Seung-Hwan Lee, M.D., Ph.D.

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cholesterol level in type 2 diabetic patients without cardiovascular disease: a randomized

1 ICDM, DMJ session Statin discontinuation after achieving a target low-density lipoprotein cholesterol level in type 2 diabetic patients without cardiovascular disease: a randomized controlled study Seung-Hwan Lee, M.D., Ph.D. Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St.Mary s Hospital,The Catholic University of Korea

Introduction The prevalence of dyslipidemia is increased in patients with type 2 diabetes, which contributes to their higher incidence of cardiovascular diseases, resulting in higher

2 Introduction The prevalence of dyslipidemia is increased in patients with type 2 diabetes, which contributes to their higher incidence of cardiovascular diseases, resulting in higher morbidity and mortality. The benefits of a lipid-lowering therapy, mainly with statins (HMG CoA reductase inhibitors), in primary and secondary prevention have been well established by major trials.

3 Introduction Recent guidelines now recommend a stricter control of lipid levels. Standards of medical care in diabetes 2015, ADA However, because there are no specific criteria for the discontinuation of statins, it is unclear whether statins should be administered throughout the patient s lifetime or if they can be withdrawn in some patients.

4 Statin discontinuation after an acute vascular event has detrimental effects Eur Heart J 2008:29;

5 Statin discontinuation after an acute vascular event has detrimental effects N=86, HR=2.93 (1.64, 6.27) N=1151, HR=1.69 (0.92, 3.56) N=369 Circulation 2002:105;

Statin discontinuation after an acute vascular event has detrimental effects 89 patients with ischemic stroke were randomly assigned either to statin

6 Statin discontinuation after an acute vascular event has detrimental effects 89 patients with ischemic stroke were randomly assigned either to statin withdrawal for the first 3 days after admission (n=46) or to immediately receive atorvastatin 20 mg/day (n=43). 3 month follow-up Neurology 2007:69;

7 Mechanisms that may be responsible for an adverse outcome after discontinuing statins Not only from the lost benefits from the therapy, but also from the rebound phenomenon Statins increase the production of nitric oxide and downregulate angiotensin II AT(1) receptors, endothelin-1, vascular inflammatory adhesion molecules, and inflammatory cytokines. Anti-inflammatory effects are rapidly abrogated after statin withdrawal Deterioration of endothelial function within hrs Beneficial effects on hemostasis and blood rheology are abrogated

8 Safety of discontinuing statin therapy Circulation 2004:110;2333-5

9 Safety of discontinuing statin therapy JAMA Intern Med 2015:175;

10 Outcome studies on statin discontinuation in low-risk subjects are lacking Evidence supporting continuous administration of statins Lower LDL-C level is better for patient with CVD. Statin discontinuation may induce a rebound phenomenon. Adherence to statin treatment was associated with a reduced incidence of major coronary events, irrespective of prior CHD. Unfavorable aspects of an intensive statin treatment A dose-dependent effect on liver dysfunction. Increased risk of new-onset diabetes. Acute renal failure or myopathy.

11 Aims The rate of relapse following short-term statin discontinuation after achieving a target LDL-C level in type 2 diabetic patients without CVD? Factors predicting the relapse of dyslipidemia? Clinical outcome of statin discontinuation?

12 Methods

of CVD (CHD, CVA, PAD) Type 1 diabetes, secondary diabetes, other diabetes Patients taking other classes of anti-hyperlipidemic

13 Methods P B 10±2 weeks F Rosuvastatin 10 mg Statin maintenance Statin discontinuation Screening Randomization Inclusion criteria Type 2 diabetes Age Pretreatment LDL-C 100~160 mg/dl Baseline LDL-C < 100 mg/dl HbA1c < 10% Exclusion criteria Previous Hx. of CVD (CHD, CVA, PAD) Type 1 diabetes, secondary diabetes, other diabetes Patients taking other classes of anti-hyperlipidemic agents Hx. of steroid treatment or herb medication ingestion in previous 3 months Patients with abnormal liver, kidney, thyroid dysfunctions

14 Results Median (25-75%) duration of statin treatment: 12 (9-15) months

15 Results Relapse rate 79% in discontinuation group 3% in maintenance group

16 Results

17 Results maintenance group discontinuation, non-relapse group discontinuation, relapse group

18 Results Adjusted for age, sex, BMI, OHA treatment, waist-hip ratio, fibrinogen, HbA1c There were no symptomatic CVD events in either group during the study period.

19 Summary In this study of type 2 diabetic patients without a CVD history, Statin discontinuation after achieving a target LDL-cholesterol level leads to a significant relapse rate of dyslipidemia. The pre-treatment LDL and HDL-cholesterol levels were independently associated with the relapse. The pre-treatment LDL-cholesterol was the most useful parameter for predicting a relapse in these subjects. (cutoff 123 mg/dl) During the short follow-up period, no CVD events were noted.

20 Conclusion Discontinuation of statins should be carefully decided based on the lipid profiles, their ratios, and whether the patients have any side effects to statin treatment (in limited cases). The long-term clinical outcomes of statin discontinuation and the pros and cons of an intensive statin treatment in low-risk subjects need further investigation.

B. Patient has not reached the percentage reduction goal with statin therapy

B. Patient has not reached the percentage reduction goal with statin therapy Managing Cardiovascular Risk: The Importance of Lowering LDL Cholesterol and Reaching Treatment Goals for LDL Cholesterol The Role of the Pharmacist Learning Objectives 1. Review the role of lipid levels