Severe Hypoglycemia and Risks of Vascular Events and Death

Sophia Zoungas, M.D., Ph.D., Anushka Patel, M.D., Ph.D., John Chalmers, M.D., Ph.D., Bastiaan E. de Galan, M.D., Ph.D., Qiang Li, M.Biostat., Laurent Billot, M.Sc., Mark Woodward, Ph.D., Toshiharu Ninomiya, M.D., Ph.D., Bruce Neal, M.D., Ph.D., Stephen MacMahon, D.Sc., Ph.D., Diederick E. Grobbee, M.D., Ph.D., Andre Pascal Kengne, M.D., Ph.D., Michel Marre, M.D., Ph.D., and Simon Heller, M.D. for the ADVANCE Collaborative Group N Engl J Med 2010; 363:1410-1418 - October 7, 2010

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.

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.

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.

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.)

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Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity

Mikael Knip, M.D., D.M.Sc., Suvi M. Virtanen, M.D., D.M.Sc., Karri Seppä, M.Sc., Jorma Ilonen, M.D., D.M.Sc., Erkki Savilahti, M.D., D.M.Sc., Outi Vaarala, M.D., D.M.Sc., Antti Reunanen, M.D., D.M.Sc., Kari Teramo, M.D., D.M.Sc., Anu-Maaria Hämäläinen, M.D., D.M.Sc., Johanna Paronen, M.D., D.M.Sc., Hans-Michael Dosch, M.D., Timo Hakulinen, Ph.D., and Hans K. Åkerblom, M.D., D.M.Sc. for the Finnish TRIGR Study Group

Background: Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children.

Methods: In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cow's-milk–based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age.

Results: The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups.

Conclusion:Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity — markers that may reflect an autoimmune process leading to type 1 diabetes. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00570102.)

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Diets with High or Low Protein Content and Glycemic Index for Weight-Loss Maintenance

Thomas Meinert Larsen, Ph.D., Stine-Mathilde Dalskov, M.Sc., Marleen van Baak, Ph.D., Susan A. Jebb, Ph.D., Angeliki Papadaki, Ph.D., Andreas F.H. Pfeiffer, M.D., J. Alfredo Martinez, Ph.D., Teodora Handjieva-Darlenska, M.D., Ph.D., Marie Kunešová, M.D., Ph.D., Mats Pihlsgård, Ph.D., Steen Stender, M.D., Ph.D., Claus Holst, Ph.D., Wim H.M. Saris, M.D., Ph.D., and Arne Astrup, M.D., Dr.Med.Sc. for the Diet, Obesity, and Genes (Diogenes) Project

Background: Studies of weight-control diets that are high in protein or low in glycemic index have reached varied conclusions, probably owing to the fact that the studies had insufficient power.

Methods: We enrolled overweight adults from eight European countries who had lost at least 8% of their initial body weight with a 3.3-MJ (800-kcal) low-calorie diet. Participants were randomly assigned, in a two-by-two factorial design, to one of five ad libitum diets to prevent weight regain over a 26-week period: a low-protein and low-glycemic-index diet, a low-protein and high-glycemic-index diet, a high-protein and low-glycemic-index diet, a high-protein and high-glycemic-index diet, or a control diet.

Results: A total of 1209 adults were screened (mean age, 41 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 34), of whom 938 entered the low-calorie-diet phase of the study. A total of 773 participants who completed that phase were randomly assigned to one of the five maintenance diets; 548 completed the intervention (71%). Fewer participants in the high-protein and the low-glycemic-index groups than in the low-protein–high-glycemic-index group dropped out of the study (26.4% and 25.6%, respectively, vs. 37.4%; P=0.02 and P=0.01 for the respective comparisons). The mean initial weight loss with the low-calorie diet was 11.0 kg. In the analysis of participants who completed the study, only the low-protein–high-glycemic-index diet was associated with subsequent significant weight regain (1.67 kg; 95% confidence interval [CI], 0.48 to 2.87). In an intention-to-treat analysis, the weight regain was 0.93 kg less (95% CI, 0.31 to 1.55) in the groups assigned to a high-protein diet than in those assigned to a low-protein diet (P=0.003) and 0.95 kg less (95% CI, 0.33 to 1.57) in the groups assigned to a low-glycemic-index diet than in those assigned to a high-glycemic-index diet (P=0.003). The analysis involving participants who completed the intervention produced similar results. The groups did not differ significantly with respect to diet-related adverse events.

Conclusion: In this large European study, a modest increase in protein content and a modest reduction in the glycemic index led to an improvement in study completion and maintenance of weight loss.

