lowering and reduction of cardiovascular events.

In a recent meta-analysis, long-acting GLP-1 receptor agonists did not reduce non-fatal MI and heart failure but improved CV mortality and adverse CV events.55 LDL-C, total cholesterol, and triglycerides were modestly reduced by GLP-1 receptor agonists, but HDL-C was not significantly improved. In addition to glucose lowering, GLP-1 receptor agonists are also reno-protective, produce substantial weight loss, and may modestly lower blood pressure. More studies are needed to determine the mechanisms underlying cardiovascular benefits of these agents.56 Dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists, such as tirzepatide that was recently FDA-approved for treatment of type 2 diabetes in the United States, may facilitate greater weight loss compared to GLP-1 receptor agonists, but the effects on cardiovascular outcomes are unknown and this drug class is unavailable in India.

The LAI recommends consideration of treatment with GLP-1 agonists as adjunctive therapy in patients with type 2 diabetes for glucose lowering and reduction of ASCVD events. Consistent with other guidelines6 SGLT2 inhibitors and GLP-1 agonists can be used irrespective of metformin use or HbA1c level or target.

The landmark ODYSSEY OUTCOMES57 and FOURIER52 trials documented the cardiovascular benefits of LDL-C lowering to very low levels (<30 mg/dl) with PCSK9 inhibitors added to background statin therapy. A meta-analysis of data from 38 trials suggested that PCSK9 inhibitors do not affect glucose metabolism or diabetes risk, but the LDL-C lowering efficacy was similar among patients with and without diabetes.58 In the FOURIER trial of persons with pre-existing ASCVD, in which 40% of participants had diabetes, treatment with evolocumab 140 mg SQ biweekly lowered LDL-C to a median of 30 mg/dl (0.8 mmol/l), resulting in a 15% relative reduction in the risk of composite primary endpoint at about 2 years.52 The NNT was lower for patients with diabetes as a consequence of greater baseline risk and absolute reductions in cardiovascular events compared to patients without diabetes.

In patients with diabetes and dyslipidemia, PCSK9 inhibitors may be a useful option for management of refractory hypercholesterolemia, especially when statin intolerance prevents high intensity statin therapy. Persons with both diabetes and ASCVD have higher absolute risk of subsequent CVD events than those with ASCVD alone and can benefit from such therapies.

The results of population-based studies showed a 62% lower risk of CVD events when all three of these factors (dyslipidemia, HbA1c, and blood pressure) were at goal compared to none at goal.59 Yet, fewer than 20% of US adults are at recommended goals for these risk factors.60 Data are needed in the Indian population to examine these issues of composite risk factor control and management.

The 2016 LAI consensus statement on treatment of hyperlipidemia addressed common issues related to lipid management in routine clinical practice. Patients with diabetes were categorized as either high risk or very high-risk depending upon the presence or absence of target organ damage and major risk factors for ASCVD such as smoking, hypertension and/or dyslipidemia. The recommended LDL-C goals were <50 mg/dl in very high risk individuals and <70 mg/dl in high risk individuals.14 Subsequent 2016 European Society of cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for the management of dyslipidaemia recommended LDL-C goals <70 mg/dl and <100 mg/dl in very high risk and high risk patients, respectively.61 In contrast, the AHA/ACC 2018 lipid management guidelines recommended moderate-intensity statin therapy in patients 40 to 75 years of age with diabetes mellitus and LDL-C ≥70 mg/dl (≥1.8 mmol/l), regardless of estimated 10-year ASCVD risk. In patients with diabetes mellitus at higher risk, especially those with multiple risk factors or ≥20% 10-year risk of ASCVD, it is reasonable to use a high-intensity statins to reduce the LDL-C level by ≥50%.7

The 2019 revised ESC/EAS guidelines8,9 categorized patients with diabetes as moderate, high or very high risk on the basis of age, duration of diabetes, target organ damage and ASCVD risk factors. In very high-risk patients, LDL-C goals <55 mg/dl were recommended, which is close to the goals recommended by the LAI in 2016.14 Similarly, in the ESC/EASD guidelines, patients with diabetes and ASCVD or target organ damage (retinopathy, LVH, proteinuria, eGFR <30 ml/min) or three or more major risk factors (age, smoking, hypertension, obesity, dyslipidemia) are designated as having very high risk with a recommended LDL-C goal <55 mg/dl or at least 50% reduction.10

