Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2008 年５月 29 日 8:20-8:50 B 棟８階 カンファレンス室

Lancet 2008; 371: 1753–60 Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (Prof J Weng MD, M Li MD, Y Chen MD, L Zeng MD); First Affiliated Hospital of Sun Yat- Sen University, Guangzhou, China (Prof Y Li MD, J Liu MD, W Xu MD); Affi liated Hospital of Guiyang Medical College, Guizhou, China (Prof L Shi MD, Q Zhang MD); Gulou Hospital of Nanjing University, Nanjing, China (Prof D Zhu MD, Y Hu MD); Xiangya Second Affiliated Hospital of Central South University, Changsha, China (Prof Z Zhou MD, X Yan MD); West China Hospital of Sichuan University, Chengdu, China (Prof H Tian MD, X Ran MD); First Affiliated Hospital of Guangxi Medical University, Nanning, China (Prof Z Luo MD, J Xian MD); Second Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China (Prof L Yan MD, Prof Z Fu MD, F Li MD, Prof H Cheng MD); and First Affiliated Hospital of Fujian Medical University, Fuzhou, China (Prof L Yang MD, S Yan MD) 孫逸仙， 中山大学，広州

Early intensive insulin therapy in patients with newly diagnosed type 2 diabetes might improve β-cell function and result in extended glycaemic remissions. We did a multicentre, randomised trial to compare the effects of transient intensive insulin therapy (continuous subcutaneous insulin infusion [CSII] or multiple daily insulin injections [MDI]) with oral hypoglycaemic agents on β-cell function and diabetes remission rate. Background

382 patients, aged 25–70 years, were enrolled from nine centres in China between September, 2004, and October, The patients, with fasting plasma glucose of 7 ・ 0–16 ・ 7 mmol/L, were randomly assigned to therapy with insulin (CSII or MDI) or oral hypoglycaemic agents for initial rapid correction of hyperglycaemia. Treatment was stopped after normoglycaemia was maintained for 2 weeks. Patients were then followed-up on diet and exercise alone. Intravenous glucose tolerance tests were done and blood glucose, insulin, and proinsulin were measured before and after therapy withdrawal and at 1-year follow-up. Primary endpoint was time of glycaemic remission and remission rate at 1 year after short-term intensive therapy. Analysis was per protocol. This study was registered with ClinicalTrials.gov, number NCT Methods

Newly diagnosed type 2 diabetes, according to WHO diagnostic criteria (1999), who had not received previous antihyperglycaemic therapy, were enrolled from nine centres in China between September, 2004, and October, The patients, aged 25–70 years, had levels of FPG between 7 ・ 0 mmol/L (126mg/dl) and 16 ・ 7 mmol/L(300mg/dl). Patients were excluded if they had acute or severe chronic diabetic complications, severe intercurrent illness, or tested positive for glutamic acid decarboxylase antibody. Patients with maturity onset diabetes in youth and mitochondria diabetes mellitus were excluded. There was a 3– 7 days run-in period of diet alone

Three groups for antihyperglycaemic therapies: MDI, CSII, or oral hypoglycaemic agents. Sealed, opaque envelopes arranged in a computer-generated random order were prepared by the data-coordinating centre and distributed to each participating centre, where they were opened sequentially to determine the patients’ treatment assignments. Patients in the CSII group received human insulin (Novo Nordisk, Bagsvard, Denmark) with an insulin pump (H-Tron Plus V100; Disetronic Medical Systems). Patients in the MDI group were treated with pre-meal Novolin-R, and human insulin NPH (Novolin-N, Novo Nordisk) at bedtime. Initial insulin doses were 0 ・ 4–0 ・ 5 IU/kg and total daily doses were divided into 50% of basal and 50% of bolus injection in the CSII group and into 30%–20%–20%–30% in the MDI group. In the group treated with oral hypoglycaemic agents, patients with a body-mass index between 20 kg/m2 and 25 kg/m2 were initially treated with gliclazide (Servier, Tianjin, China) 80 mg twice a day, which was increased up to a maximum of 160 mg twice a day to achieve glycaemic control. Patients with a body-mass index of between 25 kg/m2 and 35 kg/m2 were initially treated with metformin (Glucophage, Bristol-Myers Squibb) 0 ・ 5 g twice a day and increased to a maximum of 2 ・ 0 g a day. A combination of gliclazide and metformin was used in patients who could not reach the glycaemic control goal with one oral hypoglycaemic agent or who had a fasting plasma glucose of 11 ・ 1 mmol/L or more at randomisation. The doses were titrated every day in the insulin groups and every 3 days in the hypoglycaemic agents group in order to attain the glycaemic goal. This goal was defined as a fasting capillary blood glucose of less than 6 ・ 1 mmol/L and capillary blood glucose at 2 h after each of three meals of less than 8 ・ 0 mmol/L. Treatments were maintained for 2 weeks after the glycaemic target was reached. Patients who did not achieve glycaemic control by CSII or MDI alone or by combined maximum dosage of oral hypoglycaemic agents within 2 weeks, or could not stand the side-effects of oral hypoglycaemic agents, were regarded as requiring additional or different therapy and were excluded from the efficacy analysis.

Figure 2: Kaplan-Meier estimates of time to primary endpoint After interventions were stopped, patients were instructed to continue diet and physical exercise only and were followed-up with glycaemic monitoring monthly during the initial 3 months and at 3-month intervals thereafter. Hyperglycaemia relapse was defined as either FPG of more than 7 ・ 0 mmol/L (126 mg/dl) or 2-h postprandial PG of more than 10 ・ 0 mmol/L (180 mg/dl), which was confirmed 1 week later.

