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Journal Club. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mozenson O, McGuire DK, Ray KK, Leiter LA, Raz I; the SAVOR-TIMI 53 Steering Committee and Investigators.

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journal club
Journal Club

Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mozenson O, McGuire DK, Ray KK, Leiter LA, Raz I; the SAVOR-TIMI 53 Steering Committee and Investigators.

Saxagliptinand Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus.

N Engl J Med. 2013 Sep 2. [Epub ahead of print]

Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, Haneuse S, Craft S, Montine TJ, Kahn SE, McCormick W, McCurry SM, Bowen JD, Larson EB.

Glucose levels and risk of dementia.

N Engl J Med. 2013 Aug 8;369(6):540-8. doi: 10.1056/NEJMoa1215740.

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 坂下 杏奈 

Matsuda, Masafumi, Sakashita, Anna

2013年9月19日8:30-8:55

8階 医局

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DPP-4阻害薬の心血管アウトカム試験

綿田裕孝(順天堂大学大学院代謝内分泌内科学)PharmaMedica ;30,8,157-164.2012.

clinicaltrials.gov(http://clinicaltrials.gov/)をもとに一部改変

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the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School (B.M.S., D.L.B., E.B., S.D.W., E.B.H., M.A.C., J.A.U., N.R.D.), and the VA Boston Healthcare System (D.L.B.) — all in Boston; INSERM Unité 698, Université Paris-Diderot, and DépartementHospitalo-Universitaire FIRE, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris, Paris (P.G.S.); the Divisions of Endocrinology (J.D.) and Cardiovascular Medicine (D.K.M.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas; AstraZeneca Research and Development, Wilmington, DE (B.H., P.O.); Bristol-Myers Squibb, Princeton, NJ (R.F.); the Diabetes Unit, Department of Internal Medicine, Hadassah University Hospital, Jerusalem (O.M., I.R.); the Cardiovascular Sciences Research Centre, St. George’s University of London, London (K.K.R.); and the Division of Endocrinology and Metabolism, Keenan Research Centre in the Li KaShing Knowledge Institute of St. Michael’s Hospital, University of Toronto, Toronto (L.A.L.).

N Engl J Med 2013. DOI: 10.1056/NEJMoa1307684

slide4
Background

The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear.

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Methods

We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke.

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Figure 1. Kaplan–Meier Rates of the Primary and Secondary End Points. The primary end point (Panel A) was a composite of death from cardiovascular causes, myocardial infarction, or ischemic stroke.
slide12
Figure 1. Kaplan–Meier Rates of the Primary and Secondary End Points. The secondary end point (Panel B) was a composite of death from cardiovascular causes, myocardial infarction, ischemic stroke, hospitalization for unstable angina, coronary revascularization, or heart failure.
slide20
Results

A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan–Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P = 0.99 for superiority; P<0.001 for noninferiority); the results were similar in the “on-treatment” analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan–Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P = 0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P = 0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).

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Conclusions

DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. (Funded by AstraZeneca and Bristol- Myers Squibb; SAVOR-TIMI 53 ClinicalTrials.gov number, NCT01107886.)

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Message

心血管イベント高リスクの2型糖尿病(DM)患者1万6492人を対象に、DPP-4阻害薬saxagliptinの効果を無作為化試験で評価(SAVOR-TIMI53試験)。主要複合評価項目(心血管死、心筋梗塞、虚血性脳卒中)はプラセボ群と同等だった。心不全による入院はsaxagliptin群で多かった(ハザード比1.27)

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the Departments of Medicine (P.K.C., W.M., E.B.L.), Psychiatry and Behavioral Sciences (G.L.), Pathology (T.J.M.), and Psychosocial and Community Health (S.M.M.), University of Washington; the Group Health Research Institute (R.W., R.A.H., E.B.L.); the Department of Medicine, VA Puget Sound Health Care System and University of Washington (S.E.K.); and the Swedish Neuroscience Institute ( J.D.B.) — all in Seattle; the Diabetes Center and Department of Medicine (D.M.N.) and the Biostatistics Center (H.Z.), Massachusetts General Hospital and Harvard Medical School; and the Department of Biostatistics, Harvard School of Public Health (S.H.) — all in Boston; and the Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC (S.C.).

