Intensive Glucose Control in Patients with Type 2 Diabetes - 15-Year Follow-up.

BACKGROUND: We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up. METHODS: We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome. RESULTS: There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75). CONCLUSIONS: Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).

A comparison of neuropsychiatric adverse events during early treatment with varenicline or a nicotine patch.

AIMS: We compared the risk of mental health episodes requiring hospitalization (primary aim) or out-patient clinic visits (secondary aim) associated with varenicline versus the nicotine patch (NP) in an era prior to psychiatric boxed warnings. DESIGN: Retrospective cohort. SETTING: Department of Veterans Affairs (VA), USA. PARTICIPANTS: VA patients with or without psychiatric comorbidities and a new prescription for varenicline (15 255) were propensity score-matched (1 : 2) to new users of NP (123 054) between 1 May 2006 and 30 September 2007, resulting in 11 774 and 23 548 patients in the varenicline and NP groups, respectively. MEASUREMENTS: The primary outcomes were hospitalizations with a primary discharge diagnosis of a range of mental health disorders: depression, schizophrenia, bipolar disorder, suicide attempt, post-traumatic stress disorder, other psychosis and drug-induced mental disorders. Secondary outcomes were out-patient clinic visits with a primary diagnosis of the above list of mental health disorders. FINDINGS: Background characteristics of the treatment groups were similar after matching. There was no statistically significant difference in risk of hospitalization for any of the studied mental health disorders with varenicline compared with NP. Among secondary outcomes there was an increased risk of out-patient clinic visits for schizophrenia among patients who received varenicline [hazard ratio (HR) = 1.27; 95% confidence interval (CI) = 1.07, 1.51], this increase being evident only in those with a pre-existing mental health disorder. CONCLUSION: In US VA patients studied prior to the boxed warning being implemented, use of varenicline for smoking cessation was not associated with a detectable increase compared with nicotine patches in hospitalization for any mental health outcomes. There was an increased rate of out-patient attendances with a primary diagnosis of schizophrenia amounting to five per 100 person years of treatment. This increase was found only in patients with a pre-existing mental health disorder.

Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes.

BACKGROUND: The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants. METHODS: After the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality. RESULTS: The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years). CONCLUSIONS: After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. (Funded by the VA Cooperative Studies Program and others; VADT ClinicalTrials.gov number, NCT00032487.).

Engineering practice variation through provider agreement: a cluster-randomized feasibility trial.

PURPOSE: Minimal-risk randomized trials that can be embedded in practice could facilitate learning health-care systems. A cluster-randomized design was proposed to compare treatment strategies by assigning clusters (eg, providers) to "favor" a particular drug, with providers retaining autonomy for specific patients. Patient informed consent might be waived, broadening inclusion. However, it is not known if providers will adhere to the assignment or whether institutional review boards will waive consent. We evaluated the feasibility of this trial design. SUBJECTS AND METHODS: Agreeable providers were randomized to "favor" either hydrochlorothiazide or chlorthalidone when starting patients on thiazide-type therapy for hypertension. The assignment applied when the provider had already decided to start a thiazide, and providers could deviate from the strategy as needed. Prescriptions were aggregated to produce a provider strategy-adherence rate. RESULTS: All four institutional review boards waived documentation of patient consent. Providers (n=18) followed their assigned strategy for most of their new thiazide prescriptions (n=138 patients). In the "favor hydrochlorothiazide" group, there was 99% adherence to that strategy. In the "favor chlorthalidone" group, chlorthalidone comprised 77% of new thiazide starts, up from 1% in the pre-study period. When the assigned strategy was followed, dosing in the recommended range was 48% for hydrochlorothiazide (25-50 mg/day) and 100% for chlorthalidone (12.5-25.0 mg/day). Providers were motivated to participate by a desire to contribute to a comparative effectiveness study. A study promotional mug, provider information letter, and interactions with the site investigator were identified as most helpful in reminding providers of their study drug strategy. CONCLUSION: Providers prescribed according to an assigned drug-choice strategy most of the time for the purpose of a comparative effectiveness study. This simple design could facilitate research participation and behavior change in non-research clinicians. Waiver of patient consent can broaden the representation of patients, providers, and settings.

Association of PAI-1 and fibrinogen with diabetic retinopathy in the Veterans Affairs Diabetes Trial (VADT).