The American Diabetes Association (ADA) (2022) recommends primary prevention with statin therapy only in patients with diabetes at an age of 40 years or older. For those younger than 40 years, statins are recommended if certain diabetes specific risk enhancing factors are present (long duration of diabetes [≥10 years for type 2 or ≥20 years for type 1], albuminuria ≥30 mcg of albumin/mg creatinine, eGFR <60 mL/min/1.73 m2, retinopathy, neuropathy, ABI <0.9) together with shared decision making (Fig. 1).6

The guidelines from the American Association of Clinical Endocrinology recommended that individuals with type 2 diabetes should be divided into high, very high, or extreme risk for ASCVD. Extreme-risk individuals, including patients with diabetes and ASCVD, should be treated with statins to achieve LDL-C <55 mg/dl, non-HDL-C <80 mg/dl and apo B <70 mg/dl. Individuals classified as very high risk included patients with diabetes or stage 3 or 4 CKD with 1 or more risk factors, and were recommended for treatment with statins to reduce LDL-C <70 mg/dl, non-HDL-C <100 mg/dl and apo B <80 mg/dl.12

As a consequence of unique features of dyslipidemia and ASCVD risk in Asian Indian patients with type 2 diabetes, there are notable gaps in various international guidelines for treatment of dyslipidemia in diabetes that limit their utility for dyslipidemia management in India. As a consequence, the LAI proposed updated risk stratification recommendations for determining LDL-C treatment goals based on major ASCVD risk factors of age, family history of premature ASCVD, smoking, hypertension and low HDL-C. The LAI has also considered other non-conventional ASCVD risk factors that include coronary artery calcium score, CIMT, Lp(a), fasting glucose, waist circumference and high sensitivity C-reactive protein (hsCRP). LDL-C is the primary treatment target and non-HDL-C is a co-primary target. As shown in the figure, patients are categorized as low risk, moderate risk, high risk, very high risk and extreme risk, which are associated with increasingly aggressive LDL-C and non-HDL-C goals (Fig. 2).14, 15, 16, 17,62

Patients without ASCVD and no target organ damage or ≤1 risk factor have a high risk of future adverse CV events and have a recommended LDL-C goal <70 mg/dl, whereas patients without ASCVD and target organ damage or ≥2 risk factors are at very high risk of future adverse CV events and have a recommended LDL-C goal <50 mg/dl. Patients with diabetes and ASCVD with 0–1 other major ASCVD factors and no evidence of target organ damage are classified as extreme risk category A and those with ≥2 major ASCVD risk factors or with target organ damage are classified as Extreme risk, category B, with a recommended LDL-C goal <30 mg/dl.16,17

1.

All guidelines universally recommend intensive statin therapy in patients with ASCVD and adding non-statin therapy if LDL-C levels are not at goal. However, there remains significant clinical inertia in therapy intensification to achieve LDL-C targets. Long-term studies reflect the gaps in intensification of the statin therapy. GOULD (Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management) was a prospective observational registry study involving multiple US centers, enrolling approximately 5000 patients. It demonstrated that of patients with ASCVD and suboptimal LDL-C levels at baseline, only 17.1% had lipid-lowering therapy intensification by 2 years, and two-thirds patients still had an LDL-C level ≥70 mg/dl. Thus, intensive efforts are needed to achieve optimal LDL-C management in patients with ASCVD.63 In a meta-analysis of 8 statin trials lowering LDL-C from 75–100 mg/dl to below 50 mg/dl resulted in a 19% reduction in CV events.64

2.

In the IMPROVE- IT trial, 6% of patients who achieved LDL-C <30 mg/dl had a 29% lower risk of CV events compared to those whose LDL-C remained ≥100 mg/dl.65 Results from the OSLER studies and ODYSSEY long-term phase 3 trials showed a 50% reduction in cardiac events in association with a mean achieved LDL-C level of 50 mg/dl.66,67

3.

Low levels of LDL-C (median of 30 mg/dl) achieved with evolocumab treatment added to a high intensity statin ± ezetimibe improved primary and secondary endpoints in 27,564 patients with ASCVD by 15% and 20%, respectively.52 In the ODYSSEY OUTCOMES trial, 18,924 patients treated with alirocumab and aiming at an LDL-C target of 25 to 50 mg/dl, achieved an LDL-C at 48 weeks of 53 mg/dl from 103 mg/dl at baseline, resulting in significant reduction of 15% in primary end point.57 The lower LDL-C is better has been shown in the CTT meta-analysis of statins, among patients whose LDL-C in the control arm was 65.7 mg/dl (1.7 mmol/l), the risk ratio (RR) for major vascular events was 0.78 (95% CI, 0.65–0.94) per 38.7-mg/dl (1 mmol/l) reduction in LDL-C. In meta-analysis of non-statin trials there is a consistent 22% relative risk reduction in major vascular events per 1 mmol further reduction in LDL-C in patient populations starting as low as a median of 1.6 mmol/l (63 mg/dl) and achieving levels as low as a median of 0.5 mmol/l (21 mg/dl), with no adverse effects.68 These data suggested that further lowering of LDL-C to as low as approximately 20 mg/dl, would further reduce CV risk.

