Role of Statin in Diabetes

Mini-Review

Role of Statin in Diabetes

Rishi Shukla,1 Manisha Gupta2

1 Head of the Department of Endocrinology at Regency Health Care, Kanpur, Uttar Pradesh; Chief Consultant of Center for Diabetes and Endocrine Diseases, Kanpur, Uttar Pradesh, India.

2 Consultant Endocrinology - Center for Diabetes and Endocrine Diseases, Kanpur, Uttar Pradesh, India.

Corresponding Author: Rishi Shukla, Head of the Department of Endocrinology at Regency Health Care, Kanpur, Uttar Pradesh; Chief Consultant of Center for Diabetes and Endocrine Diseases, Kanpur, Uttar Pradesh, India.

Email: drrishishukla@gmail.com

Article information

Received date: 24/08/2021; Accepted date: 31/10/2021; Published date: 10/11/2021

Abstract

Type 2 diabetes is emerging as another pandemic in India, which requires an aggressive approach in terms of treatment and care. “Diabetes Lipidus” needs on time addressing and initiation of oral hypoglycemic drugs by choosing a patient-centric approach, lipid-lowering agents to prevent the patients from micro and macrovascular complications of diabetes. Primary prevention by statins is very important. Diabetes education and awareness is the key to preventing the emotional, psychological and financial burden of the patient.

Keywords: Type 2 diabetes mellitus, cardiovascular disease, myocardial infarction, total cholesterol, high- density lipoprotein, low-density lipoprotein

Introduction

As per the Indian Council of Medical Research–India Diabetes (ICMR-INDIAB) study data, there are currently 62.4 million people from diabetes in India.1Type 2 diabetes (T2DM) is a progressive chronic lifestyle disorder that hampers the quality of life of the patients due to micro and macrovascular complications causing financial, emotional as well physical stress.(1)Diabetes and dyslipidemia are commonly co-founding complications that lead to atherosclerosis and cardiovascular disease (CVD). The pathological feature of diabetic microangiopathy which occurs in a blood vessel is matrix protein synthesis and thickening of the capillary basement membrane.1Along with these changes advanced glycation end products, oxidative stress, low-grade inflammation, and neovascularization of vasa vasorum lead to macrovascular complications.2 T2DM and cardiovascular complications happen simultaneously at the time of diagnosis, and it has been documented in several studies.3-6Nearly all patients, even those under the age of 40 years in India, are at a high risk of CV events and require lipid-lowering therapy in the form of statins to ameliorate the risk.7However, CVD remains the leading cause of morbidity and mortality in individuals with T2DM and rates of CVD mortality are two to four times higher in diabetes than in those without diabetes.8,9 Approximately, >55% of the Indian population is suffering from dyslipidemia. Diabetic dyslipidemia or “diabetes lipidus” is a new evolving terminology. These are two separate risk factors for atherosclerosis. Diabetes and dyslipidemia are two parallel roads that lead to an overt diagnosis of diabetes.10

As we are already overburdened with 2nd highest population in the world, these foresee complications can be prevented by appropriate intervention in terms of optimizing weight, drug compliance, lifestyle modification and promoting physical activity. Initiation of appropriate oral hypoglycemic drugs along with timely detection of high-risk cardiac patients, intervention with statins can prevent them from going into disastrous outcome of myocardial infarction. In India, due to unawareness, people often look for a complete cure of diabetes and opt for “wonder medicine” which is often misleading. Medicine non- compliance is the biggest challenge we face in our clinical practice. Lipid-lowering agents are being missed either by clinician or patient’s negligence. One of the main reasons for this negligence could be resource-limited setting, cost of statin (as the patient and some health care providers withdraw statin from prescriptions of diabetes patients as they think that statins are extra pills in the treatment of diabetes patients), financial constraints, etc.