N Engl J Med 2013;369:540-8. DOI: 10.1056/NEJMoa1215740

slide25
Background

Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes.

slide26
Methods

We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension.

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The sample for the current study was limited to 2067 participants who had at least one follow-up visit, had been enrolled in Group Health for at least 5 years before study entry, and had at least five measurements of glucose or glycated hemoglobin (measured as hemoglobin A1c or as total glycated hemoglobin, with the latter measurement reflecting an older hemoglobin assay) over the course of 2 or more years before study entry.
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Identification of Dementia

Study participants were assessed for dementia every 2 years with the use of the Cognitive Abilities Screening Instrument, for which scores range from 0 to 100 and higher scores indicate better cognitive functioning. Patients with scores of 85 or less underwent further clinical and psychometric evaluation, including a battery of neuropsychological tests. The results of these evaluations and laboratory testing and imaging records were then reviewed in a consensus conference. Diagnoses of dementia and of probable or possible Alzheimer’s disease were made on the basis of research criteria. Dementia-free participants continued with scheduled follow-up visits. The incidence date for dementia was recorded as the halfway point between the study visit at which dementia was diagnosed and the previous visit.

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Risk Factors Assessed

Glucose Levels

Diabetes

Apolipoprotein E Genotype

Other Risk Factors

exercise level

smoking status

blood pressure

atrial fibrillation

treatment of hypertension

obesity?

slide33
We transformed values for total glycated hemoglobin to hemoglobin A1c values using this formula:

hemoglobin A1c = (0.6 × total glycated hemoglobin) + 1.7

We then transformed the calculated hemoglobin A1c values to daily average glucose values with this formula:

daily average glucose = (28.7 × hemoglobin A1c) –46.7

Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ. Translating the A1C assay into estimated average glucose values. Diabetes Care 2008;31:1473-8. [Erratum, Diabetes Care 2009;32:207.] (ref.10)

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Dementia, Alzheimer’s Disease, and Glycemia

Over a median follow-up period of 6.8 years, dementia developed in 524 of the 2067 participants (25.4%), including 450 of the 1724 participants who did not have diabetes at the end of follow-up (26.1%) and 74 of the 343 participants who had diabetes at the end of follow-up (21.6%). A total of 403 participants (19.5%) had probable or possible Alzheimer’s disease at the end of follow-up, 55 (2.7%) had dementia from vascular disease, and 66 (3.2%) had dementia from other causes.

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Figure 1. Risk of Incident Dementia Associated with the Average Glucose Level during the Preceding 5 Years, According to the Presence or Absence of Diabetes.

Solid curves represent estimates of the hazard ratios for the risk of incident dementia across average glucose levels relative to a reference level of 100 mg per deciliter for participants without diabetes (Panel A) and 160 mg per deciliter for participants with diabetes (Panel B). The dashed lines represent pointwise 95% confidence intervals. To convert the values for glucose to millimoles per liter, multiply by 0.05551.

slide38
We also found an inverse association between glucose level and risk of dementia among people with diabetes who had relatively low levels of glucose, although this association appeared to be driven by glucose levels in three participants with atypical courses of type 2 diabetes.
slide42
This figure shows spline curves for the relationship between glycemia and dementia for participants with diabetes, stratified by age at study entry. Ages at study entry range from 70 in the top left panel to 78 at the bottom right panel (the inter‐quartile range of age at study entry for people with diabetes). Higher risk associated with both higher and lower levels of glycemia appear to be especially prominent among people who were older at study entry. We performed these analyses for people with diabetes because of the suggestive p value for the age at study entry interaction term for all‐cause dementia among people with diabetes (p=0.13).
slide43
Results

During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P = 0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P = 0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76).

slide44
Conclusions

Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes.

(Funded by the National Institutes of Health.)

slide45
Message

高齢者における機能変化を検討したAdult Changes in Thought研究の参加者2067人(平均年齢76歳)を対象に、血糖値と認知症の関係を検討。非糖尿病者では過去5年の平均血糖高値が認知症リスク増加と関連し(P=0.01)、糖尿病(DM)患者でも平均血圧高値がリスク増加と関連した(P=0.002)。

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