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n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction

Daan Kromhout, M.P.H., Ph.D., Erik J. Giltay, M.D., Ph.D., and Johanna M. Geleijnse, Ph.D. for the Alpha Omega Trial Group

Background: Results from prospective cohort studies and randomized, controlled trials have provided evidence of a protective effect of n−3 fatty acids against cardiovascular diseases. We examined the effect of the marine n−3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and of the plant-derived alpha-linolenic acid (ALA) on the rate of cardiovascular events among patients who have had a myocardial infarction.

Methods: In a multicenter, double-blind, placebo-controlled trial, we randomly assigned 4837 patients, 60 through 80 years of age (78% men), who had had a myocardial infarction and were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy to receive for 40 months one of four trial margarines: a margarine supplemented with a combination of EPA and DHA (with a targeted additional daily intake of 400 mg of EPA–DHA), a margarine supplemented with ALA (with a targeted additional daily intake of 2 g of ALA), a margarine supplemented with EPA–DHA and ALA, or a placebo margarine. The primary end point was the rate of major cardiovascular events, which comprised fatal and nonfatal cardiovascular events and cardiac interventions. Data were analyzed according to the intention-to-treat principle, with the use of Cox proportional-hazards models.

Results: The patients consumed, on average, 18.8 g of margarine per day, which resulted in additional intakes of 226 mg of EPA combined with 150 mg of DHA, 1.9 g of ALA, or both, in the active-treatment groups. During the follow-up period, a major cardiovascular event occurred in 671 patients (13.9%). Neither EPA–DHA nor ALA reduced this primary end point (hazard ratio with EPA–DHA, 1.01; 95% confidence interval [CI], 0.87 to 1.17; P=0.93; hazard ratio with ALA, 0.91; 95% CI, 0.78 to 1.05; P=0.20). In the prespecified subgroup of women, ALA, as compared with placebo and EPA–DHA alone, was associated with a reduction in the rate of major cardiovascular events that approached significance (hazard ratio, 0.73; 95% CI, 0.51 to 1.03; P=0.07). The rate of adverse events did not differ significantly among the study groups.

Conclusion: Low-dose supplementation with EPA–DHA or ALA did not significantly reduce the rate of major cardiovascular events among patients who had had a myocardial infarction and who were receiving state-of-the-art antihypertensive, antithrombotic, and lipid-modifying therapy.

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Everolimus for Advanced Pancreatic Neuroendocrine Tumors

James C. Yao, M.D., Manisha H. Shah, M.D., Tetsuhide Ito, M.D., Ph.D., Catherine Lombard Bohas, M.D., Edward M. Wolin, M.D., Eric Van Cutsem, M.D., Ph.D., Timothy J. Hobday, M.D., Takuji Okusaka, M.D., Jaume Capdevila, M.D., Elisabeth G.E. de Vries, M.D., Ph.D., Paola Tomassetti, M.D., Marianne E. Pavel, M.D., Sakina Hoosen, M.D., Tomas Haas, Ph.D., Jeremie Lincy, M.Sc., David Lebwohl, M.D., and Kjell Öberg

Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.

Methods: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus.

Results: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).

Conclusions: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events.

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Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors

Eric Raymond, M.D., Ph.D., Laetitia Dahan, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Yung-Jue Bang, M.D., Ivan Borbath, M.D., Ph.D., Catherine Lombard-Bohas, M.D., Juan Valle, M.D., Peter Metrakos, M.D., C.M., Denis Smith, M.D., Aaron Vinik, M.D., Ph.D., Jen-Shi Chen, M.D., Dieter Hörsch, M.D., Pascal Hammel, M.D., Ph.D., Bertram Wiedenmann, M.D., Ph.D., Eric Van Cutsem, M.D., Ph.D., Shem Patyna, Ph.D., Dongrui Ray Lu, M.Sc., Carolyn Blanckmeister, Ph.D., Richard Chao, M.D., and Philippe Ruszniewski, M.D.

Background: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.

Methods: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors–defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.

Results: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.

Conclusions: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.)

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Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes

The ACCORD Study Group

Background: Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events.

Methods: We randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial.

Result: Before the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.

Conclusion: As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.)

