Review

20200305

Presenter: R2 劉奕辰

Supervisor: VS 朱柏齡

statin therapy increased risk of developing diabetes

• Hepatic dysfunction

• Muscle injury

• Renal dysfunction

• Behavioral and cognitive

• Diabetes mellitus

• Other possible associations(Cancer, Cataract, Neuropathy, Lupus, Androgen synthesis , Immune response)

SIDE EFFECTS of statins

Mechanism of action of Statins

THE HEALTH GATE Crestor (Rosuvastatin)

Mechanism of action of PCSK9 inhibitor

Michael M Page, Gerald F Watts, PCSK9 inhibitors – mechanisms of action

(Proprotein convertase subtilisin/kexin type 9)

The American College of Cardiology/American Heart Association 2013 Blood Cholesterol Guideline classified statin regimens as being of low intensity (eg, <30% LDL cholesterol reduction with simvastatin 10 mg daily), moderate intensity (eg, 30% to <50% reduction with simvastatin 20–40 mg, atorvastatin 10–20 mg, or rosuvastatin 5–10 mg daily), or high intensity (eg, ≥50% reduction with atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily).

Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016 Nov 19;388(10059):2532-2561

Rosuvastatin: Crestor (10mg/20mg), Roty 5mg/10mg Atorvastatin: Lipitor(10mg/20mg), Atorcal 20mg Fluvastatin: Lescol XL 80mg Lovastatin: Linicor 500/20mg (Niacin+Lovastatin) Pravastatin: Pravafen 40/160mg (Pravastatin+Fenofibrate) Simvastatin: Vytorin 10/20mg (Ezetimibe+ Simvastatin) Pitavastatin: Livalo 2mg, Zulitor 4mg

《10年ASCVD風險計算機》：http://www.cvriskcalculator.com/

2017台灣高風險病人血脂異常臨床治療指引

中華民國血脂及動脈硬化學會

N Engl J Med. 2008 Nov 20;359(21):2195-207

• people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.

• randomly assigned 17,802 apparently healthy men and women with LDL cholesterol levels of less than 130 mg per deciliter and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo

• primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

• stopped after a median follow-up of 1.9 years

(JUPITER study)

增加25%

Lancet. 2010;375(9716):735. Epub 2010 Feb 16. .

• We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years.(included only trials with more than 1000 patients)

• Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR]1.09; 95% CI 1.02-1.17), with little heterogeneity (I(2)=11%) between trials.

• Treatment of 255 (95% CI 150-852) patients with statins for 4 years resulted in one extra case of diabetes.

Lancet. 2010;375(9716):735. Epub 2010 Feb 16. .

• Subgroup analyses also showed no clear difference between statins in terms of diabetes risk. Lipophilic (OR 1·10, 0·99–1·22, I²=0%) and hydrophilic (OR 1·08, 0·98–1·20, I²=36%) statins were associated with very similar risks. Results of analyses without JUPITER (OR 1·08, 1·01–1·15, I²=1·5%) or MEGA (1·09, 1·01–1·18, I²=18·4%) were similar to the overall analysis.

J Am Coll Cardiol. 2012 Oct 2;60(14):1231-8

• aimed to evaluate the association of statin exposure and incident diabetes

• From Taiwan National Health Insurance beneficiaries age≥45 years (men) and≥55 years (women) before 2004, subjects continuously treated with statins≥30 days during 2000 to 2003 and nonusers before 2004 were identified

• Among nondiabetic individuals at the cohort entry

• Over a median of 7.2 years annual rates of diabetes were significantly higher in statin users (2.4% vs. 2.1%, p<0.001)

J Am Coll Cardiol. 2012 Oct 2;60(14):1231-8

• MACE (hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.68 to 0.98 for myocardial infarction; HR: 0.94; 95% CI: 0.86 to 1.03 for ischemic stroke; HR: 0.91; 95% CI: 0.84 to 0.99 for MACE]) and in-hospital mortality (HR: 0.61; 95% CI: 0.55 to 0.67]) were less

• The risk-benefit analyses suggested that statin treatment was favorable in high-risk (HR: 0.89; 95% CI: 0.83 to 0.95) and secondary prevention (HR: 0.89; 95% CI: 0.83 to 0.96) populations.

Lancet. 2012;380(9841):565.

• In this analysis, participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes: metabolic syndrome, impaired fasting glucose, body-

mass index 30 kg/m(2) or higher, or glycated haemoglobin A(1c) greater than 6%

• a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed (In individuals with one or

more risk factors)

• total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed (no major diabetes risk factors)

• In the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes.

JAMA. 2011 Jun 22;305(24):2556-64

• In 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)

• Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 74%) 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.

JAMA. 2011 Jun 22;305(24):2556-64

Mechanism of statin-induced DM

• Negative effects on both b-cell secretion and insulin sensitivity.

• b-cell dysfunction might be related to LDLR-mediated increased levels of intracellular cholesterol

• Addition of LDL-C to culture medium of rat islet b cells resulted in cell death.

• Patients with familial hypercholesteremia showed that prevalence of type 2 DM was significantly lower in familial hypercholesteremia patients than unaffected relatives

Mechanism of statin-induced DM

• Insulin receptor substrate 1(IRS-1) plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 (IGF-1) receptors to intracellular pathways PI3K / Akt

• Simvastatin down-regulated PI3k/Akt signalling,, and up-regulated FOXO transcription factors and downstream gene

targets ( MAFbx, MuRF-1) known to be implicated in

proteasomal- and lysosomal-mediated muscle proteolysis, carbohydrate oxidation, oxidative stress and inflammation

• Muscle insulin resistance

Mallinson JE, Constantin-Teodosiu D, Sidaway J, Westwood FR, Greenhaff PL. Blunted Akt/FOXO signalling and activation of genes controlling atrophy and fuel use in statin myopathy. J Physiol. 2009;587:219–230.

Mechanism of statin-induced DM

• decreased genetic hydroxymethylglutaryl (HMG) CoA reductase activity is associated with a higher risk of type 2 diabetes

• Swerdlow et al studied single-nucleotide polymorphism in HMGCR genes and used rs17238484 and rs12916 as proxies for HMGCR inhibition by statins. Associated with higher body weight, waist circumference, lower LDL-C, and increased plasma glucose concentration.

HMG coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385:351–361.

Conclusion

Statin增加糖尿病風險

Statin造成DM風險因子: statin強度、糖尿病危險因子(如代謝症候群、糖尿病前期、BMI???)、年齡

Thanks for attention