Diabetes Mellitus, Metabolism Journal Club Ｎｏｖｅｍｂｅｒ ２７， ２０ ０８ Rei Suganaga, MD Diabetes and Endocrine Department, Kameda Medical Center Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein, The primary objective of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) NEJM; Nov 20, 2008 vol. 359 no. 21 Low-Dose Aspirin for Primary Prevention of Atherosclerotic Events in Patients With Type 2 Diabetes, A Randomized Controlled Trial The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial JAMA, November 12, 2008 Vol 300, No. 18

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein The primary objective of the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) NEJM; Nov 20, 2008 vol. 359 no. 21

Background ・血管病変や糖尿病、高脂血症患者には MI 、 stroke 、 death from CV cause の予防に statin が推奨されて いる。 ・しかし実際、 MI や Stroke の半数が正常 LDL 患者に発症している。 ・高感度 CRP の測定が future vascular events の独立予測因子であり LDL 値に関わらずリスク改善効果がある。 ・すでに statin が高感度 CRP 減少効果ありとの報告あり。 ・「正常 LDL だが高感度 CRP 上昇患者」 に対する statin 加療の利益について、前向き研究はない。 ・ JUPITER では rosuvastatin20mg/day 投与での CV events について分析した。

Methods ■ A randomized, double-blind, placebo-controlled, multicenter trial conducted at 1315 sites in 26 countries ・ intention-to-treat basis ■ Inclusion Criteria ・ did not have a Hx of cardiovascular disease LDL ≦ 130 mg/dl and high-sensitivity CRP ≧ 2.0 mg/l a willingness to participate for the duration of the trial TG ≦ 500 mg/dl

Methods ■ Exclusion criteria: ・ previous or current use of lipid-lowering therapy, ・ current use of postmenopausal HRT ・ hepatic dysfunction, CK ↑, Cr >2,0mg/dl ・ sBP>190 or dBP >100 ・ cancer within 5 years before ・ uncontrolled hypothyroidism ・ a recent Hx of alcohol or drug abuse or another medical

Methods ■ Trial Protocol randomly assigned in a 1:1 ratio to receive either ・ Rosuvastatin 20 mg daily, ・ Placebo Follow-up visits ： occur at 13weeks and then 6, 12, 18, 24, 30, 36, 42, 48, 54,60 months after randomize

End points ■ Primary outcome occurrence of a first major cardiovascular event, defined as nonfatal MI, nonfatal stroke, hospitalization for unstable angina, an arterial revascularization procedure, or confirmed death from cardiovascular causes. ■ Secondary end points the components of the primary end point considered individually and death from any cause.

Results ■ Baseline Characteristics ・ Feb 4, 2003 ～ Dec 15, 2006 ・ 89,800 enrollment →72,088 ineligible (80.2%) (LDL>130(52.2%), CRP <2.0(36.1%)) →17,802 assigned Rosuvastatin ; 8,901 Placebo ; 8,901

Results ■ Effect of Rosuvastatin ・ Compliance; 75% -37% -50% +4% -17%

Results ■ End points ・ median follow-up ; 1.9 years (max 5.0 years) ・ first major CV event ; 142 Rosuvastatin vs 251 placebo

NNT NNT: ･･ 25 (2years) (4years) (5years)

Results ■ Subgroup analyses

Results ■ Adverse events

Conclusions □ Among apparently healthy men & women who didn’t have HL but have elevated level of CRP, ・ Rosuvastatin significantly reduced the incidence of major CV events, and death from any cause. ・ Consistent effects were observed in all sub- groups ・ no significant increase about adverse events

Limitations 1.Not include people with low level of CRP 2.Short follow-up time →longer-term therapy should be considered.