Diabetes and Macrovascular Association

Patient with uncontrolled diabetes is at risk of micro and macrovascular complications, particularly CVD. Diabetic patients without previous history of myocardial infarction (MI) have a high risk of MI as nondiabetic patients with previous MI,11 therefore all diabetic patients should be treated aggressively for the prevention of CVD events. Elevated LDL cholesterol levels should be addressed initially with tight glycemic control which can be achieved with diet, exercise, and antidiabetic agents may substantially improve the lipid profile and reduce the risk of CVD in some patients as per the current American Diabetes Association (ADA) and National Cholesterol Education Program (NCEP) guidelines.12,13However, few patients might need intensive lipid-lowering therapy to reduce their cardiovascular risk, most commonly with one of the statins or fibric acid derivatives.14The Collaborative Atorvastatin Diabetes Study (CARDS) has shown significant improvement before and after statin treatment.15

In this randomized study, 2800 diabetic patients without any history of cardiovascular disease were given statin 10 mg versus placebo. At the end of the study, they concluded a relative risk reduction of 37% (p= 0.001).

Collaborative Atorvastatin Diabetes Study: Atorvastatin Significantly Reduces Major Cardiovascular Events in Diabetes Mellitus Patients15

Patients were randomized to atorvastatin 10 mg/day (n=1,428) or placebo (n=1,410). Total cholesterol was reduced by 54 mg/ dL and LDL by 46 mg/dL in the atorvastatin arm (p<0.0001 each) (Table 1). The primary endpoint occurred significantly less frequently in the atorvastatin arm versus placebo (5.8% vs. 9.0%, relative risk reduction [RRR] 37%, p=0.001), as did acute coronary events (3.6% vs. 5.5%, RRR 36%), and stroke (1.5% vs. 2.8%, RRR 48%).

Pharmacological Therapy in Dyslipidemia

The priority is to bring down LDL levels in diabetic dyslipidemia. Statins are considered as the first drug choice, followed by ezetimibe (a novel cholesterol-lowering drug that acts at the brush border of the small intestine), then fenofibrate or niacin.

The 2013 ACC/AHA guidelines have divided individuals into 4 groups as per atherosclerotic cardiovascular disease (ASCVD) events with a good margin of safety from moderate- or high-intensity statin therapy.16

Four statin benefit groups:

1. Individuals with clinical ASCVD
2. Individuals with primary elevations of low-density lipoprotein cholesterol (LDL-C) 190 mg/dL
3. Individuals 40 to 75 years of age with diabetes and LDL-C 70 to 189 mg/dL without clinical ASCVD
4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age and have LDL-C 70 to 189 mg/dL and an estimated 10-year ASCVD risk of 7.5%. This requires a clinician-patient discussion.

If a single agent is inadequate to achieve lipid goals, combinations of the preceding drugs may be used. For elevated triglyceride levels, hyperglycemia must be controlled first by using a patient-centric approach. If triglyceride or high-density lipoprotein levels remain uncontrolled, pharmacologic agents should be considered. Fibrates are slightly more effective than niacin in terms of lowering triglyceride levels, but niacin is the only drug that increases HDL levels appreciably more than fibrates.17In this line stream, we have another molecule, saroglitazar which is an insulin sensitizer that acts as a dual PPAR agonist at the subtypes α (alpha) and γ (gamma) of the peroxisome proliferator-activated receptor (PPAR). This is in indicated patients with diabetic dyslipidemia uncontrolled solely on statins.18

Statins are a class of drugs widely known as 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors which work by inhibiting the synthesis of cholesterol in the liver by the enzyme HMG-CoA reductase. Several statins are available with various efficacy. Different statins require different dosing to reach the same LDL level such as rosuvastatin, atorvastatin and simvastatin. Statins, except atorvastatin, are usually dosed at night because of higher nocturnal cholesterol synthesis.19Some studies have shown the effectiveness of alternate-day dosing of simvastatin.13

Statin therapy should be added as adjunctive therapy to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients >40 years irrespective of gender or type of diabetes. Risk doubles with overt cardiovascular disease or family history of CVD. In 2006, a target of <70 mg/dL LDL goal has become a “reasonable goal” in the guidelines for secondary prevention jointly issued by the American Heart Association (AHA) and the American College of Cardiology (ACC).9

New Recommendations for Dyslipidemia in Diabetes Mellitus as per the European Society of Cardilogy, 201910

  • In patients with T2DM at very high risk (this group includes those with established cardiovascular disease and additional risk factors such as diabetes mellitus, continued cigarette smoking, metabolic syndrome, renal failure and acute coronary syndrome), LDL-C reduction >50% from baseline and LDL-C goal of <1.4mmol /L (<55mg/dL) is recommended.
  • In patients with T2DM at high risk, LDL-C reduction of > 50% from baseline and LDL-C goal of <1.8mmol /L (<70mg/ dL) is recommended.
  • Statins are recommended in type 1 diabetes mellitus (T1DM) patients who are at high or very high risk.

