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Journal Club

Journal Club. Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, Woodward M, Ninomiya T, Neal B, MacMahon S, Grobbee DE, Kengne AP, Marre M, Heller S; ADVANCE Collaborative Group . Severe hypoglycemia and risks of vascular events and death.

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Journal Club

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  1. Journal Club Zoungas S, Patel A, Chalmers J, de Galan BE, Li Q, Billot L, Woodward M, Ninomiya T, Neal B, MacMahon S, Grobbee DE, Kengne AP, Marre M, Heller S; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010 Oct 7;363(15):1410-8. Ratner RE, Rosenstock J, Boka G; DRI6012 Study Investigators. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with Type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabet Med. 2010 Sep;27(9):1024-32. 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 2010年10月14日8:30-8:55 ８階　医局

  2. ACCORD 累積イベント発症率（%） 良い 良い 症例数 強化療法 通常療法 HbA1Cの推移 主要評価項目 9.0 中央値 バーは四分位範囲 25 9.5 差がない！ 通常療法 20 9.0 通常療法 8.5 HbA1C（%） 15 8.0 7.5 強化療法 10 7.0 6.5 5 6.0 強化療法 0.0 0 0 観察期間（年） 1 2 3 4 5 6 0 観察期間（年） 1 2 3 4 5 6 症例数 通常療法 強化療法 5,109 5,119 4,774 4,768 4,588 4,585 3,186 3,165 1,744 1,706 455 476 436 471 5,128 5,123 4,843 4,827 4,390 4,262 2,839 2,702 1,337 1,186 475 440 448 395

  3. VADT 良い 良い HbA1Cの推移 非致死性イベント 10.5 中央値 100 差がない！ 通常療法（8.4%） 10.0 強化療法 9.5 80 9.0 8.5 60 HbA1C（%） 通常療法 非発症率（%） 8.0 7.5 40 7.0 6.5 20 6.0 強化療法（6.9%） 5.5 0.0 0 登録時 観察期間（年） 1 2 3 4 5 6 観察期間（年） 0 1 2 3 4 5 6 7

  4. ADVANCE 10.0 P<0.001 9.5 9.0 8.5 8.0 平均HbA1C（%） 累積イベント発症率（%） 7.5 強化療法 7.0 6.5 6.0 5.5 通常療法 5.0 良い 0.0 0 観察期間（ヵ月） 6 12 18 24 30 36 42 48 54 60 66 良い HbA1C値 症例数 通常療法 強化療法 7.32 7.01 7.30 6.93 7.29 6.70 7.29 6.53 7.31 6.50 7.33 6.52 7.29 6.53 強化療法 通常療法 HbA1Cの推移 大血管症+細小血管症への影響 差があったが10%程度！ 25 通常療法 20 15 強化療法 10 5 0 0 観察期間（ヵ月） 6 12 18 24 30 36 42 48 54 60 66 5,570 5,569 5,457 5,448 5,369 5,342 5,256 5,240 5,100 5,065 4,957 4,903 4,867 4,808 4,756 4,703 4,599 4,545 4,044 3,992 1,883 1,921 447 470

  5. N Engl J Med 2010;363:1410-8.

  6. the George Institute for International Health, University of Sydney, Sydney (S.Z., A.P., J.C., B.E.G., Q.L.M., L.B., M.W., T.N., B.N., S.M., A.P.K.); the School of Public Health, Monash University, Melbourne, Australia (S.Z.); the Department of General Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen (B.E.G.), and the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht (D.E.G.) — both in the Netherlands; Mount Sinai School of Medicine, New York (M.W.); Hôpital Bichat–Claude Bernard and Université Paris, Paris (M.M.); and the University of Sheffield and Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, United Kingdom (S.H.). N Engl J Med 2010;363:1410-8.

  7. Background Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes.

  8. Methods We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization.

  9. Figure 1. Annual Rates of Severe Hypoglycemia According to Treatment Assignment and Adverse Clinical Outcomes among Patients with Severe Hypoglycemia. Panel A shows the rates of severe hypoglycemia in the group assigned to the intensive glucose-lowering intervention (P<0.001 for trend) and the group assigned to standard glucose control (P = 0.38 for trend). Panel B shows the frequency of adverse clinical outcomes after the occurrence of a severe hypoglycemic episode.