4.

In a post hoc analysis of data from the FOURIER trial, among 2036 enrolled patients with median baseline LDL-C of 66 mg/dl, treatment with resulted in achieved median LDL-C levels of 21 mg/dl. This resulted in a 30% RRR in CV events.69

5.

Lowering LDL-C to <10 mg/dl from baseline LDL-C levels >100 mg/dl resulted in significant 31% RRR in the primary end point and 41% RRR in secondary end points without any significant adverse effects compared to placebo.70

6.

In a post hoc analysis of data from the ODYSSEY OUTCOMES trial, among 730 patients (7.7%) who achieved ultra-low LDL-C of <15 mg/dl compared to propensity matched 2152 patients with placebo, the risk of CV events was reduced 29%.71

7.

In another post hoc analysis of data from the ODYSSEY OUTCOMES trial, the lowest all-cause mortality was seen at an achieved LDL-C of 31 mg/dl at 4 months.72

The above data show that in patients with high risk stable ASCVD and in high-risk post-ACS patients, lowering LDL-C to below 30 mg/dl results in further reduction in CV events.

Lifestyle modification is the cornerstone of ASCVD prevention and includes attention to heart healthy dietary habits, regular physical activity, and avoiding alcohol and tobacco usage. Dietary patterns with higher fat and lower carbohydrate content, high protein content, and intermittent fasting or time-restricted eating are all associated with modest weight loss and triglyceride lowering, but dietary patterns that include whole grains and other complex carbohydrates in combination with high fiber intake may also produce modest weight loss and triglyceride lowering. Simple sugars increase triglycerides more than complex carbohydrates, particularly high fructose corn syrup. Dietary fibers attenuate the triglyceride increasing effect of carbohydrates. Sugar-sweetened beverages (soft drinks, fruit drinks, sweet tea, etc.) should be avoided. A combination of oils rich in PUFA and MUFA should be used, avoiding the use of partially hydrogenated oils (rich in trans fats), palm oil, coconut oil, and animal fats. The smoke point of oils should also be taken into consideration. Mustard and canola oils appear to be the most suitable oils for routine use in Indian cooking, although there is controversy regarding the consumption of mustard oil containing high levels of erucic acid.73

Cold-pressed oils may be better than refined oils as they retain higher levels of antioxidants and micronutrients that are degraded by high temperatures and chemicals. Overall, an Indo-Mediterranean diet, that focuses on consumption of fruits, vegetables, whole grains, nuts, fatty fish, mustard seeds, flax seeds and mustard oil appears to be the most suited.74,75

The consumption of tobacco products in any form, including e-cigarettes, should be completely avoided. Alcohol impairs chylomicron hydrolysis and also increases triglyceride production and secretion of triglyceride-rich VLDL and should be avoided. However, for patients who consume alcohol, the amount should not exceed 2 drinks/day for men and 1 drink/day for women.14 Patients with severe hypertriglyceridemia ideally should not consume alcohol.

Aerobic physical activity and endurance training boost fatty acid oxidative clearance and enhance triglyceride hydrolysis and fatty acid oxidation in skeletal muscle. Regular aerobic exercise decreases triglycerides by about 11% and resistance exercise decreases triglycerides by about 6%. It is recommended that adults should engage in at least 150 min per week of total moderate-intensity or 75 min per week of vigorous-intensity aerobic physical activity. An ideal body weight should be maintained, if possible, but an achievable goal for many patients is modest weight loss. A BMI >23 kg/m2 is considered overweight and ≥25 kg/m2 is obese according to Asian Indian-specific guidelines.76

1.

Patients with diabetes and no ASCVD, no target organ damage and having ≤1 risk factor are designated as high risk and LDL-C goal <70 mg/dl is recommended.

2.

Patients with diabetes and no ASCVD, with target organ damage or having ≥2 risk factors are designated as very high risk and LDL-C goal <50 mg/dl is recommended.

3.