    • 2019 American College of Cardiology and American Heart Association Guidelines on the Primary Prevention of Cardiovascular Disease Statin Recommendations20

    For Type 1 Diabetes Mellitus Patients (Table 2)
  • All people with T1DM and age >40 years (moderate intensity)
  • Diabetes >10 years (moderate intensity)
  • All T1DM <40 years with documented nephropathy (moderate intensity)
  • T1DM <40 years with CVD risk (moderate intensity)
  • T1DM >20 years of duration, less or more than 40 years (high intensity)

    • Precautions in Statins Therapy

    Very recent guidelines from the American College of Physicians recommend, once lipid-lowering therapy is started, patients should receive at least a moderate dosage of a statin; and for statins, routine monitoring of liver function tests or muscle enzymes is not recommended except in special situation.12

    A noteworthy number of diabetic patients will require combination therapy. Except for those that have been previously mentioned, most combinations are safe and effective in diabetic patients.17 Cautiously, the benefits of combination therapy should be weighed against the risks. Statins are associated with a variety of serious side adverse effects, including myalgia and myopathy along with changes in plasma enzymes of hepatic origin.24 Before prescribing these drugs, a complete medical history should be elicited from the patient to minimize the occurrence of myotoxicity (Table 3). A treating physician should be aware of drug-drug interactions between each statin and specific other drugs and take measures to prevent them.24 Certain drugs should be avoided consuming with other drugs or substances which are known to hamper the absorption of statin.24 Patients with renal insufficiency should be closely monitored. Moreover, the risk of myotoxicity may be less when combining a statin with niacin versus a fibrate.17


    Abbreviations:

    atorva- Atorvastatin; fluva- Fluvastatin; lova- Lovastatin; Pitava- Pitavastatin; prava- Pravastatin; rosuva- Rosuvastatin; simva- Simvastatin

    Statin therapy is not recommended in pre-menopausal patients with diabetes considering pregnancy or not using adequate contraception.10 More awareness needs to be created at the level of primary physician and emphasis should be laid upon drug compliance in form of “Diabetes Education”.22

    Conclusion

    A lot has happened in terms of our understanding of diabetic dyslipidemia. The key authorities in guiding dyslipidemia have joined hands to come out with special recommendations to reduce the controversies. The most important fact is that every people with type 2 diabetes mellitus must be initiated with a statin as primary prevention. Although the current LDL goal of less than 100 mg/dL is controversial, recent trials suggest an even more aggressive approach. Monotherapy with a statin may be sufficient for many patients. However, since patients with diabetes often have multiple lipoprotein abnormalities, it is important to use all available treatment options. More awareness needs to spread at the level of primary care physicians and emphasis should be laid upon drug compliance in form of “Diabetes Education”. The entire population of clinicians should be updated for this. The bigger challenge is at the level of patients who frequently stop because of inadequate “Diabetes Knowledge”. A pill a day; may save our diabetic population from macrovascular accidents. This tiny effort may also save lots of patients’ personal as well as national resources.

    Declaration of conflicting interests

    The authors declares no conflict of interest.

    Funding

    No funds were received for the study and publishing of this article.

