Statins and New guidelines – Are they relevant to Indian Population

The American College of Cardiology (ACC) and the American Heart association (AHA) established new guidelines for the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Atherosclerotic Cardiovascular Disease (ASCVD) includes coronary heart disease (CHD), stroke, and peripheral arterial disease. These recommendations are based on careful consideration of higher quality randomized controlled trials (RCTs), and systematic reviews and meta-analyses of RCTs.  

Important Points

The expert panel acknowledged the absence of clinical trial data that support treatment to specific low-density lipoprotein cholesterol (LDL-C) and non-HDL-C goals. The guideline identifies four major groups of patients for whom cholesterol-lowering HMG-CoA reductase inhibitors, or statins, have the greatest chance of preventing stroke and heart attacks. The guideline also emphasizes the importance of adopting a heart-healthy lifestyle to prevent and control high blood cholesterol. Four major populations identified by these guidelines that benefit from statins are as follows:

1.       Adults with clinical ASCVD:  high-intensity statin therapy (Table1) should be used to achieve at least a 50% reduction in LDL - C unless otherwise contraindicated. For those age > 75 yrs., moderate dose statin may be used.

2.        Adults with primary elevations of LDL–C ≥190 mg/dL: high-intensity statin therapy should be used to achieve at least a 50% reduction in LDL -C unless otherwise contraindicated.

3.      Adults 40 to 75 years of age with diabetes & without clinical ASCVD with LDL-C 70-189 mg/dL: A moderate-intensity statin- that lowers LDL-C 30% to 49%. High-intensity statin is a reasonable choice if the patient also has a 10-year risk of atherosclerotic cardiovascular disease exceeding 7.5%. In adults with diabetes mellitus, who are <40 or >75 years of age, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects, for drug-drug interactions, and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy.

4.      Adults without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL-C 70-189 mg/dL and an estimated 10-year ASCVD risk of 7.5% or higher: a moderate- or high-intensity statin therapy should be used.

High-Intensity Statin Therapy	Moderate-Intensity Statin Therapy	Low-Intensity Statin Therapy
Daily dose lowers LDl-C on average, by approximately≥50%	Daily dose lowers LDl-C on average, by approximately 30% to < 50%	Daily dose lowers LDl-C on average, by < 30%
Atorvastatin(40†)-80mg Rosuvastatin 20 (40) mg	Atorvastatin 10(20)mg Rosuvastatin (5) 10 mg Simvastatin 20-40 mg‡ Pravastatin 40(80) mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2-4 mg	Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 40 mg bid Pitavastatin 1 mg

Table 1: High, Moderate and Low intensity statin therapy (adapted from ACC/AHA Guidelines)

•       Treating to LDL -C targets and lower the better is no longer recommended

•       With few exceptions, use of lipid-modifying drugs other than statins is discouraged. Only statins have data of CV protection. Non-statin lipid lowering drugs have no evidence of CV protection

•        The guideline offers a new approach to risk assessment- Ten-year ASCVD risk — which includes both coronary events & stroke — is determined using online calculators that can be accessed through the AHA and ACC websites. It contain modifiable and non modifiable risk factors like sex, age, race, total cholesterol, HDL- cholesterol, systolic blood pressure and its treatment, diabetes and smoking. 

•       Adherence to a healthy diet and lifestyle is the keystone of cardiovascular health and it is recommended for all patients, regardless of cholesterol-lowering drug therapy.

•       No evidence of statin benefit if NYHA Class II-IV heart failure, or if on haemodialysis.

•       Individuals Not in a Statin Benefit Group: No recommendations are made to inform treatment decisions in selected individuals who are not included in the four statin benefit groups. In these individuals whose 10-year risk is <7.5% or when the decision is unclear, other factors including family history of premature ASCVD, LDL-C >160 mg/dl, high-sensitivity C-reactive protein ≥2 mg/dl, coronary calcium score ≥300 Au or ≥75th percentile for age, sex, ethnicity, and ankle-brachial index <0.9, or elevated lifetime risk of ASCVD may be used to enhance the treatment decision making. 