Table 2: Comparison between remission group and non-remission group before and after treatment

25 g of glucose (50 mL of 50% glucose), with serum samples obtained before and 1, 2, 4, 6, and 10 min after intravenous glucose load to measure insulin.

More patients achieved target glycaemic control in the insulin groups (97 ・ 1% [133 of 137] in CSII and 95 ・ 2% [118 of 124] in MDI) in less time (4 ・ 0 days [SD 2 ・ 5] in CSII and 5 ・ 6 days [SD 3 ・ 8] in MDI) than those treated with oral hypoglycaemic agents (83 ・ 5% [101 of 121] and 9 ・ 3 days [SD 5 ・ 3]). Remission rates after 1 year were significantly higher in the insulin groups (51 ・ 1% in CSII and 44 ・ 9% in MDI) than in the oral hypoglycaemic agents group (26 ・ 7%; p=0.0012). β-cell function represented by HOMA-B and acute insulin response improved significantly after intensive interventions. The increase in acute insulin response was sustained in the insulin groups but significantly declined in the oral hypoglycaemic agents group at 1 year in all patients in the remission group. Summary

Early intensive insulin therapy in patients with newly diagnosed type 2 diabetes has favourable outcomes on recovery and maintenance of β-cell function and protracted glycaemic remission compared with treatment with oral hypoglycaemic agents. Interpretation

Other factors beyond the elimination of glucotoxicity might be relevant. These data might support the concept of a beneficial effect of “β-cell rest” with insulin therapy. Alternatively, other biological actions of insulin might be contributory, including anti-inflammatory activity and the potential direct effects of insulin-receptor signaling on β-cell growth and survival. Although the relevant biological mechanisms and target tissues contributing to preferential improvement in β- cell function remain unclear, these data suggest that the use of intensive insulin therapy early in the course of type 2 diabetes warrants further clinical investigation. Comments

Lancet 2008; 371: 1783–89 Department of Endocrinology, China-Japan Friendship Hospital, Beijing, China (Prof G Li MD, Prof W Yang MD, Q Gong MD, Ho Li PhD, Y An MD, Y Shuai MS, B Zhang MD); Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA (P Zhang PhD, E W Gregg PhD, T J Thompson MS, R B Gerzoff MS); Department of Cardiology, Da Qing First Hospital, Da Qing, China (J Wang MD, Hu Li MD, Y Jiang BS, J Zhang RS, Y Hu MD); Department of Chronic Diseases and Health Promotion, World Health Organization, Geneva, Switzerland (G Roglic MD); and Phoenix Epidemiology and Clinical Research Branch, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA (P H Bennett FRCP) 大慶

Panel: Summary of concerns about the metabolic syndrome Criteria are ambiguous or incomplete; rationale for thresholds is ill-defined Value of including diabetes in definition is questionable Insulin resistance as unifying cause is uncertain No clear basis for including or excluding other cardiovascular risk factors Cardiovascular risk value is variable and dependent on specific risk factors present Cardiovascular risk associated with the syndrome seems to be no greater than sum of its parts Treatment of syndrome is no diff erent from treatment for each of its components Medical value of diagnosing the syndrome is unclear

Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance, but how long these benefits extend beyond the period of active intervention, and whether such interventions reduce the risk of cardiovascular disease (CVD) and mortality, is unclear. We aimed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes, diabetes- related macrovascular and microvascular complications, and mortality. Background

In 1986, 577 adults with impaired glucose tolerance from 33 clinics in China were randomly assigned to either the control group or to one of three lifestyle intervention groups (diet, exercise, or diet plus exercise). Active intervention took place over 6 years until In 2006, study participants were followed-up to assess the long-term effect of the interventions. The primary outcomes were diabetes incidence, CVD incidence and mortality, and all-cause mortality. Methods

Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537–44.

Table 1: Characteristics of study participants by group at baseline (1986), end of the 6-year active intervention (1992), and end of follow-up (2006)

Table 2 Incidence of diabetes, CVD, and mortality in the active intervention (1986–92) and entire follow-up period (1986–2006), and CVD and mortality in the post intervention period (1993–2006)

Figure 3: Cumulative incidence of all-cause mortality (A), first CVD event (B), and CVD mortality (C) during follow-up in China Da Qing Diabetes Prevention Outcome Study

Compared with control participants, those in the combined lifestyle intervention groups had a 51% lower incidence of diabetes (hazard rate ratio [HRR] 0∙49; 95% CI 0∙33−0∙73) during the active intervention period and a 43% lower incidence (0∙57; 0∙41−0∙81) over the 20 year period, controlled for age and clustering by clinic. The average annual incidence of diabetes was 7% for intervention participants versus 11% in control participants, with 20-year cumulative incidence of 80% in the intervention groups and 93% in the control group. Participants in the intervention group spent an average of 3 ・ 6 fewer years with diabetes than those in the control group. There was no significant difference between the intervention and control groups in the rate of first CVD events (HRR 0∙98; 95% CI 0∙71−1∙37), CVD mortality (0∙83; 0∙48−1∙40), and all-cause mortality (0∙96; 0∙65−1∙41), but our study had limited statistical power to detect differences for these outcomes. Summary

Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention. However, whether lifestyle intervention also leads to reduced CVD and mortality remains unclear. Interpretation

Hazard ratios (95% CIs) for events of cardiovascular disease and incident diabetes associated with metabolic syndrome, and individual criteria for metabolic syndrome