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Journal Club

Journal Club. Cholesterol Treatment Trialists ' Ctt Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012 May 16. [ Epub ahead of print ]

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Journal Club

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  1. Journal Club Cholesterol Treatment Trialists' Ctt Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012 May 16. [Epub ahead of print] Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Hólm H, Ding EL, Johnson T, Schunkert H, Samani NJ, Clarke R, Hopewell JC, Thompson JF, Li M, Thorleifsson G, Newton-Cheh C, Musunuru K, Pirruccello JP, Saleheen D, Chen L, Stewart AF, Schillert A, Thorsteinsdottir U, Thorgeirsson G, Anand S, Engert JC, Morgan T, Spertus J, Stoll M, Berger K, Martinelli N, Girelli D, McKeown PP, Patterson CC, Epstein SE, Devaney J, Burnett MS, Mooser V, Ripatti S, Surakka I, Nieminen MS, Sinisalo J, Lokki ML, Perola M, Havulinna A, de Faire U, Gigante B, Ingelsson E, Zeller T, Wild P, de Bakker PI, Klungel OH, Maitland-van der Zee AH, Peters BJ, de Boer A, Grobbee DE, Kamphuisen PW, Deneer VH, Elbers CC, Onland-Moret NC, Hofker MH, Wijmenga C, Verschuren WM, Boer JM, van der Schouw YT, Rasheed A, Frossard P, Demissie S, Willer C, Do R, Ordovas JM, Abecasis GR, Boehnke M, Mohlke KL, Daly MJ, Guiducci C, Burtt NP, Surti A, Gonzalez E, Purcell S, Gabriel S, Marrugat J, Peden J, Erdmann J, Diemert P, Willenborg C, König IR, Fischer M, Hengstenberg C, Ziegler A, Buysschaert I, Lambrechts D, Van de Werf F, Fox KA, El Mokhtari NE, Rubin D, Schrezenmeir J, Schreiber S, Schäfer A, Danesh J, Blankenberg S, Roberts R, McPherson R, Watkins H, Hall AS, Overvad K, Rimm E, Boerwinkle E, Tybjaerg-Hansen A, Cupples LA, Reilly MP, Melander O, Mannucci PM, Ardissino D, Siscovick D, Elosua R, Stefansson K, O'Donnell CJ, Salomaa V, Rader DJ, Peltonen L, Schwartz SM, Altshuler D, Kathiresan S. Plasma HDL cholesterol and risk of myocardial infarction: a mendelianrandomisation study. Lancet. 2012 May 17. [Epub ahead of print] 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 2012年5月24日8:30-8:55 ８階　医局