The members of the writing group (Hertzel C. Gerstein, M.D., McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Michael E. Miller, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Saul Genuth, M.D., Case Western Reserve University, Cleveland; Faramarz Ismail-Beigi, M.D., Ph.D., Case Western Reserve University, Cleveland; John B. Buse, M.D., Ph.D., University of North Carolina, Chapel Hill; David C. Goff, Jr., M.D., Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Jeffrey L. Probstfield, M.D., University of Washington, Seattle; William C. Cushman, M.D., Memphis Veterans Affairs Medical Center, Memphis; Henry N. Ginsberg, M.D., Columbia University College of Physicians and Surgeons, New York; J. Thomas Bigger, M.D., Columbia University College of Physicians and Surgeons, New York; Richard H. Grimm, Jr., M.D., Ph.D, University of Minnesota, Berman Center for Outcomes and Clinical Research, Minneapolis; Robert P. Byington, Ph.D., Wake Forest University School of Medicine, Winston-Salem, NC; Yves D. Rosenberg, M.D., National Heart, Lung, and Blood Institute, Bethesda, MD; and William T. Friedewald, M.D., Columbia University College of Physicians and Surgeons, New York) assume responsibility for the content of this article.

Supported by the National Heart, Lung, and Blood Institute (contracts N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, IAA#Y1-HC-9035, and IAA#Y1-HC-1010), and partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Eye Institute and by General Clinical Research Centers at many sites; substudies within the ACCORD trial on cost-effectiveness and health-related quality of life were supported by the Centers for Disease Control and Prevention. The following companies provided study medications, equipment, or supplies: Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer HealthCare, Closer Healthcare, GlaxoSmithKline, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis, and Schering-Plough.

Dr. Bigger reports receiving consulting fees and travel support from Merck and Roche and patent fees and royalties from the Massachusetts Institute of Technology for risk-stratification software; Dr. Buse, receiving consulting fees from Novo Nordisk, Amylin, Becton Dickinson, Eli Lilly, Hoffmann–La Roche (now Genentech), Glyco-Mark, Wyeth, Daiichi Sankyo, Bristol-Myers Squibb, Bayhill Therapeutics, LipoScience, MannKind, Veritas, MicroIslet, GlaxoSmithKline, Abbott, Exsulin, and GI Dynamics and grant support from Amylin, Novo Nordisk, Medtronic, Eli Lilly, Novartis, Tolerex, Osiris, Halozyme, Pfizer, Hoffmann–La Roche, InterKrin, Merck, Sanofi-Aventis, Dexcom, Johnson & Johnson, Bristol-Myers Squibb, Fujisawa, and the American Academy of Family Practice Foundation, holding stock in Insulet, and providing expert testimony for Novo Nordisk; Dr. Cushman, receiving consulting fees from Novartis, Takeda, Sanofi-Aventis, Bristol-Myers Squibb, King, Daiichi-Sankyo, Gilead, Theravance, Pharmacopeia, and Sciele and institutional grant support to the Memphis Veterans Affairs Medical Center from Novartis, GlaxoSmithKline, and Merck; Dr. Genuth, receiving consulting fees from Merck and Daiichi Sankyo and holding stock in Novartis and Johnson & Johnson; Dr. Gerstein, receiving consulting fees from Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Roche, Medtronic, Merck, Bayer, Bioavail, and Janssen-Ortho, institutional grant support to McMaster University from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, Merck, Pronova, Roche, Eli Lilly, and Boehringer Ingelheim, and lecture fees from Sanofi-Aventis, GlaxoSmithKline, Solvay, Boehringer Ingelheim, Servier, Bayer, Eli Lilly, Novo Nordisk, and Takeda; Dr. Ginsberg, being a member of the board of Merck and Schering-Plough and the global advisory board of Bristol-Myers Squibb/AstraZeneca and receiving consulting fees from GlaxoSmithKline, Merck, Bristol-Myers Squibb, AstraZeneca, Regeneron/Sanofi-Aventis, Abbott, Roche, Isis/Genzyme, Novartis, and Pfizer, institutional grant support to the Columbia University College of Physicians and Surgeons from Merck, Roche, Isis/Genzyme, and AstraZeneca, and payment from Pfizer for development of an educational presentation; Dr. Goff, being a member of the data and safety monitoring board for Takeda and receiving institutional grant support to the Wake Forest University School of Medicine from Merck; Dr. Grimm, being a member of the board of Pfizer, receiving consulting fees from Pfizer, Merck, and Novartis, personal and institutional grants to the University of Minnesota from Pfizer, Merck, and Novartis, lecture fees from Pfizer, Merck, Novartis, Forest, Schering-Plough, and Takeda, and travel support from Takeda and Roche, and attending the AstraZeneca symposium at the Cleveland Clinic and investigator meetings for Merck, Novartis, and Pfizer; Dr. Ismail-Beigi, receiving consulting fees from Eli Lilly; Dr. Miller, receiving consulting fees from Roche; and Dr. Probstfield, receiving institutional grant support to the University of Washington School of Medicine from Sanofi-Aventis, Boehringer Ingelheim, and Abbott.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.