OBJECTIVE: To test the hypothesis that high levels of plasminogen-activating inhibitor (PAI)-1 and fibrinogen at baseline were associated with the onset or progression of diabetic retinopathy (DR) during the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS: The VADT was an open-label, prospective, randomized controlled trial to test the effect of standard glycemic control (STD) compared with intensive control (INT) on cardiovascular events in patients with advanced type 2 diabetes mellitus (T2DM). Diabetic retinopathy (DR) outcomes were also collected. Incidence and progression of DR were assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later taken in 858 of a total of 1,791 participants who completed both eye examinations. RESULTS: Assignment to INT was not independently associated with decreased risk of onset of DR. However, after adjustment for multiple covariates, baseline level of PAI-1 was an independent risk factor for the onset of DR. The risk for incidence of DR increased by 12% for each 10 ng/dL increase in baseline PAI-1 concentration (odds ratio [OR] 1.012 [95% CI 1.00-1.024], P = 0.042). Assignment to INT was not independently associated with decreased risk of progression of DR. However, there was an interaction between glycemic treatment assignment and fibrinogen level at baseline. INT was associated with decreased progression of retinopathy in those with fibrinogen <296 mg/dL (OR 0.55 [95% CI 0.31-1.00], P = 0.03). CONCLUSIONS: The results require confirmation but are consistent with greater hypercoagulabilty and inflammation, as measured by higher levels of PAI-1 and fibrinogen, being related to DR and responsiveness to INT.

Improvement of guideline ß-blocker prescribing in heart failure: a cluster-randomized pragmatic trial of a pharmacy intervention.

BACKGROUND: Treatment with specific beta-blockers and doses recommended by guidelines is often not achieved in practice. We evaluated an intervention directed to the pharmacy to improve prescribing. METHODS AND RESULTS: We conducted a pragmatic cluster-randomized trial, where facilities (n = 12) with patients (n = 220) were the clusters. Eligible patients had a beta-blocker prescription that was not guideline concordant. Level 1 intervention included information to a pharmacist on facility guideline concordance. Level 2 also provided a list of patients not meeting guideline goals. Intervention and follow-up periods were each 6 months. Achievement of full concordance with recommendations was low (4%-5%) in both groups, primarily due to lack of tolerability. However, compared with level 1, the level 2 intervention was associated with 1.9-fold greater odds of improvement in prescribing (95% confidence interval [CI] 1.1-3.2). Level 2 patients also had greater odds of a higher dose (1.9, 95% CI 1.1-3.3). The intervention was aided by the patient lists provided, the electronic medical record system, and staff support. CONCLUSIONS: In actual practice, full achievement of guideline goals was low. However, a simple intervention targeting pharmacy moved patients toward guideline goals. As health care systems incorporate electronic medical records, this intervention should have broader feasibility.

Follow-up study of a pharmacovigilance signal: no evidence of increased risk with risperidone of pituitary tumor with mass effect.

INTRODUCTION: Pharmacovigilance studies of spontaneous adverse event report databases are used to raise hypotheses about potential safety events. Such studies have found a disproportionately higher number of pituitary tumor reports for risperidone. Because there is a high prevalence of clinically "silent" pituitary adenomas, any increased workup in risperidone users, for example, secondary to hyperprolactinemia, might account for the increased reports. We undertook a detailed study of medical record-confirmed newly diagnosed pituitary tumors with mass effect in patients prescribed antipsychotics to evaluate the effect of risperidone. METHODS: We conducted retrospective studies in 2 large administrative health care databases with access to medical records. Patients were classified into risperidone or other atypical antipsychotic exposure groups. Records with administrative codes indicative of possible cases in the follow-up period were reviewed to confirm the diagnosis of new pituitary tumor and presence of mass effects. RESULTS: The hazard ratio of confirmed pituitary tumors with mass effect was 1.0 (95% confidence interval, 0.5-1.9). Whereas the precision of the hazard ratio was limited by low event rates, despite examination of 409,823 patients' records, ancillary analyses supported the interpretation of no elevated risk. Evidence was found for detection bias that may explain previous pharmacovigilance findings. DISCUSSION: There was no evidence of increased risk of pituitary tumor with mass effect with risperidone in either cohort or case-control analyses. We cannot rule out a small risk (<2-fold), or a risk that may develop with additional years of exposure or follow-up, or a risk of microadenomas or prolactinomas.

Research leadership and investigators: gender distribution in the federal government.

