1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2009 年 4 月 23 日 8:30-8:55 ８階 医局 Indian Polycap Study (TIPS), Yusuf S, Pais P, Afzal R, Xavier D, Teo K, Eikelboom J, Sigamani A, Mohan V, Gupta R, Thomas N. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009 Apr 18;373(9672):1341-51. Haritoglou C, Gerss J, Sauerland C, Kampik A, Ulbig MW; CALDIRET study group. Effect of calcium dobesilate on occurrence of diabetic macular oedema (CALDIRET study): randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2009 Apr 18;373(9672):1364-71.

2. Salim Yusuf, Population Health Research Institute, Hamilton Health Sciences and McMaster University Lancet 2009; 373: 1341–51

3. The combination of three blood-pressure- lowering drugs at low doses, with a statin, aspirin, and folic acid (the polypill), could reduce cardiovascular events by more than 80% in healthy individuals. We examined the effect of the Polycap on blood pressure, lipids, heart rate, and urinary thromboxane B2, and assessed its tolerability. Background

4. In a double-blind trial in 50 centres in India, 2053 individuals without cardiovascular disease, aged 45–80 years, and with one risk factor were randomly assigned, by a central secure website, to the Polycap (n=412) consisting of low doses of thiazide (12 ・ 5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorthiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure- lowering drugs plus aspirin. The primary outcomes were LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinary 11- dehydrothromboxane B2 for the antiplatelet effects of aspirin, and rates of discontinuation of drugs for safety. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00443794. Methods

6. Total-C 4.7 mM = 181mg/dl LDL-C 3.0 mM = 116mg/dl HDL-C 1.1 mM = 42mg/dl TG 1.9 mM = 168 mg/dl LDL cholesterol was measured with a direct enzymatic photocolourimetric assay (Roche Hitachi 912 analyser with LDL cholesterol second generation kits; Roche Diagnostics, Mannheim, Germany)

12. =-31mg/dl

18. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels. Design We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta- analysis of 15 trials of low dose (50-125 mg/day) aspirin. BMJ VOLUME 326 28 JUNE 2003 bmj.com 1419

19. Compared with groups not receiving blood-pressure-lowering drugs, the Polycap reduced systolic blood pressure by 7 ・ 4 mm Hg (95% CI 6 ・ 1–8 ・ 1) and diastolic blood pressure by 5 ・ 6 mm Hg (4 ・ 7–6 ・ 4), which was similar when three blood-pressure-lowering drugs were used, with or without aspirin. Reductions in blood pressure increased with the number of drugs used (2 ・ 2/1 ・ 3 mm Hg with one drug, 4 ・ 7/3 ・ 6 mm Hg with two drugs, and 6 ・ 3/4 ・ 5 mm Hg with three drugs). Polycap reduced LDL cholesterol by 0 ・ 70 mmol/L (95% CI 0 ・ 62–0 ・ 78), which was less than that with simvastatin alone (0 ・ 83 mmol/L, 0 ・ 72–0 ・ 93; p=0 ・ 04); both reductions were greater than for groups without simvastatin (p<0 ・ 0001). The reductions in heart rate with Polycap and other groups using atenolol were similar (7 ・ 0 beats per min), and both were signifi cantly greater than that in groups without atenolol (p<0 ・ 0001). The reductions in 11-dehydrothromboxane B2 were similar with the Polycap (283 ・ 1 ng/mmol creatinine, 95% CI 229 ・ 1–337 ・ 0) compared with the three blood-pressure-lowering drugs plus aspirin (350 ・ 0 ng/mmol creatinine, 294 ・ 6–404 ・ 0), and aspirin alone (348 ・ 8 ng/mmol creatinine, 277 ・ 6–419 ・ 9) compared with groups without aspirin. Tolerability of the Polycap was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill. Findings

20. Interpretation This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk. Funding Cadila Pharmaceuticals, Ahmedabad, India. TIPS does take a first and crucial step forward and raises hope that, in conjunction with other global efforts to improve diet and exercise, the polypill could one day substantially reduce the burden of cardiovascular disease in the world.

22. Lancet 2009; 373: 1364–71 Department of Ophthalmology, Ludwig-Maximilians- University, Munich, Germany (C Haritoglou MD, A Kampik MD, M W Ulbig MD); and Department of Medical Informatics and Biomathematics, University of Munster, Munster, Germany (J Gerss PhD, C Sauerland MSc)

23. Calcium dobesilate, a venotonic drug, has beneficial effects in vascular diseases such as chronic venous insufficiency and haemorrhoids and is prescribed in more than 60 countries. It seems to be safe, with infrequent complications including fever, gastrointestinal disorders, skin reactions, arthralgia, and very rarely, agranulocytosis (0 ・ 32 cases per million). In general, pharmacological data for calcium dobesilate indicate its ability to decrease capillary permeability, platelet aggregation, and blood viscosity.

25. Medical treatment for diabetic retinopathy could have an important role in prevention of complications such as visual loss. We aimed to assess the effect of calcium dobesilate on occurrence of diabetic macular oedema. Background

26. We undertook a randomised, double-blind, placebo-controlled, multicentre study in 40 centres in 11 countries. We enrolled outpatients with adult-onset type 2 diabetes and mild-to- moderate non-proliferative diabetic retinopathy, and randomly allocated them via sealed envelopes either calcium dobesilate (1500 mg per day) or placebo. The primary endpoint was development of clinically significant macular oedema (CSME) within a follow-up period of 5 years. Patients who dropped out of the study early were censored. Analysis was by intention to treat. Methods

29. Figure 2: Estimated cumulative 5-year event probability The log-rank test was used to calculate p values. (A) Total population (intention-to-treat analysis). (B) Subpopulation with HbA1c concentrations 9% or higher and systolic blood pressure of 140 mm Hg or more (post-hoc analysis). (C) Women with HbA1c concentrations 9% or higher and systolic blood pressure of 140 mm Hg or more (post-hoc analysis).

33. We enrolled 635 patients. 324 were randomly allocated calcium dobesilate and 311 were assigned placebo. In the calcium dobesilate group, 86 patients developed CSME compared with 69 in the placebo group. Accounting for censored cases, estimated cumulative 5-year CSME probability was 35% and 28%, respectively (hazard ratio 1 ・ 32, 95% CI 0 ・ 96–1 ・ 81; p=0 ・ 0844). Adverse events did not differ between treatment groups (78 [24%] on calcium dobesilate and 90 [29%] with placebo). No relevant drug-related complications were noted. Nine patients (3%) died in the calcium dobesilate group and eight (3%) deaths were recorded on placebo. Findings

34. Calcium dobesilate did not reduce the risk of development of CSME. Funding Sanofi ; OM Pharma; and Synthelabo. Interpretation