Patients with established ASCVD do not have similar risk of future adverse CV events. Selected ASCVD patients have higher risk because of the presence of disease in other vascular territories (e.g., prior stroke or peripheral artery disease) and/or the presence of other risk factors. The number, type and severity of risk factors determine the risk of subsequent adverse CV events. Based on the presence of risk factors and/or target organ damage, LAI proposed Extreme risk category requiring aggressive LDL-C management. LDL-C <50 mg/dl is recommended for most extreme risk patients (Extreme risk category A), with an optional target of ≤30 mg/dl. For those who continue to suffer events despite achieving an LDL-C <50 mg/dl or having one or more features of very high risk group with CAD (Extreme risk category B), LDL-C goal of ≤30 mg/dl is recommended (Fig. 3).

Patients with diabetes frequently have high levels of triglyceride-rich atherogenic apo B containing lipoproteins such as remnants of very low density lipoproteins and chylomicrons. Measurements of LDL-C may not accurately reflect the full burden of atherogenic lipoproteins, which may mislead providers to believe that an LDL-C concentration at goal is indicative of adequate lipid-lowering treatment. In this setting, measurement of non-HDL-C is especially important to capture all atherogenic apo B-containing lipoproteins. Monitoring non-HDL-C is a simple, readily accessible tool to guide lipid-lowering treatment decisions since it does not require a fasting blood sample and includes all atherogenic lipoproteins. Meta-analyses of data obtained from 62,154 statin-treated patients enrolled in 8 clinical trials published between 1994 and 2008 highlighted the importance of elevated non-HDL-C as among statin-treated patients with controlled LDL-C as a risk factor for ASCVD risk.51

Statins remain the first line agent for lipid lowering, regardless of whether LDL-C or non-HDL-C is the therapeutic target. Increasing the dosage of statin or switching to a more potent statin and intensifying lifestyle measures should be the first step to achieve further non-HDL-C lowering, even when the LDL-C goal has been achieved. The addition of ezetimibe can be considered as the next step when additional non-HDL-C lowering is needed. Icosapent ethyl, now available in India, is a useful adjunct to lower triglycerides at doses of 4 g/day. The purified prescription form used in the REDUCE-IT study also reduced ASCVD risk 25% beyond statin therapy in patients with LDL-C 41-100 mg/dl and hypertriglyceridemia >150 mg/dl and established ASCVD or diabetes and multiple risk factors.77

It is not known, however, whether generic forms of icosapent ethyl will have similar benefit.

1.

Non-HDL-C is a co-primary target, as important as LDL-C.

2.

In all individuals, non-HDL-C goals are 30 mg/dl above recommended LDL-C levels.

1.

For routine screening, a fasting lipid profile is not mandatory but a fasting profile should be considered at second visit (if not considered earlier) in Indian patients before embarking on treatment.

2.

In patients with elevated triglyceride levels, rule out secondary causes of hypertriglyceridemia.

3.

Maintain triglycerides <150 mg/dl, but preferably <100 mg/dl through interventions that include dietary modification, regular physical; activity, weight loss, and pharmacotherapy.

Patients with hypertriglyceridemia should be evaluated for ASCVD risk. In the current era, several options are available to reduce plasma triglycerides. These include lifestyle changes, fish oil products and fibrates. Niacin lowers plasma triglyceride levels, but there is controversy regarding effects on ASCVD risk. Niacin can also induce insulin resistance and aggravate hyperglycemia. Angiopoietin-like protein 3 and apolipoprotein CIII are newer targets for triglyceride lowering.

A recent meta-analysis found an increased risk for incident CV events (OR 1.06, CI 1.02–1.09) in patients with diabetes and hypertriglyceridemia.78 Progression of Early Subclinical Atherosclerosis (PESA) was an observational, longitudinal, and prospective cohort study of 3754 middle-aged individuals with low to moderate cardiovascular risk which suggested that even when LDL-C levels are normal, individuals with hypertriglyceridemia had increased risk of subclinical atherosclerosis (OR 1.85; 95% CI 1.08–3.18; p =0.008) and vascular inflammation (OR 2.09; 95% CI 1.29–3.40; p =0.003).79 Thus, an assessment of atherogenic lipoproteins other than LDL-C is needed in light of the high prevalence elevated triglycerides, non-HDL-C and Lp(a) in Indian patients. A meta-analysis of data from 5 studies demonstrated that PPAR agonist therapy added in combination with ongoing statin therapy significantly reduced CV events by 35% in 4726 patients with triglycerides >204 mg/dl and HDL-C <34 mg/dl.80 A secondary analysis of the ACCORDION trial (long-term follow-up of the ACCORD trial) suggested that fibrate treatment in the initial period had a legacy benefit of improved survival during follow-up.81 The REDUCE-IT trial demonstrated the additive cardiovascular benefit of treatment with icosapent ethyl in patients with triglycerides > 150 mg/dl,77