BACKGROUND: The National Academies reported in Beyond Bias and Barriers: Fulfilling the Potential of Women in Academic Science and Engineering (2006) that "women are very likely to face discrimination." In academic medicine, gender distribution is becoming more balanced. In the federal government, women also have made progress, doubling their representation in professional positions to 44%. The Department of Veterans Affairs (VA) has a research program and a mission to train health care professionals; however, its gender distribution has not been described. METHODS: We conducted a descriptive study using public data for positions in the VA, National Institutes of Health (NIH), and Agency for Healthcare Research and Quality (AHRQ). We followed with a case-control analysis of predictors of receipt of grant funding in the VA. Participants were 224 leadership positions and 132 principal investigators. RESULTS: Women comprised 33% (AHRQ), 27% (NIH), and 0% (VA) of the top research leadership. Across all VA research levels, women comprised 45% to 0%, depending on the service. In the case-control analysis of principal investigators, men had greater odds (odds ratio 8.0) of a Cooperative Studies Program (CSP) trial award. History of first, last, or any authorship on a clinical trial publication in the 10 years before the index trial was only weakly associated with award of a CSP trial. The gender imbalance was not explained by publication history. CONCLUSIONS: Marked gender disparities were seen in the VA, except in Health Services Research. Organizations must investigate their practices to reveal disparities, investigate underlying factors, and intervene as needed.

Translational potential of thyroid hormone and its analogs.

Thyroid hormone has unique properties affecting the heart, and the vasculature and cholesterol metabolism. There is interest in using thyromimetic agents as possible treatment options for heart failure based on data demonstrating the ability of these agents to improve systolic and diastolic left ventricular function as well as their vasodilatory action. The inverse relationship between heart failure severity and serum triiodothyronine (T3) levels has also been interpreted by some as an indication that thyroid hormone therapy might be useful. In the 1950s, investigators began developing thyroid hormone analogs that could lower cholesterol, that selectively bind to ß1-type nuclear thyroid hormone receptors (TR), which are responsible for cholesterol-lowering activity, without activating α1-type receptors in the heart. The identification of 3,5-diiodothyropropionic acid (DITPA) that binds to both α- and ß-type TRs with relatively low affinity was unique in that this analog improves left ventricular function in heart failure as well as lowers cholesterol. The aim of this review is to summarize information known about the interactions between thyroid hormones and the cardiovascular system, and the potential therapeutic effects of thyroid analogs in chronic heart disease. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

Intensive glucose-lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial participants with lower calcified coronary atherosclerosis.

OBJECTIVE: This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS: At baseline, 301 type 2 diabetic participants in the VADT, a randomized trial comparing the effects of intensive versus standard glucose lowering on cardiovascular events, had baseline coronary atherosclerosis assessed by coronary artery calcium (CAC) measured by computed tomography. Participants were followed over the 7.5-year study for development of cardiovascular end points. RESULTS: During a median follow-up duration of 5.2 years, 89 cardiovascular events occurred. Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the substudy cohort as a whole, there was evidence that the response was modified by baseline CAC, as indicated by significant P values for treatment by log(CAC + 1) interaction terms in unadjusted and multivariable-adjusted models (0.01 and 0.03, respectively). Multivariable-adjusted hazard ratios (HRs) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC. Subgroup analyses were also conducted for clinically relevant CAC categories: those above and below an Agatston score of 100. Among those randomized to intensive treatment, for the subgroup with CAC >100, 11 of 62 individuals had events, while only 1 of 52 individuals with CAC < or = 100 had an event. The multivariable HR for intensive treatment for those with CAC >100 was 0.74 (95% CI 0.46-1.20; P = 0.21), while for the subgroup with CAC < or = 100, the corresponding HR was 0.08 (0.008-0.77; P = 0.03), with event rates of 39 and 4 per 1,000 person-years, respectively. CONCLUSIONS: These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis.

Severe dysglycemia with the fluoroquinolones: a class effect?