  2. METHODS AND MATERIALS RESULTS (figures) ABSTRACT We compared directly these two medications in 16 type 2 diabetic patients. Pioglitazone (n=2) and metformin (n=9) were continued in 11 subjects. Patients received SIT (50mg qd for 1 week and 100mg qd for an additional week) or MIT (10mg tid for 2 weeks). After 2 Both sitagliptin (SIT) and mitiglinide (MIT) have potency to reduce the plasma glucose (PG) conc. after an oral glucose load. However, the differences through affecting hormonal levels after an oral glucose load are not studied well, when similar levels of PG are achieved. We compared directly these two agents in 16 type 2 diabetic patients (M/F=10/6, Age: 66±3 y.o., BMI: 24±4kg/m2, HbA1c: 6.6±0.5%, FPG: 116±27mg/dl). Pioglitazone (n=2) and metformin (n=9) were continued in 11 subjects. Patients received SIT (50mg qd for 1 week and 100mg qd for an additional week) or MIT (10mg tid for 2 weeks). After 2 weeks, patients crossed-over to an alternative treatment. 75 g oral glucose tolerance tests (OGTT) were conducted before the study and after interventions. The average of area under the curve (aAUC) up to 180 min of PG response was similar in both agents and lower than before (CON) (SIT 179±53, MIT 174±50 vs CON 222±60 mg/dl, p<0.0001). Insulinogenic index was highest in MIT (0.3±0.3 vs SIT 0.2±0.2, p<0.01; vs CON 0.1±0.1, p<0.01), while the Matsuda index was similar in 3 OGTTs (MIT 10±5, SIT 11±7, CON 11±7). aAUC of GLP-1 was increased in SIT (15±14 vs MIT 6±5, p<0.001; vs CON 5±4 pmol/L, p<0.001). The incremental aAUC of glucagon was lower in SIT (-2.4±12.9 vs MIT 6.2±14.0, p<0.05; vs CON -0.7±15.0 ng/ml), although basal glucagon levels were paradoxically higher in SIT (77±17, vs MIT 71±18 p<0.05; vs CON 74±20 ng/ml). aAUC of proinsulin was decreased in SIT (15.0±3 8, vs MIT 21.4±9.8, p<0.01; vs CON 17.2±8.6 pmol/L, p<0.05). Triglyceride levels were reduced by MIT. There were no differences between subjects who randomly started with SIT first and those with MIT first. While clinical doses of SIT and MIT resulted in a similar PG control, SIT enhanced less insulin secretion with less glucagon responses and much less proinsulin responses compared with MIT. Thus these changes of hormonal profiles by SIT favor islet functions compared with MIT in clinical use. Effects of sitagliptin versus mitiglinide on insulin, proinsulin, glucagon and GLP-1responses after oral glucose load: a randomized, cross-over studyMASAFUMI MATSUDA, TOMOKO MORITA, NATSUKO OSHITANI, YOSHITAKA AKIYAMA, YUUKO OONO, YOSHIMASA ASO, TOSHIHIKO INUKAI, MASAFUMI KAKEI, MASANOBU KAWAKAMI, TAKUYA AWATA, SHIGEHIRO KATAYAMADepartment of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University, Kawagoe-shi, JAPAN weeks, patients crossed-over to the alternative treatment. 75 g oral glucose tolerance tests were conducted before and after the 2-weeks’ intervention. SUBJECTS SUMMARY Average of area under the curve (aAUC) up to 180 min. of glucose response was similar in both groups and significantly lower than before (CON). Insulinogenic index (II) was highest in MIT, while Matsuda index was similar in 3 groups. aAUC of GLP-1 was increased in SIT vs MIT or CON. Incremental aAUC of glucagon was lower in SIT vs MIT or CON, although basal glucagon levels are paradoxically higher in SIT vs MIT or CON. aAUC of proinsulin was markedly decreased in SIT vs MIT or CON. Triglyceride levels were reduced in MIT. You can copy and paste your background text here. RESULTS BACKGROUND AND AIM CONCLUSION Both sitagliptin (SIT) and mitiglinide (MIT) have potency to reduce plasma glucose concentration after oral glucose load. However, mechanistic differences with regard to hormonal differences after an oral glucose load are not well known, when similar levels of glucose concentration are achieved. We compared directly these two medications in 16 type 2 diabetic patients While clinical doses of sitagliptin and mitiglinide resulted with similar plasma glucose control, sitagliptin enhanced less insulin secretion with less glucagon responses and much less proinsulin responses compared with mitiglinide. It is expected that these changes of hormonal profiles of sitagliptin favored islet functions compared with mitiglinide in clinical use.

  3. LDL-コレステロール値と冠動脈イベント発症率との関係LDL-コレステロール値と冠動脈イベント発症率との関係 30 4S - Placebo ２次予防（一度心筋梗塞を起こした人） 25 Rx – スタチン治療 PRA – プラバスタチン ATV – アトロバスタチン 4S - Rx 20 LIPID - Placebo 冠動脈イベント(心筋梗塞)発症(%) 15 CARE - Placebo LIPID - Rx CARE - Rx HPS - Placebo HPS - Rx TNT – ATV10 10 PROVE-IT - PRA WOSCOPS – Placebo TNT – ATV80 PROVE-IT – ATV AFCAPS - Placebo 6 5 AFCAPS - Rx WOSCOPS - Rx ASCOT - Placebo １次予防（心筋梗塞をおこしてない人） ASCOT - Rx 0 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) 200 (5.2) LDL-コレステロール mg/dL (mmol/L) Adapted from Rosensen RS. Exp OpinEmerg Drugs 2004;9(2):269-279 LaRosa JC et al. N Engl J Med 2005;352:1425-1435