    References

    1. Mohan V, Shah S, Saboo B. Current glycemic status and diabetes related complications among type 2 diabetes patients in India: data from the A1chieve study. J Assoc Physicians India. 2013; 61(1 Suppl):12-5.
    2. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: Distinct or continuum? Indian J Endocrinol Metab. 2016; 20(4):546-51.
    3. 10 Things to Know About Lipoprotein(a). Online available at: https://www.amgen.com/stories/2019/02/10-things-to-knowabout-lipoproteina. Accessed date- 22/10/2021.
    4. Sosale A, Prasanna Kumar KM, Sadikot SM, Nigam A, Bajaj S, Zargar AH, et al. Chronic complications in newly diagnosed patients with type 2 diabetes mellitus in India. Indian J Endocrinol Metab. 2014; 18:355–60.
    5. Rema M, Premkumar S, Anitha B, Deepa R, Pradeepa R, Mohan V. Prevalence of diabetic retinopathy in urban India: The Chennai urban, rural epidemiology study (CURES) eye study, I. Invest Ophthalmol Vis Sci. 2005;46:2328–333.
    6. Unnikrishnan RI, Rema M, Pradeepa R, Deepa M, Shanthirani CS, Deepa R, et al. Prevalence and risk factors of diabetic nephropathy in an urban South Indian population: The Chennai urban, rural epidemiology study (CURES 45). Diabetes Care. 2007; 30:2019–024.
    7. Premalatha G, Shanthirani S, Deepa R, Markovitz J, Mohan V. Prevalence and risk factors of peripheral vascular disease in a selected South Indian population: The Chennai urban population study. Diabetes Care. 2000; 23:1295–300.
    8. JSosale B, Sosale AR, Mohan AR, Kumar PM, Saboo B, Kandula S. Cardiovascular risk factors, micro and macrovascu- lar complications at diagnosis in patients with young onset type 2 diabetes in India: CINDI 2. Indian J Endocrinol Metab. 2016;20(1):114-118.
    9. IDF Diabetes Atlas 9th edition 2019. Online available at: https://www.diabetesatlas.org/en/resources/
    10. Wei YQ. Treating dyslipidemia in the high-risk group patients-current management and future approach. Cardiometabolic risk update unit no. 3. Online available at: https://www.cfps.org.sg/publications/the-singapore-family-physician/article/284_pdf
    11. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020; 41(1):111–88.
    12. Haffner SM , Letho S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; 339:229–34.
    13. American Diabetes Association. Standards of medical care in diabetes-- 2008. Diabetes Care. 2008; 31(Suppl. 1): S12– S54.
    14. Snow V, Aronson MD, Hornbake ER, Mottur-Pilson C, Weiss KB, Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2004; 140:644-49.
    15. Henry RR. Preventing Cardiovascular Complications of Type 2 Diabetes: Focus on Lipid Management. Clinical Diabetes. 2001; 19(3):113-20.
    16. Colhoun HM, Betteridge DJ, Durrington PN, HitmanGA, Neil HAW, Livingstone SJ, et al. Primary prevention of cardiovas- cular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre ran- domised placebo-controlled trial. Colhoun HM et al. Lancet. 2004; 364:685-96.
    17. Stone NJ, Robinson JG, Lichtenstein AH, Merz CNB, Blum CB, Eckel RH, 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. 2014; 63(25 Pt B):2889-934.
    18. Moon YS, Kashyap ML. Pharmacologic treatment of type 2 diabetic dyslipidemia. Pharmacotherapy. 2004; 24(12):1692-713.
    19. Lipaglyn (Saroglitazar) for Treating Hypertriglyceridemia in Type II Diabetes, India. Online available at: https://www.clinical- trialsarena.com/projects/lipaglyn-saroglitazar-treating-type-ii-diabetes/.
    20. Kreisberg RA, Oberman A. Medical Management of Hyperlipidemia/Dyslipidemia. J Clin Endocrinol Metab. 2003; 88(6):2445‐461.
    21. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019; 140(11):e596-e646.
    22. Chou R, Dana T, Blazina I, Daeges M, Bougatsos C, Grusing S, et al. Statin Use for the Prevention of Cardiovascular Disease in Adults: A Systematic Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Nov. (Evidence Syntheses, No. 139.) Table 1, Statin Dosing and ACC/AHA Classification of Intensity. Online available at: https://www.ncbi.nlm.nih.gov/books/NBK396417/table/ch1.t1/
    23. American Diabetes Association. Standards of Medical Care for Patients with Diabetes Mellitus. Diabetes Care. 2003; 26 (suppl 1):s33-s50.
    24. Shukla R, Gupta M. Addressing Dyslipidaemia in Diabetes: A Personal Viewpoint. IJADD.
    25. Kellick KA, Bottorff M, Toth PP. The National Lipid Association’s Safety Task Force. A clinician’s guide to statin drug-drug interaction. J Clin Lipidol. 2014;8(3 Suppl):S30-46.
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