Low-Dose Aspirin for Primary Prevention of Atherosclerotic Events in Patients With Type 2 Diabetes A Randomized Controlled Trial The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial JAMA, November 12, 2008 Vol 300, No. 18

Background ・糖尿病は心血管障害の大きなリスク因子である。 Framingham Heart Study ; Odds Ratios -Coronary heart disease( 男・女 ) ； 1.5 ・ 1.8 -Stroke:1.4 ・ 1.7 ・ aspirin は心血管障害の一次及び二次予防として確立してる。 ・糖尿病に代表されるような心血管障害のリスク因子をもつ患 者には 禁忌事項がない限り asprin 投与が推奨されている。 ADA ； recommend use of aspirin for DM + α (α ； 40y.o.<, Fx of coronary, HTN, smoke, HL, UAE) ・しかし糖尿病患者に対する予防効果としてはこれまでの大規 模研究 / サブグループ解析でも証明されていない。 ・そのため糖尿病患者の一次予防としての aspirin 効果について 前向き研究を行った。

Methods ■ The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial ■ A prospective, randomized, open-label, controlled trial with blinded end-point assessment. ・ Patients were enrolled and followed up at 163 institutions throughout Japan.

Methods ■ Inclusion Criteria Dx of type 2 DM Age 30 – 85 ability to provide informed consent.

Methods ■ Exclusion criteria: ECG changes(ST↑↓,Qwave) Hx of coronary heart disease(confirmed by angiography) Hx of cerebrovascular disease Hx of arteriosclerotic disease Af ・ Pregnancy Use of antiplatelet or antithrombotic therapy Hx of severe gastric or duodenal ulcer; Severe liver/renal dysfunction ・ allergy to aspirin.

Methods ■ Trial Protocol randomly assigned 81 mg or 100 mg of aspirin once daily. Non aspirin group Follow-up visits ： every 2 weeks for patients seen in a clinic setting every 4 weeks for patients seen in a hospital setting Non aspirin group were allowed to use antiplatelet/thrombotic therapy, including aspirin, if needed and vice versa.

End points ■ Primary outcome any atherosclerotic event sudden death(coronary,cerebrovascular, and aortic causes) nonfatal AMI; AP; newly developed exertional angina nonfatal ischemic and hemorrhagic stroke; TIA nonfatal aortic and peripheral vascular disease (ASO,dissection, mesenteric arterial thrombosis) ■ Secondary end points each primary end point Combinations of primary end points death from any cause.

Adverse events ■ Adverse events gastrointestinal (GI) events any hemorrhagic events other than hemorrhagic stroke

Results ・ screened Dec May 2005 ・ follow-up until Apr 2008 ・ median follow-up; 4.37years ■ study population

Results ■ Baseline Characteristics ・ 2,567 screened →2539 randomized ･ aspirin 1262 vs nonaspirin1262 ･ 193 lost to follow-up ・ median follow-up; 4.37years By the end of the study ・ aspirin group;123(10%) patients had stopped taking Med ・ nonaspirin group; 6(0.5%) aspirin, 3(0.2%) other antiplatelet

Results ･ total 154 events occurred ･ primary end point; there is no significant difference ・ secondary - ; fatal coronary and cerebrovascular events > significantly (P=.0037)

Results ■ Subgroup Analyses ・ 65 ≦ ; the events was significantly lower in aspirin group (HR 0.68, 32% relative reduction) ・ other subgroup show non-significant difference.

Results ■ Adverse events

Results ■ Adverse events ・ serious bleeding that required transfusion asipirin; 4 vs nonasipirin; 0 ・ But no increase in hemorrhagic strokes in aspirin group

Limitations 1.Did not have advantages of a double-blind, randomized. (prospective, randomized, open-label, controlled trial with blinded end-point assessment) 2. Event rate was low and the study was underpowered →larger trial is needed to determine the efficacy

Conclusions □ JPAD trial is the first prospectively designed trial to evaluate the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in patients with type2 DM ・ Low-dose aspirin as primary prevention didn’t reduce the risk of cardiovascular events. -As for fatal coronary and cerebrovascular events, low-dose aspirin reduced the events significantly(P=.0037 HR0.10) -65 ≦ ； 32% relative reduction in total atherosclerotic events ・ no increase in hemorrhagic strokes but a small increase in serious GI hemorrhagic events