Predicting reamputation risk in patients undergoing lower extremity amputation due to the complications of peripheral artery disease and/or diabetes.

BACKGROUND: Patients undergoing amputation of the lower extremity for the complications of peripheral artery disease and/or diabetes are at risk of treatment failure and the need for reamputation at a higher level. The aim of this study was to develop a patient-specific reamputation risk prediction model. METHODS: Patients with incident unilateral transmetatarsal, transtibial or transfemoral amputation between 2004 and 2014 secondary to diabetes and/or peripheral artery disease, and who survived 12 months after amputation, were identified using Veterans Health Administration databases. Procedure codes and natural language processing were used to define subsequent ipsilateral reamputation at the same or higher level. Stepdown logistic regression was used to develop the prediction model. It was then evaluated for calibration and discrimination by evaluating the goodness of fit, area under the receiver operating characteristic curve (AUC) and discrimination slope. RESULTS: Some 5260 patients were identified, of whom 1283 (24·4 per cent) underwent ipsilateral reamputation in the 12 months after initial amputation. Crude reamputation risks were 40·3, 25·9 and 9·7 per cent in the transmetatarsal, transtibial and transfemoral groups respectively. The final prediction model included 11 predictors (amputation level, sex, smoking, alcohol, rest pain, use of outpatient anticoagulants, diabetes, chronic obstructive pulmonary disease, white blood cell count, kidney failure and previous revascularization), along with four interaction terms. Evaluation of the prediction characteristics indicated good model calibration with goodness-of-fit testing, good discrimination (AUC 0·72) and a discrimination slope of 11·2 per cent. CONCLUSION: A prediction model was developed to calculate individual risk of primary healing failure and the need for reamputation surgery at each amputation level. This model may assist clinical decision-making regarding amputation-level selection.

Mortality prediction following non-traumatic amputation of the lower extremity.

BACKGROUND: Patients who undergo lower extremity amputation secondary to the complications of diabetes or peripheral artery disease have poor long-term survival. Providing patients and surgeons with individual-patient, rather than population, survival estimates provides them with important information to make individualized treatment decisions. METHODS: Patients with peripheral artery disease and/or diabetes undergoing their first unilateral transmetatarsal, transtibial or transfemoral amputation were identified in the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database. Stepdown logistic regression was used to develop a 1-year mortality risk prediction model from a list of 33 candidate predictors using data from three of five Department of Veterans Affairs national geographical regions. External geographical validation was performed using data from the remaining two regions. Calibration and discrimination were assessed in the development and validation samples. RESULTS: The development sample included 5028 patients and the validation sample 2140. The final mortality prediction model (AMPREDICT-Mortality) included amputation level, age, BMI, race, functional status, congestive heart failure, dialysis, blood urea nitrogen level, and white blood cell and platelet counts. The model fit in the validation sample was good. The area under the receiver operating characteristic (ROC) curve for the validation sample was 0·76 and Cox calibration regression indicated excellent calibration (slope 0·96, 95 per cent c.i. 0·85 to 1·06; intercept 0·02, 95 per cent c.i. -0·12 to 0·17). Given the external validation characteristics, the development and validation samples were combined, giving a total sample of 7168. CONCLUSION: The AMPREDICT-Mortality prediction model is a validated parsimonious model that can be used to inform the 1-year mortality risk following non-traumatic lower extremity amputation of patients with peripheral artery disease or diabetes.

Association of parental health literacy with oral health of Navajo Nation preschoolers.

Health literacy is 'the capacity to obtain, process and understand basic health information and services needed to make appropriate health decisions'. Although numerous studies show a link between health literacy and clinical outcomes, little research has examined the association of health literacy with oral health. No large-scale studies have assessed these relationships among American Indians, a population at risk for limited health literacy and oral health problems. This analysis was conducted as part of a clinical trial aimed at reducing dental decay among preschoolers in the Navajo Nation Head Start program. Using baseline data for 1016 parent-child dyads, we examined the association of parental health literacy with parents' oral health knowledge, attitudes, and behavior, as well as indicators of parental and pediatric oral health. More limited health literacy was associated with lower levels of oral health knowledge, more negative oral health attitudes, and lower levels of adherence to recommended oral health behavior. Parents with more limited health literacy also had significantly worse oral health status (OHS) and reported their children to have significantly worse oral health-related quality of life. These results highlight the importance of oral health promotion interventions that are sensitive to the needs of participants with limited health literacy.

Randomized Trial of Motivational Interviewing to Prevent Early Childhood Caries in American Indian Children.

