William C. Duckworth

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.)

Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy

BACKGROUND Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

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.).

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 ≤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 ≤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.

Design of the cooperative study on glycemic control and complications in diabetes mellitus type 2 Veterans Affairs Diabetes Trial

INTRODUCTION Long-term glycemic control trials in type 2 diabetes show as the main clinical benefit a difference in retinal photocoagulation (3/1000 in the UK Prospective Diabetes Study [UKPDS]), but no effect on visual acuity or renal failure. No intensive glycemic control trial has yet affected cardiovascular (CV) events, the main cause of morbidity and mortality. By contrast, modest blood pressure reduction has protective effects on visual acuity, renal function, CV events, and mortality. Optimal glycemic control goals are not established in elderly, obese persons with advanced complications, the most common patients in the Veterans Affairs (VA) system. The earlier feasibility trial in such patients (VA-CSDM) suggested potentially worse CV outcomes with lower attained hemoglobin A1c (HbA1c) levels. OBJECTIVES The primary objective of the Veterans Affairs Diabetes Trial (VADT) is the assessment of the effect of intensive glycemic treatment on CV events. Other objectives are effects on microangiopathy, quality of life, and cost effectiveness. RESEARCH DESIGN AND METHODS The VADT, started in December 2000, is enrolling 1700 men and women previously uncontrolled on insulin or maximum doses of oral agents at 20 VA medical centers. Accrual is 2 years and follow-up is 5-7 years, with visits every 1.5 months. The study has a power of 86% to detect a 21% relative reduction in major CV events (CV death, myocardial infarction [MI], cerebrovascular accident [CVA], congestive heart failure [CHF], revascularization and amputation for ischemia). Subjects are randomized to an intensive arm aiming at normal HbA1c levels or to a standard arm with usual, improved glycemic control. An HbA1c separation of >1.5% is to be maintained (expected 2%). Both arms receive step therapy: glimepiride or metformin plus rosiglitazone and addition of insulin or other oral agents to achieve goals. Strict control of blood pressure and dyslipidemia, daily aspirin, diet, and education are identical in both arms. Plasma fibrinogen, plasminogen-activating inhibitor I (PAI-I), lipids, renal function parameters, and ECG are measured throughout. Stereo retinal photographs are obtained at entry and 5 years, eye examinations yearly, and intervention as needed to prevent visual deterioration. Recruitment is proceeding on schedule: the current mean HbA1c at entry is 9.4+/-1.6% and mean duration of diagnosed diabetes 11+/-8 years.

Degradation of Amylin by Insulin-degrading Enzyme

A pathological feature of Type 2 diabetes is deposits in the pancreatic islets primarily composed of amylin (islet amyloid polypeptide). Although much attention has been paid to the expression and secretion of amylin, little is known about the enzymes involved in amylin turnover. Recent reports suggest that insulin-degrading enzyme (IDE) may have specificity for amyloidogenic proteins, and therefore we sought to determine whether amylin is an IDE substrate. Amylin-degrading activity co-purified with IDE from rat muscle through several chromatographic steps. Metalloproteinase inhibitors inactivated amylin-degrading activity with a pattern consistent with the enzymatic properties of IDE, whereas inhibitors of acid and serine proteases, calpains, and the proteasome were ineffective. Amylin degradation was inhibited by insulin in a dose-dependent manner, whereas insulin degradation was inhibited by amylin. Other substrates of IDE such as atrial natriuretic peptide and glucagon also competitively inhibited amylin degradation. Radiolabeled amylin and insulin were both covalently cross-linked to a protein of 110 kDa, and the binding was competitively inhibited by either unlabeled insulin or amylin. Finally, a monoclonal anti-IDE antibody immunoprecipitated both insulin- and amylin-degrading activities. The data strongly suggest that IDE is an amylin-degrading enzyme and plays an important role in the clearance of amylin and the prevention of islet amyloid formation.

Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.

Insulin Resistance Caused by Massive Degradation of Subcutaneous Insulin

Severe resistance to subcutaneous insulin but sensitivity to intravenous insulin persisted for 15 months in a 17-year-old diabetic girl. Heat-labile insulin-degrading activity was present in the patients ketotic sera and in the 100,000 g fraction (soluble fraction) of adipose tissue. Serum-degrading activity was not inhibited by N-ethylmaleimide. The soluble fraction also degraded glucagon and B chain but not growth hormone or myoglobin. It was inhibited by incubation with the patients nonketotic sera, normal sera, or Trasylol. Glutathione-insulintranshydrogenase (GIT) activity was 66% of normal. The biopsy of adipose tissue at remission showed a normal level of insulin- and glucagon-degrading activity. The activity was eluted from Sephadex G200 as a single peak and had properties consistent with those of the insulin-specific protease (ISP). The increased degrading activity present during insulin resistance had properties not shared with ISP, suggesting the presence of an uncharacterized protease.

Direct measurement of plasma proinsulin in normal and diabetic subjects

Abstract Over 650 separate plasma samples from ninety-five subjects in whom oral glucose tolerance tests were performed were analyzed for glucose, total immunoreactive insulin (TIR) and immunoreactive proinsulin (IRP) content. These subjects were divided into seven groups: (1) young normal subjects (twenty to forty years old), (2) older normal subjects (forty to sixty years old), (3) young diabetic subjects (twenty to forty years old), (4) older diabetic subjects, normal weight (forty to sixty years old), (5) older diabetic subjects, obese (forty to sixty years old), (6) obese subjects (forty to sixty years old), and (7) borderline diabetic subjects. IRP levels, total IRP response and the ratio of IRP:TIR response were established for each group. Age apppeared to be a significant factor in influencing IRP levels in the normal subjects since the older subjects (group 2) had a significantly greater IRP response and IRP: TIR response than the younger subjects (group 1). Obesity and carbohydrate intolerance were each associated with slightly increased IRP levels, but the combination of obesity and carbohydrate intolerance was associated with marked increases in IRP levels and a significant increase in IRP:TIR response. The duration of diabetes may be important in the pattern of IRP release since rises in IRP levels after the oral intake of glucose occurred earlier (by thirty minutes) in both the young diabetic and borderline diabetic subjects (groups 1 and 7) than in the other groups.

Factors affecting diabetes knowledge in Type 2 diabetic veterans

Aims/hypothesisTo describe the clinical, psychological and social factors affecting diabetes knowledge of veterans with established Type 2 diabetes.MethodsWe conducted an observational study of 284 insulin-treated veterans with stable Type 2 diabetes. All subjects completed the University of Michigan Diabetes Research and Training Centre Knowledge Test, the Diabetes Care Profile, the Mini-Mental State Examination, the Geriatric Depression Scale, and the Diabetes Family Behaviour Checklist. Stepwise multiple linear regression was used to develop a model for the diabetes knowledge score based upon clinical and psychosocial variables.ResultsOne hundred eighty subjects were evaluated in a derivation set. The mean age ± SD was 65.4±9.6 years, 94% were men, and 36% were members of a minority group. Performance on the diabetes knowledge test was poor (64.9±15.3% correct). Self-perceived understanding of all management objectives explained only 6% of the variance in the knowledge scores. Multivariate analysis showed that age, years of schooling, duration of treatment, cognitive function, sex, and level of depression were independent determinants of the knowledge score. When the model was applied to 104 subjects in a validation set, there was a strong correlation between observed and predicted scores (r=0.537; p<0.001).Conclusions/interpretationStable, insulin-treated veterans have major deficiencies in diabetes knowledge that could impair their ability to provide self-care. A multivariate model comprised of demographic variables and psychosocial profiling can identify patients who have limited diabetes knowledge and be used to assess individual barriers to ongoing diabetes education.