Members of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group are listed in the Supplementary Appendix, available at NEJM.org.

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Diabetes Mellitus, Fasting Glucose, and Risk of Cause-Specific Death

The Emerging Risk Factors Collaborationp

Background: The extent to which diabetes mellitus or hyperglycemia is related to risk of death from cancer or other nonvascular conditions is uncertain.

Methods: We calculated hazard ratios for cause-specific death, according to baseline diabetes status or fasting glucose level, from individual-participant data on 123,205 deaths among 820,900 people in 97 prospective studies.

Result: After adjustment for age, sex, smoking status, and body-mass index, hazard ratios among persons with diabetes as compared with persons without diabetes were as follows: 1.80 (95% confidence interval [CI], 1.71 to 1.90) for death from any cause, 1.25 (95% CI, 1.19 to 1.31) for death from cancer, 2.32 (95% CI, 2.11 to 2.56) for death from vascular causes, and 1.73 (95% CI, 1.62 to 1.85) for death from other causes. Diabetes (vs. no diabetes) was moderately associated with death from cancers of the liver, pancreas, ovary, colorectum, lung, bladder, and breast. Aside from cancer and vascular disease, diabetes (vs. no diabetes) was also associated with death from renal disease, liver disease, pneumonia and other infectious diseases, mental disorders, nonhepatic digestive diseases, external causes, intentional self-harm, nervous-system disorders, and chronic obstructive pulmonary disease. Hazard ratios were appreciably reduced after further adjustment for glycemia measures, but not after adjustment for systolic blood pressure, lipid levels, inflammation or renal markers. Fasting glucose levels exceeding 100 mg per deciliter (5.6 mmol per liter), but not levels of 70 to 100 mg per deciliter (3.9 to 5.6 mmol per liter), were associated with death. A 50-year-old with diabetes died, on average, 6 years earlier than a counterpart without diabetes, with about 40% of the difference in survival attributable to excess nonvascular deaths.

Conclusion: In addition to vascular disease, diabetes is associated with substantial premature death from several cancers, infectious diseases, external causes, intentional self-harm, and degenerative disorders, independent of several major risk factors. (Funded by the British Heart Foundation and others.)

Drs. Thompson, Di Angelantonio, Gao, and Sarwar contributed equally to this article.

The members of the writing committee (Sreenivasa Rao Kondapally Seshasai, M.D., Stephen Kaptoge, Ph.D., Alexander Thompson, Ph.D., Emanuele Di Angelantonio, M.D., Pei Gao, Ph.D., and Nadeem Sarwar, Ph.D., University of Cambridge, Cambridge, United Kingdom; Peter H. Whincup, F.R.C.P., St. George's University of London, London; Kenneth J. Mukamal, M.D., Harvard University, Boston; Richard F. Gillum, M.D., Centers for Disease Control and Prevention, Atlanta; Ingar Holme, Ph.D., Ullevål University Hospital, Oslo; Inger Njølstad, M.D., University of Tromsø, Tromsø, Norway; Astrid Fletcher, Ph.D., London School of Hygiene and Tropical Medicine, London; Peter Nilsson, M.D., Lund University, Lund, Sweden; Sarah Lewington, D.Phil., and Rory Collins, F.Med.Sci., University of Oxford, Oxford, United Kingdom; Vilmundur Gudnason, M.D., Icelandic Heart Association and the University of Iceland, Reykjavik; Simon G. Thompson, D.Sc., Medical Research Council Biostatistics Unit, Cambridge, United Kingdom; Naveed Sattar, F.R.C.P., University of Glasgow, Glasgow, United Kingdom; Elizabeth Selvin, Ph.D., Johns Hopkins University, Baltimore; Frank B. Hu, M.D., Harvard University, Boston; and John Danesh, F.R.C.P., University of Cambridge, Cambridge, United Kingdom) of the Emerging Risk Factors Collaboration assume responsibility for the overall content and integrity of this article.

Supported by grants from the British Heart Foundation (RG/08/014), the U.K. Medical Research Council, and Pfizer (to the ERFC Coordinating Centre), as well as the Gates Cambridge Trust Scholarship, an Overseas Research Studentship Award, and an Addenbrooke's Charitable Trust Clinical Research Fellowship (to Dr. Kondapally Seshasai). Various sources have supported recruitment, follow-up, and laboratory measurements in the cohorts contributing to the ERFC. Investigators of several of these studies have contributed to a list (http://ceu.phpc.cam.ac.uk/research/erfc/studies) naming relevant funding sources.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

The study investigators are listed in the Supplementary Appendix, available at NEJM.org.

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