BACKGROUND: Although gatifloxacin is no longer available, other fluoroquinolones may significantly interfere with glucose homeostasis. The objective of the present study was to compare the risk of severe hypo- and hyperglycemia in a cohort of patients treated with gatifloxacin, levofloxacin, ciprofloxacin, or azithromycin. METHODS: This was a retrospective inception cohort study of outpatients with a new prescription for gatifloxacin, levofloxacin, ciprofloxacin, or azithromycin from 1 October 2000 through 30 September 2005 in the Veterans Affairs health care system. For patients who received one of these antibiotics, we identified outcomes of hospitalization with a primary diagnosis of hypo- or hyperglycemia. Multivariable logistic regression was used to determine the odds of hypo- and hyperglycemia with the individual fluoroquinolones versus azithromycin. RESULTS: The crude incidence rates for severe hypo- and hyperglycemia among those who received gatifloxacin, levofloxacin, ciprofloxacin, and azithromycin were 0.35 and 0.45, 0.19 and 0.18, 0.10 and 0.12, and 0.07 and 0.10 cases per 1000 patients, respectively. Among patients with diabetes, the odds ratios for hypoglycemia compared with azithromycin were 4.3 (95% confidence interval [CI], 2.7-6.6) for gatifloxacin, 2.1 (95% CI, 1.4-3.3) for levofloxacin, and 1.1 (95% CI, 0.6-2.0) for ciprofloxacin. The odds ratios for hyperglycemia were 4.5 (95% CI, 3.0-6.9) for gatifloxacin, 1.8 (95% CI, 1.2-2.7) for levofloxacin, and 1.0 (95% CI, 0.6-1.8) for ciprofloxacin. CONCLUSIONS: The odds of severe hypo- and hyperglycemia were significantly greater with gatifloxacin and levofloxacin, but not ciprofloxacin, than with azithromycin. Thus, the risk of a clinically relevant dysglycemic event appears to vary among the fluoroquinolones.

DITPA (3,5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study.

BACKGROUND: In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. METHODS AND RESULTS: This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (-20%), low-density lipoprotein cholesterol (-30%), and body weight (-11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. CONCLUSIONS: DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.

Glucose control and vascular complications in veterans with type 2 diabetes.

BACKGROUND: The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. METHODS: We randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. RESULTS: The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group. CONCLUSIONS: Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria (P = 0.01) [added]. (ClinicalTrials.gov number, NCT00032487.)

Baseline achievement of lipid goals and usage of lipid medications in patients with diabetes mellitus (from the Veterans Affairs Diabetes Trial).

The American Diabetes Association has established lipid goals for patients with diabetes. Although diabetic populations historically have poor low-density lipoprotein (LDL) cholesterol goal adherence, little is known about adherence to triglyceride and high-density lipoprotein (HDL) cholesterol goals. To determine the degree of lipid goal attainment among patients with diabetes, and to characterize the patterns of lipid medication use, we evaluated the baseline data from 1,742 enrollees of the national Veterans Affairs Diabetes Trial. Using current American Diabetes Association lipid guidelines, we calculated the proportion of participants achieving a LDL cholesterol level <100 mg/dl, triglyceride level <150 mg/dl, and HDL cholesterol level >40 mg/dl in men (>50 mg/dl in women). We also performed a descriptive analysis of the use of lipid medications in this population. The baseline LDL cholesterol level was 111 +/- 63 mg/dl, triglyceride level was 213 +/- 277 mg/dl, and HDL cholesterol was 36 +/- 10 mg/dl. At enrollment, 44% of veterans met the LDL cholesterol goal, 58% met the triglyceride goal, and 16% met the HDL cholesterol goal, but only 6% met all 3 goals. Of the 1,742 enrollees, 2/3 were receiving lipid therapy, with statins (58%) the most commonly used drug. Combination lipid therapy was used by 11% of enrollees. Although the enrollees of the Veterans Affairs Diabetes Trial demonstrated better adherence to the American Diabetes Association's LDL cholesterol goal than other diabetic populations recently studied, more aggressive and directed lipid medication use is needed to treat the overall lipid profile better.

Control of cardiovascular risk factors in the Veterans Affairs Diabetes Trial in advanced type 2 diabetes.

OBJECTIVE: To present a status report on the Veterans Affairs Diabetes Trial (VADT), a multisite long-term study examining the effect of glucose control on cardiovascular (CV) complications in older patients with established, poorly controlled type 2 diabetes. METHODS: We review the rationale, objectives, and design of the VADT and summarize the baseline data and the results achieved thus far. RESULTS: The main objective of this 20-site, 1,792-patient study is to ascertain whether intensive glucose control can reduce major CV events in patients with difficult-to-control type 2 diabetes. The study design consists of a standard treatment arm and an intensive treatment arm, with a goal of 1.5% difference in hemoglobin A1c values between the two groups. The trial is now in its fifth year, with completion expected in December 2007. The planned glucose separation has been achieved and maintained to this point. Blood pressure and hemoglobin A1c levels have been reduced from baseline values, and established CV risk factors are within recommended ranges. CONCLUSION: The current results of the VADT show that excellent control of glucose and CV risk factors can be achieved and maintained in the population studied. The results of these interventions on CV outcomes will ultimately have important implications for the clinical care of older patients with advanced type 2 diabetes.