•       Potential for ASCVD risk reduction benefit, potential for adverse effects, drug-drug interactions, and patient preferences should be discussed.

Limitations of Guidelines

The new guideline has caused much controversy by changing the fundamentals of cholesterol treatment from an approach that treats to specific LDL-C and non-HDL-C targets to one that treats specific patient populations regardless of their lipid profile. Guideline focus on patient groups who are well represented in RCTs. So the recommendations are designed to inform clinical judgment, not to replace it. Clinician judgment is important for several patient groups for whom the RCT evidence is insufficient like in younger adults (<40 years of age) who have a low estimated 10-year ASCVD risk, but a high lifetime ASCVD risk and those with serious co morbidities and increased ASCVD risk e.g., individuals with HIV, rheumatologic or inflammatory diseases, or who have undergone a solid organ transplant.

Indian perspective

Relevance to India

•          Under-representation of Indian Population: Guidelines for dyslipidemia management and treatment have largely been derived from clinical trials comprised of mostly Non Hispanic World populations, which have often under-represented Asian population.

•          Need for Non Statin Drugs:  Atherogenic triad comprises of high triglycerides, Low HDL and increased small dense LDL particles is common in Indian and associated with high CVD risk, so statins alone may not be enough.

•           Unfortunate Young Indians:  Indians get DM and CVD at an early age, around ten years earlier then the western population, probably because of high prevalence of Metabolic Syndrome. The new guideline recommendations for using statins in primary prevention are limited to patients 40-75 years old unless their LDL-C is ≥ 190 mg/dL. However, the process of atherosclerosis starts at very young age and therefore failure to start lipid-lowering medications in the younger dyslipidemic population is a failure of primary prevention. Despite the absence of RCTs that address statin therapy in the young age group, a moderate or high dose statin may be considered in certain high-risk individuals.

•          Underutilization of Statins: New ASCVD risk calculator underestimate the cardiovascular risk, hence sratins may remain underutilized.

•          High Vs moderate Dose of Statins: Possibly, Asian population respond well with moderate dose of statins to decrease LDL-C level <50% as compare to high dose of statins in western population possibly because of low BMI. Therefore lesser side effects and lesser chances of getting new onset DM

•          Statin Induced Risk of Diabetes mellitus:  Indians are having high incidence and prevalence of Diabetes Mellitus and IGT and statins are increasingly being linked for diabetes.

Atherogenic Dyslipidemia

A combination of hypertriglyceridemia, low levels of HDL-cholesterol and high levels of small dense low density lipoprotein, termed as “atherogenic dyslipidemia” is particularly seen in Asian Indians. Diet( increased carbohydrate food intake, increased dairy products consumption and low Omega 3 polyunsaturated fatty acids), lack of Physical activity and abnormal body composition like large adipocytes and it’s abnormal regional distribution are responsible for development of Atherogenic dyslipidemia. Diabetic patients are known to have high levels of serum triglyceride (TG) and low levels of high-density lipoproteins (HDL).                                 

                                

Role of Non Statins

The new guideline makes it clear that statins are a must, but it does not strongly recommend the use of non-statin lipid lowering medications because of the lack of definitive data that proves its efficacy. As previously stated that the combination of a lower dose statin and another lipid-lowering medication is more effective at lowering LDL-C than a high dose statin alone.² Non-statin lipid lowering medications are very effective at lowering LDL-C and most experts would add one or more when the LDL-C level remains elevated or when patients have recurrent ASCVD despite high dose statin therapy. 

