Therapeutics

In type 1 diabetes, intensive insulin therapy for 6.5 y reduced mortality at 27 y compared with usual care Clinical impact ratings:

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Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, Zinman B, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA. 2015; 313:45-53.

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Question In patients with type 1 diabetes, does intensive insulin therapy (IIT) for a mean 6.5 years reduce long-term mortality compared with conventional treatment?

Methods Design: Long-term follow-up (Epidemiology of Diabetes Interventions and Complications [EDIC], ClinicalTrials.gov NCT00360893) of a randomized controlled trial (Diabetes Control and Complications Trial [DCCT], ClinicalTrials.gov NCT00360815). Allocation: {Concealed}*.† Blinding: Blinded† {central outcome assessors}‡. Follow-up period: Mean 27 years (including mean 6.5-y treatment period). Setting: 27 clinical centers in Canada and the USA. Patients: 1441 patients 13 to 39 years of age (mean age 27 y, 53% boys and men) who had type 1 diabetes. Exclusion criteria included hypertension, hypercholesterolemia, cardiovascular disease, diabetes for >15 years, or ≥ 200 mg albuminuria per 24 hours. Intervention: IIT, with the goal of achieving glycemia as close to the nondiabetic range as possible (n = 711), or conventional treatment, with the goal of avoiding symptomatic hypoglycemia and hyperglycemia (n = 730). Study-directed treatment continued for a mean 6.5 years, after which diabetes care was returned to personal physicians. During the study treatment period, the IIT and conventional groups achieved mean hemoglobin A1c levels of 7% and 9%, respectively. Outcome: All-cause mortality. Patient follow-up: > 99% (intention-to-treat analysis).

Main results IIT reduced long-term all-cause mortality compared with conventional treatment (Table).

Conclusion In patients with type 1 diabetes, intensive insulin therapy for a mean 6.5 years reduced mortality at a mean 27 years compared with conventional treatment. *ACP Journal Club. Prior intensive insulin treatment reduced long-term risk for peripheral neuropathy in type 1 diabetes. Abstract of: Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. [Diabetes Care. 2010]. Ann Intern Med. 2010;153(8):JC4-3.

Sources of funding: National Institute of Diabetes and Digestive and Kidney Diseases; National Eye Institute; National Institute of Neurological Disorders and Stroke; Clinical Translational Science Center Program; General Clinical Research Center Program. LifeScan, Roche Diabetes Care, sanofi-aventis, Eli Lilly, OmniPod, Becton Dickinson, Animas, Abbott Diabetes Care; Medtronic Diabetes, Bayer Diabetes Care, Extend Nutrition, Nipro Home diagnostics, Nova Diabetes Care, Perrigo Diabetes Care, and Omron contributed free or discounted supplies and/or equipment. For correspondence: Dr. T.J. Orchard, University of Pittsburgh, Pittsburgh, PA, USA. E-mail [email protected] 

Commentary Pursuing IIT in patients with type 1 diabetes involves trade-offs between treatment-related benefits, harms, and burdens. Because IIT reduces risk for microvascular (1) and macrovascular (2) complications, it may prolong life. On the other hand, IIT increases risk for severe hypoglycemia (1), which is associated with higher mortality (3). To date, the effect of IIT on all-cause mortality in type 1 diabetes has not been clear. Orchard and colleagues analyzed long-term follow-up data of the DCCT to answer this question. DCCT was not designed to evaluate the effect of IIT on mortality because few deaths were expected in young patients with type 1 diabetes. Therefore, the vital status of > 99% of the original trial participants was assessed during long-term follow-up (when participants were no longer receiving the randomized treatment). They found fewer deaths in the group that received ITT. This beneficial effect was small and emerged > 15 years after randomization, after a period of increased mortality during IIT. The estimate of this beneficial effect is also imprecise: The number needed to treat intensively for 6.5 years to save 1 additional life over the following 2 decades may be as small as 22 or > 1000. Small, inconsistent, and imprecise effects reduce our confidence in the conclusion that IIT prolongs life in patients with type 1 diabetes. Perhaps some patients accrue a substantial survival benefit from IIT, whereas others are harmed. In the absence of personalized estimates of these effects, we can tell our young, relatively healthy patients with type 1 diabetes that IIT may confer a small survival benefit. Decisions to pursue IIT must balance this possible benefit with other established benefits, the risk for severe hypoglycemia, and the burden of treatment on the patient. Kasia J. Lipska, MD, MHS Yale School of Medicine New Haven, Connecticut, USA Victor M. Montori, MD Mayo Clinic Rochester, Minnesota, USA

†See Glossary. ‡Information provided by author. References

Intensive insulin therapy (IIT) vs conventional treatment in type 1 diabetes§ Outcome

All-cause mortality

Event rates

At a mean 27 y

IIT

Conventional treatment

RRR (95% CI)

NNT (CI)

6.0%

8.8%

32% (1 to 53)

36 (22 to 1194)

§Abbreviations defined in Glossary. RRR, NNT, and CI calculated from conventional treatment event rate and hazard ratio in article.

姝 2015 American College of Physicians

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1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-86. 2. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005; 353:2643-53. 3. Cooper MN, de Klerk NH, Jones TW, Davis EA. Clinical and demographic risk factors associated with mortality during early adulthood in a populationbased cohort of childhood-onset type 1 diabetes. Diabet Med. 2014;31: 1550-8.

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19 May 2015

ACP Journal Club. In type 1 diabetes, intensive insulin therapy for 6.5 y reduced mortality at 27 y compared with usual care.

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