  10. Results During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death.

  11. Conclusion Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.)

  12. Message/Comments ADVANCE研究で低血糖が心血管イベントと関連が非常に強いことが判明した！

  13. GLP-1受容体刺激薬 Albugon CJC-1131 CJC-1134 Taspoglutide (R1583/BIM51077) (Exendine-4) ExenatideLAR a nasal spray formulation ofrecombinant human GLP-1 a stabilized GLP-1 analogue

  14. Diabet. Med. 27, 1024–1032 (2010)

  15. Aim To evaluate the dose–response relationship of lixisenatide (AVE0010), a glucagon-like peptide-1 (GLP-1) receptor agonist, in metformin-treated patients with Type 2 diabetes.

  16. Methods Randomized, double-blind, placebo-controlled, parallel-group, 13 week study of 542 patients with Type 2 diabetes inadequately controlled [glycatedhaemoglobin (HbA1c) ≧7.0 and < 9.0% (≧53 and < 75 mmol⁄mol)] on metformin (≧ 1000 mg ⁄ day) treated with subcutaneous lixisenatide doses of 5, 10, 20 or 30 mg once daily or twice daily or placebo. The primary end-point was change in HbA1c from baseline to 13 weeks in the intent-to-treat population.

  17. Table 1 Patient disposition, demographics and baseline characteristics (safety population)

  18. FIGURE 1 Changes in glycatedhaemoglobin (HbA1c) levels following 13 weeks’ treatment with lixisenatideonce daily or twice daily, according to dosage and regimen. Top panel shows change inmean (sem) HbA1c over time. Bottom panel shows least square (LS) mean change in HbA1c from baseline to 13 week

  19. FIGURE 2 Percentage of patients with glycatedhaemoglobin (HbA1c) level of < 7.0% (53 mmol⁄ mol; top panel) and < 6.5% (48 mmol⁄ mol; bottom panel) following 13 weeks’ treatment with lixisenatide once daily or twice daily, according to dosage and regimen.

  20. Table 2 The least square adjusted mean ± sem changes in fasting plasma glucose, daily averaged self-monitored seven-point blood glucose and 2 h postprandial plasma glucose following 13 weeks of treatment with lixisenatide once daily or twice daily according to dosage and regimen in the ITT population

  21. Table 3 Number (%) of patients with treatment-emergent adverse events occurring in ≧10% in any one group and symptomatic hypoglycaemia in the safety population

  22. Results Lixisenatide significantly improved mean HbA1c from a baseline of 7.55% (59.0 mmol⁄ mol); respective mean reductions for 5, 10, 20 and 30 mg doses were 0.47, 0.50, 0.69 and 0.76% (5.1, 5.5, 7.5 and 8.3 mmol⁄ mol), on oncedaily and 0.65, 0.78, 0.75 and 0.87% (7.1, 8.5, 8.2 and 9.5 mmol⁄ mol) on twice-daily administrations vs. 0.18% (2.0 mmol⁄ mol) with placebo (all P < 0.01 vs. placebo). Target HbA1c < 7.0% (53 mmol⁄ mol) at study end was achieved in 68% of patients receiving 20 and 30 mg once-daily lixisenatide vs. 32% receiving placebo (P < 0.0001). Dose-dependent improvements were observed for fasting, postprandial and average self-monitored seven-point blood glucose levels. Weight changes ranged from -2.0 to -3.9 kg with lixisenatide vs. -1.9 kg with placebo. The most frequent adverse event was mild-to-moderate nausea.

  23. Conclusion Lixisenatide significantly improved glycaemic control in mildly hyperglycaemic patients with Type 2 diabetes on metformin. Dose–response relationships were seen for once- and twice-daily regimens, with similar efficacy levels, with a 20 mg once-daily dose of lixisenatide demonstrating the best efficacy-to-tolerability ratio. This new, oncedaily GLP-1 receptor agonist shows promise in the management of Type 2 diabetes to be defined further by ongoing long-term studies.

  24. Message/Comments GLP-1受容体作動薬の分野にもサノフィーアベンティス社も参入！

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