Fibrates are more effective than statins in reducing serum triglyceride levels and increasing HDL-cholesterol levels.³Atherogenic dyslipidemia in Asian Indians may be well managed by the use of fibrates, although the combination may have more adverse effects BUT recent evidence indicates that combination is well tolerated by Indian population.^4,5

Niacin is more effective than either statins or fibrates in increasing HDL- cholesterol levels (~35%), however it may not be tolerated? And has failed in clinical trials ( AIM HIGH and HPS2 THRIVE )

When to add Fibrates

In a major systematic review and meta-analysis⁶ including 45058 participants, fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia. According to this review fibrates therapy produced a 10% RR reduction (95% CI 0—18) for major cardiovascular events (p=0·048) and a 13% RR reduction (95% CI7—19) for coronary events (p<0·0001), but had no benefit on stroke (−3%, −16 to 9; p=0·69). No effect of fibrate therapy was noted on the risk of all-cause mortality (0%, −8 to 7; p=0·92), cardiovascular mortality (3%, −7 to 12; p=0·59), sudden death (11%, −6 to 26; p=0·19), or non-vascular mortality (−10%, −21 to 0·5; p=0·063). Fibrates reduced the risk of albuminuria progression by 14% (2—25; p=0·028). Improvement in microvascular complications like retinopathy was also observed. Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1·21, 0·91—1·61; p=0·19), although increases in serum creatinine concentrations were common (1·99, 1·46—2·70; p<0·0001) (Fig 1).

  

Fig 1: Adopted from Jun et al lancet 2010

 Underestimation of CV Risk

ACC/AHA provided a CV Risk calculator for estimation of 10-year risk for ASCVD in men and women 40 through 79 years of age. But the guidelines also state that, ‘These estimates may underestimate the risk for persons from some race/ethnic groups, especially American Indians, some Asian Americans (e.g., of south Asian ancestry), and some Hispanics (e.g., Puerto Ricans)’ Therefore, usage of same CV Risk calculator may underestimate ASCVD risk in Indian population. This could be understood in the following case example:

40 years old Indian male, who was smoker with positive family history and no h/o diabetes mellitus and hypertension with dyslipidemia (TC- 180, HDL- 36 and LDL- 115). His 10 year risk calculated on new risk  calculator was 4.9%, hence no statin was prescribed. After 3 months, patient presented with chest discomfort with bilateral arm pain, his ECG was suggestive of anterior wall MI. Coronary angiography revealed 99% thrombus containing lesion in proximal left anterior descending (LAD) artery, subsequently PCI to LAD was done.  

Once you underestimate the ASCVD risk in any patient, following the guidelines, based on the ASCVD risk will lead to underutilization of Statin therapy as in above case. The high prevalence of CHD in early age in Indian population further necessitates the usage of statin therapy earlier & more aggressively.

Statin and Risk of Dysglycaemia

In a meta-analysis⁷ Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% CI 1.02-1.17), but the risk is low both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change (Fig: 2)

Fig 2: Adopted from Sattar N, Preiss D Ray, KK et al. Lancet 2010; 375: 735-42

Results from three large randomized clinical trials (TNT, IDEAL, SPARCL) were compared⁸. High dose of atorvastatin in SPARCL trial is associated with a slightly increased risk of new-onset T2DM (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). While no significant difference was found with Atorvastatin 80 mg Vs Atorvastatin 10 mg  in TNT trial  (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226) and atorvastatin 80 mg Vs Simvastatin 20 mg in IDEAL trial  (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.

Prognosis of Patients with New-Onset T2DM

In multivariate analysis of three trials (TNT, IDEAL, SPARCL) major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69).⁸

The landmark Heart Protection Study clearly establishes that statins are safe and effective as cardioprotective therapy. In this study (mostly secondary prevention), for every 1 person newly diagnosed with diabetes due to statin use, 5 deaths, 6 nonfatal myocardial infarctions, and 4 strokes were prevented in 5 years.⁹

The expert panel emphasizes that the occurrence of major CVD event (MI or stroke) represent a much greater harm to health status than does an increase in blood glucose leading to a diagnosis of diabetes. The net absolute benefit of statin therapy may be considered as a comparison of the absolute risk reduction for CVD compared with the absolute excess risk including that for diabetes. Benefit also could be understood as a comparison of the number of statin treated patients that would result in prevention of 1 case of major ASCVD with number of statin – treated patients that would result in 1 extra case of diabetes.   

Prognosis or MACE for long term new onset diabetes is not known and no data for Indian population. 