Traditionally blood samples for lipid profile testing are obtained after an overnight fast, but the requirement for fasting can be a deterrent to testing. Non-fasting lipid profile measurements have the advantage of simplifying blood sampling for patients and physicians, thereby facilitating the diagnosis of dyslipidemia and subsequent monitoring. Among patients with normal triglyceride levels, a clinically insignificant rise in postprandial triglyceride concentrations occurs usually between 3 and 4 h after eating normal meals, by an average of 18 to 36 mg/dl (0.2–0.4 mmol/l).82 In contrast, patients with marked fasting hypertriglyceridemia can experience a substantial increase in the plasma triglyceride concentration, particularly after consuming a large amount of dietary fat. The results of previous studies indicated that a 2-h postprandial triglyceride measurement may be a better predictor of ASCVD risk than a fasting triglyceride measurement.83,84 When possible, fasting lab testing allows accurate measurements of fasting glucose and triglyceride levels in patients with diabetes, but non-fasting lipid profile testing is preferable to no testing.

Apo B is another important marker of ASCVD risk that reflects all atherogenic lipoproteins in plasma.16 An apo B concentration ≥110 mg/dl of apo B may roughly correspond to an LDL-C concentration ≥130 mg/dl, but the ratio between apo B and LDL-C varies depending on the size and density of LDL particles as well as the proportion of apo B carried in remnant lipoproteins and lipoprotein(a). When testing is available, measurements of serum or plasma apo B may enhance ASCVD risk prediction in patients with diabetes, metabolic syndrome, obesity, hypertriglyceridemia or very low LDL-C levels. Elevated Apo B levels may identify individuals who have high residual cholesterol risk and may warrant more intensive statin therapy and use of non-statin drugs.

1.

Apo B measurement should be included in standard lipid panel, initial and follow up, when possible. Where apo B measurement is not possible, non-HDL-C should be assessed and utilized as a co-primary treatment target.

2.

Apo B measurement is recommended in high-risk and extreme risk group subjects, after LDL-C and non-HDL-C goals have been achieved.

3.

Apo B goals in diabetes are <65 or <50 mg/dl for extreme risk group category A and B, respectively (Fig. 5).

There are limited data to guide decisions on management of Lp(a) elevation in diabetes, but the LAI offers the following considerations.16

1.

The LAI recommends estimation of Lp(a) levels by isoform insensitive assay for risk stratification in all patients with diabetes regardless of presence of ASCVD.

2.

A level ≥20 mg/dl indicates increased ASCVD risk in Indians, Lp(a) ≥50 mg/dl (125 nmol/L) is a high-risk feature. Lipoprotein (a) 20–49 mg/dl is a moderate risk nonconventional risk factor.

3.

The recommendations for measuring Lp(a) are especially important in individuals with:

a.

Family history of premature ASCVD.

b.

Personal history of premature ASCVD.

c.

High LDL-C levels despite on aggressive lipid lowering therapy (<50% reduction in LDL-C, in spite of high intensity statin therapy).

d.

Recurrent CVD events despite high-intensity statin treatment.

e.

Familial hypercholesterolemia.

4.

Observational studies have suggested that Lp(a) levels are inversely related to the diabetes risk. However, more data are needed. There are no data to guide management of diabetic individuals without ASCVD but elevated Lp(a) levels. Aggressive risk factor management along with LDL-C goal of <50 mg/dl is recommended in such individuals.

5.

None of the lipid lowering therapies are approved for isolated Lp(a) elevation. Statins have no effect on Lp(a) levels. PCSK9 inhibitor monoclonal antibodies decrease Lp(a) levels by 25–30%. Presently, in diabetic individuals with increased Lp(a) levels, control of risk factors including adequate diabetes management, heart healthy lifestyle and high intensity statins +/- ezetimibe are recommended. PCSK9 inhibitors may be considered in individuals with very high Lp(a) levels and extreme risk category B after detailed discussion with patient regarding cost and risk-benefit (shared decision).

On the basis of the above data and discussion, the LAI recommendations for management of diabetic dyslipidemia are presented in Fig. 6.

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