  4. スタチン介入大規模臨床試験におけるLDL-Cと冠動脈疾患イベント発症率の関係スタチン介入大規模臨床試験におけるLDL-Cと冠動脈疾患イベント発症率の関係 4S DM (placebo) 糖尿病　心血管病あり 心血管病あり 心血管病なし 30 CARE DM (placebo) 4S DM (simvastatin) LIPID DM (placebo) 20 4S (placebo) LIPID DM (pravastatin) 20 CARE DM (pravastatin) Patient with CHD event(mean%) 4S (simvastatin) LIPID (placebo) 15 CARE (placebo) WOSCOPS (placebo) 10 CARE (pravastatin) WOSCOPS (pravastatin) LIPID (pravastatin) 5 AFCAPS (lovastatin) AFCAPS (placebo) 0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 154 58 77 116 193 Mean LDL cholesterol( mmol / l )(mg/dl) Fisher M:Heart,90(3),336-340(2004)

  5. Inclusion criteria:LDL≦130 mg/dl and high-sensitivity CRP≧ 2.0 mg/l ■Effect of Rosuvastatin(20mg) ・Compliance; 75% n = 8901 ｘ 2 = 17802 -37% -50% +4% -17% N Engl J Med 2008;359:2195-207.

  6. The combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular cause HR=0.56; 95% CI, 0.46 to 0.69; P<0.00001) 20 mg NNT:95 31 ･･25 (2years)(4years)(5years) N Engl J Med 2008;359:2195-207.

  7. Lancet 2009; 373: 1175–82 LDL-C 70mg/dl For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRPare indicators of successful treatment with rosuvastatin.

  8. However, to immediately translate these findings into clinical practice without appropriate and careful discussion of their implications is not prudent. TURBO STATIN Helene Trudel Jean-Pierre Despres www.thelancet.com Vol 373:1178 April 4, 2009

  9. CTT Secretariat, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Richard Doll Building, Old Road Campus, Oxford OX3 7LF, UK www.thelancet.com Published online May 17, 2012 DOI:10.1016/S0140-6736(12)60367-5

  10. Background Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.

  11. Methods This meta-analysis included individual participant data from 22 trials of statin versus control (n=134 537; mean LDL cholesterol difference 1・08 mmol/L; median follow-up 4・8 years) and five trials of more versus less statin (n=39 612; difference 0・51 mmol/L; 5・1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1・0 mmol/L LDL cholesterol reduction was estimated. LDL-C 1 mmol/L1/0.0259 = 38.6mg/dl

  12. Figure 3: Effects on vascular and non-vascular deaths per 1・0 mmol/L reduction in LDL cholesterol at different levels of risk, by history of vascular disease MVE=major vascular event. RR=rate ratio. CI=confidence interval. There were a further 179 (statin/more statin) versus 210 (control/less statin) deaths of unknown cause among participants without vascular disease and 309 (statin/ more statin) versus 338 (control/less statin) deaths of unknown cause among participants with vascular disease.

  13. Figure 3: Effects on vascular and non-vascular deaths per 1・0 mmol/L reduction in LDL cholesterol at different levels of risk, by history of vascular disease MVE=major vascular event. RR=rate ratio. CI=confidence interval. There were a further 179 (statin/more statin) versus 210 (control/less statin) deaths of unknown cause among participants without vascular disease and 309 (statin/ more statin) versus 338 (control/less statin) deaths of unknown cause among participants with vascular disease.

  14. Findings Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0・79, 95% CI 0・77–0・81, per 1・0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1・0 mmol/L reduction from lowest to highest risk: 0・62 [99% CI 0・47–0・81], 0・69 [99% CI 0・60–0・79], 0・79 [99% CI 0・74–0・85], 0・81 [99% CI 0・77–0・86], and 0・79 [99% CI 0・74–0・84]; trend p=0・04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0・57, 99% CI 0・36–0・89, p=0・0012, and 0・61, 99% CI 0・50–0・74, p<0・0001) and in coronary revascularisations (RR 0・52, 99% CI 0・35–0・75, and 0・63, 99% CI 0・51–0・79; both p<0・0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1・0 mmol/L LDL cholesterol reduction 0・76, 99% CI 0・61–0・95, p=0・0012) was also similar to that seen in higher risk categories (trend p=0・3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1・0 mmol/L LDL cholesterol reduction 0・85, 95% CI 0・77–0・95) and all-cause mortality (RR 0・91, 95% CI 0・85–0・97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1・0 mmol/L LDL cholesterol reduction 1・00, 95% CI 0・96–1・04), cancer mortality (RR 0・99, 95% CI 0・93–1・06), or other non-vascular mortality.

