Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

Background: Controversy still surrounds the cardiovascular benefits associated with intensive glucose control in patients with long-standing type 2 diabetes mellitus.

Objective: The purpose of the study was to compare the effects of intensive and standard glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus.

Methods: This was a randomized, controlled, multicenter, open-label, parallel group study.  Patients who had inadequate responses to maximal doses of oral antidiabetic agents or insulin therapy were enrolled from 20 Veterans Affairs sites.  Patients were excluded from the study if they had an A1C <7.5%, an occurrence of a cardiovascular event during the previous 6 months, advanced congestive heart failure, severe angina, a life expectancy <7 years, a BMI >40, a serum creatinine >1.6mg/dL or an alanine aminotransferase level >3 times the upper limit of normal range. Overall, 1,792 patients were randomized to receive either standard or intensive treatment.  In both groups, patients with a BMI ≥27 were started on metformin plus rosiglitazone and those with a BMI <27 were started on glimepiride plus rosiglitazone.  Treatment guidelines for blood pressure and lipid control as well as for dietary, exercise and diabetes education were provided to all patients as treatment for other modifiable cardiovascular risk factors.  All patients were also prescribed aspirin and a statin unless contraindicated.   In the intensive therapy group, patients were started on maximum doses of antidiabetic medications and those not achieving an A1C of <6% (in an unspecified timeframe) were started on insulin before changes in oral therapy were made.  In the standard therapy group, patients were started on half the maximum doses of antidiabetic medications and those not achieving an A1C of <9% (in an unspecified timeframe) were started on insulin before changes in oral therapy were made.  For both groups, subsequent changes in medication were determined according to local assessment and protocol guidelines that allowed the use of any approved drug at the discretion of the investigator.  The primary outcome measure was the time to first occurrence of any cardiovascular event.  Secondary outcome measures included new or worsening angina, new transient ischemic attacks, new intermittent claudication, new critical limb ischemia and death from any cause.  Microvascular complications (retinopathy, nephropathy, and neuropathy) and adverse events were also assessed.  Intent-to-treat was used in all data analysis.  Power was calculated as 86% for a sample size of 1700 to detect a difference of 21% in the rate of composite cardiovascular outcomes when comparing the standard and intensive treatment groups. 

Results: Overall, 1,532 (86.5%) patients completed the study with 760 of 899 (84.5%) in the standard therapy group and 772 of 892 (86.5%) in the intensive therapy group.  Cardiovascular events occurred in 264 patients in the standard therapy group and 235 patients in the intensive therapy group (HR in the intensive therapy group 0.88; 95% CI 0.74 to 10.05; p=0.14). No significant difference in time to death from cardiovascular causes was seen and no significant difference in time to death from any cause was seen (HR 1.07; 95% CI 0.82 to 1.42; p=0.62).  The most significant adverse events were hypoglycemia (p<0.001) and dyspnea (p=0.006) and were seen more in the intensive therapy group.  No significant differences were found in the progression of retinopathy, nephropathy or neuropathy.

Strengths: Baseline characteristics between the two treatment groups were equal.  Attempts were made at controlling for dyslipidemia and hypertension that would affect the measurement based on current ADA treatment guidelines.  However, specific drugs used for treatment of these conditions were not reported.  The current study mimicked previous studies in design and methods in order to emulate treatment conditions and provide supporting data.

Weaknesses: Blinding was not implemented in the study and could have resulted in varying treatment strategies depending on which group a patient was assigned.  The timeframe for reaching A1C goals before the addition of insulin was not specified causing additional variations in treatment regimens.  Rosiglitazone could potentially aggravate CHF potentially affecting the primary outcome.  Patients in the intensive therapy group were started on maximum doses of medication without titration and may have increased the incidence of hypoglycemia.  The use of rosiglitazone and insulin together is contraindicated due to the increased risk of CHF and myocardial ischemia which could have resulted in increased incidence of the primary endpoints.  After insulin therapy was initiated, guidelines allowed providers to use any approved drugs to achieve goals.  The types of drugs and suggested diet and exercise modifications used were not reported and their effects on the outcomes of the trial were not assessed.  Variations in drug therapies and treatment modalities could have influenced the results of the study. 

Conclusion:   While the study found no difference in cardiovascular events between intensive and standard therapy groups, it is difficult to say with certainty that intensive therapy did not benefit patients in the long run.  Given that the study results are unclear and more studies need to be completed, practitioners should still follow the standard guidelines for glucose control.  Older patients should be monitored for adverse events and their medications should be titrated slowly to prevent hypoglycemia.  Practitioners should individualize goals to each patient and only adjust medications as tolerated.   

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-39.

Michael A. Biddle, Jr., Doctor of Pharmacy Candidate