Intensity of Statin

High Vs.  Moderate dose - Statins use is associated with a very modest excess risk of new onset diabetes and also the myelgia and transaminitis.  These side effects are dose dependent and higher with higher doses of statins. This has been proved in RCTs and meta-analyses of RCTs (i.e., 0.1 excess case per 100 individuals treated 1 year with moderate-intensity statin therapy and 0.3 excess cases per 100 individuals treated for 1 year with high-intensity statin therapy). But, this should not change statin prescribing, as statins reduce cardiovascular events and all-cause mortality.

In a meta-analysis¹⁰ of 5 statin trials with 32 752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean follow-up of 4.9 +/- 1.9 years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events (Fig 3).

Fig: 3

In a large randomized trial¹¹ of statin therapy in patients of South-Asian origin with hypercholesterolemia  (from the IRIS Trial), statin therapy was well tolerated and effective in decreasing LDL cholesterol in patients of South-Asian origin, with the 10- and 20-mg doses of rosuvastatin and atorvastatin allowing most patients to reach recommended LDL cholesterol goals.

 Even guideline stated that the history of hemorrhagic stroke and asian ancestry may modify the decision to use higher statin intensities¹. Therefore in Indian population with higher prevalence of atherogenic dyslipidemia, adding fibrates to a moderate intensity statins may be suitable to reduce >50% of LDL as desired by guidelines and it is better tolerated with lesser degree of myalgia and transaminitis and also the fewer incidences of new onset diabetes mellitus (0.1/100 vs. 0.3/100).  

Should we have our own guidelines?

We need evidence based data for our population looking at the epidemiology and prevalence of dyslipidemia in India, the efficacy and clinical outcome of antilipidemic drugs . This data should provide us with answers for our population with regard to statin dosage, role of non statin drugs, age factor <40 years (atherosclerosis not uncommon)  and whether we are more prone for new onset diabetes.

Conclusions

The new ACC/AHA guidelines for dyslipidemia has focused on risk of ASCVD based on RCT and included 4 statin groups one for secondary prevention and three for primary prevention utilizing the global risk assessment chart. ASCVD risk calculator is not validated in large population including Indians and it may underestimate or overestimate the risk of ASCVD so the under/over utilization of statins. Intensity of statin therapy rather than LDL/non HDL targets is recommended for clinicians. The higher prevalence of atherogenic dyslipidemia and metabolic syndrome in Indians at a younger age, low to moderate intensity statin therapy along with or without non-statin drugs may be useful to reduce the cardiovascular events and at the same time prevent the onset of new DM. Statins may also be initiated at early age in certain high risk group.

References

1.      Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013.

2.      Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of Combination Therapy With Statin and Another Lipid-Modifying Agent Compared With Intensified Statin Monotherapy: A Systematic Review. Ann Intern Med 2014.

3.      Jonkers IJ, Mohrschladt MF, Westendorp RG.et. al. Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial. Am J Med 2002; 112:275-80.

4.      Liamis G, Kakafika A, Bairaktari E, et al. Combined treatment with fibrates and small doses of atorvastatin in patients with mixed hyperlipidemia. Curr Med Res Opin 2002; 18:125-8.

5.      Taher TH, Dzavik V, Reteff EM. et al. Tolerability of statin-fibrate and statin-niacin combination therapy in dyslipidemic patients at high risk for cardiovascular events. Am J Cardiol 2002; 89:390-394.

6.      Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis.Lancet 2010; 375:1875-84.

7.      Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statins trials. Lancet 2010; 375:735-42.

8.      Waters DD, Ho JE, DeMicco DA, Breazna A, Arsenault BJ, Wun CC, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol2011; 57:1535-45.

9.      Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7–22.

10.  Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters DD, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA2011; 305:2556-64.

11.  Deedwania PC; Gupta M; Stein M et. al. Comparison of rosuvastatin versus atorvastatin in South-Asian patients at risk of coronary heart disease (from the IRIS Trial). Am J Cardiol 2007; 99(11): 1538-43.