  15. Interpretation In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. Funding British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.

  16. Message 　無作為化試験27件を対象に、低リスク患者へのスタチンの効果をメタ解析で検討。スタチンがLDLコレステロールを下げることで重大血管イベントリスク（脳梗塞、脳卒中など）が減少した。5年リスク10％未満の患者ではLDL-C 1mmol/L減少ごとに、1000人当たり約11の血管イベントの絶対的減少が示唆された。

  17. From Kawasaki Medical School Syllabus

  18. Figure 4: Association between HDL-C and arterial inflammation as measured by MDS TBR on PET/CT and arterial inflammation and atherosclerotic burden HDL-C=high-density lipoprotein cholesterol. MDS=most-diseased-segment. TBR=target-to-background ratio. (A) Change in arterial inflammation (MDS TBR) over 6 months versus change in HDL-C over the same period grouped in tertiles (third tertile represents the greatest increase in HDL-C). (B) Early increases in arterial inflammation associated with subsequent increases in atherosclerotic burden. The change in carotid inflammation at 6 months was compared within subjects that were classified into tertiles according to the subsequent rate of change in total vessel area at 24 months. Lancet. 2011 Oct 29;378(9802):1547-59. Epub 2011 Sep 9.

  19. www.thelancet.com Published online May 17, 2012 DOI:10.1016/S0140-6736(12)60312-2

  20. Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelianrandomisationcan be used to test the hypothesis that the association of a plasma biomarker with disease is causal.

  21. Methods We performed two mendelianrandomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.

  22. Findings Carriers of the LIPG 396Ser allele (2・6% frequency) had higher HDL cholesterol (0・14 mmol/L higher, p=8×10–13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0・87, 95% CI 0・84–0・91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0・99, 95% CI 0・88–1・11, p=0・85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0・62, 95% CI 0・58–0・66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0・93, 95% CI 0・68–1・26, p=0・63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1・54, 95% CI 1・45–1・63) was concordant with that from genetic score (OR 2・13, 95% CI 1・69–2・69, p=2×10–10).

  23. SNPs affecting LDL cholesterol were consistently related to risk of myocardial infarction. However, we unexpectedly found that LIPG Asn396Ser, a genetic variant that specifically and substantially increases plasma HDL cholesterol, did not reduce risk of myocardial infarction.

  24. Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

  25. Panel: Research in context Systematic review Electronic searches of Medline and PubMed, supplemented by hand searches of reference lists of other review articles, identified reports from three large mendelianrandomisation studies for plasma HDL cholesterol. In each of these previous reports, genetically increased plasma HDL cholesterol was not associated with risk of ischaemic heart disease. Interpretation The present study tested a naturally occurring loss-of function variant in the endothelial lipase gene and, with this new instrument, we confirm that genetically raised plasma HDL cholesterol is not associated with risk of myocardial infarction. The study further extends previous work by testing an instrument consisting of 14 common variants exclusively associated with plasma HDL cholesterol. A genetic score consisting of these 14 variants was not associated with risk of myocardial infarction. These results show that some ways of raising HDL cholesterol might not reduce risk of myocardial infarction in human beings. Therefore, if an intervention such as a drug raises HDL cholesterol, we cannot automatically assume that risk of myocardial infarction will be reduced.

  26. Message 心筋梗塞患者を対象に、HDLコレステロール（HDL-C）と心筋梗塞の関連を2件のメンデルランダム化解析（総参加者数：約17万人）で検討。観察的疫学では、HDL-Cの1SD増加は心筋梗塞リスクの低下と関連した（オッズ比0.62）。しかし、遺伝的スコアによるHDL-Cの1SD増加とは関連が見られなかった（同0.93）。

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