INTRODUCTION: In a randomized controlled trial, the effectiveness of motivational interviewing (MI) combined with enhanced community services (MI + ECS) was compared with ECS alone for reducing dental caries in American Indian children on the Pine Ridge Reservation. The intervention was developed and delivered with extensive tribal collaboration. METHODS: A total 579 mother-newborn dyads were enrolled and randomized to the MI + ECS and ECS groups. They were followed for 36 mo. Four MI sessions were provided, the first shortly after childbirth and then 6, 12, and 18 mo later. Both groups were exposed to ECS, which included public service announcements through billboards and tribal radio, as well as broad distribution of brochures on behavioral risk factors for early childhood caries (ECC), toothbrushes, and toothpaste. MI impact was measured as decayed, missing, and filled tooth surfaces (dmfs). Secondary outcomes included decayed surfaces, caries prevalence, and maternal oral health knowledge and behaviors. Modified intention-to-treat analyses were conducted. Eighty-eight percent of mothers completed at least 3 of 4 MI sessions offered. RESULTS: After 3 y, dmfs was not significantly different for the 2 groups (MI + ECS = 10, ECS = 10.38, P = 0.68). In both groups, prevalence of caries experience was 7% to 9% after 1 y, 35% to 36% at 2 y, and 55% to 56% at 3 y. Mean knowledge scores increased by 5.0, 5.3, and 5.9 percentage points at years 1, 2, and 3 in the MI + ECS group and by 1.9, 3.3, and 5.0 percentage points in the ECS group (P = 0.03), respectively. Mean maternal oral health behavior scores were not statistically significantly different between the treatment arms. CONCLUSION: In summary, the MI intervention appeared to improve maternal knowledge but had no effect on oral health behaviors or on the progression of ECC (ClinicalTrials.gov NCT01116726). KNOWLEDGE TRANSFER STATEMENT: The findings of this study suggest that motivational interviewing focusing on parental behaviors may not be as effective as previously hoped for slowing the development of childhood caries in some high-risk groups. Furthermore, social factors may be even more salient determinants of oral health than what we previously supposed, perhaps interfering with the capacity to benefit from behavioral strategies that have been useful elsewhere. The improvement of children's oral health in high-risk populations characterized by poverty and multiple related life stresses may require more holistic approaches that address these formidable barriers.

A Cluster-Randomized, Community-Based, Tribally Delivered Oral Health Promotion Trial in Navajo Head Start Children.

The authors tested the effectiveness of a community-based, tribally delivered oral health promotion (OHP) intervention (INT) at reducing caries increment in Navajo children attending Head Start. In a 3-y cluster-randomized trial, we developed an OHP INT with Navajo input that was delivered by trained Navajo lay health workers to children attending 52 Navajo Head Start classrooms (26 INT, 26 usual care [UC]). The INT was designed as a highly personalized set of oral health-focused interactions (5 for children and 4 for parents), along with 4 fluoride varnish applications delivered in Head Start during academic years of 2011 to 2012 and 2012 to 2013. The authors evaluated INT impact on decayed, missing, and filled tooth surfaces (dmfs) increment compared with UC. Other outcomes included caries prevalence and caregiver oral health-related knowledge and behaviors. Modified intention-to-treat and per-protocol analyses were conducted. The authors enrolled 1,016 caregiver-child dyads. Baseline mean dmfs/caries prevalence equaled 19.9/86.5% for the INT group and 22.8/90.1% for the UC group, respectively. INT adherence was 53% (i.e., ≥3 child OHP events, ≥1 caregiver OHP events, and ≥3 fluoride varnish). After 3 y, dmfs increased in both groups (+12.9 INT vs. +10.8 UC; P = 0.216), as did caries prevalence (86.5% to 96.6% INT vs. 90.1% to 98.2% UC; P = 0.808) in a modified intention-to-treat analysis of 897 caregiver-child dyads receiving 1 y of INT. Caregiver oral health knowledge scores improved in both groups (75.1% to 81.2% INT vs. 73.6% to 79.5% UC; P = 0.369). Caregiver oral health behavior scores improved more rapidly in the INT group versus the UC group (P = 0.006). The dmfs increment was smaller among adherent INT children (+8.9) than among UC children (+10.8; P = 0.028) in a per-protocol analysis. In conclusion, the severity of dental disease in Navajo Head Start children is extreme and difficult to improve. The authors argue that successful approaches to prevention may require even more highly personalized approaches shaped by cultural perspectives and attentive to the social determinants of oral health (ClinicalTrials.gov NCT01116739).

Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy.

The perioperative consequences of preoperative aspirin administration were assessed in a large prospective cooperative study of 772 patients undergoing coronary artery bypass grafting. The 772 patients were randomized to receive either aspirin (325 mg once a day), aspirin (325 mg three times a day), aspirin plus dipyridamole (325 and 75 mg together three times a day) (aspirin group), sulfinpyrazone (267 mg three times a day) or placebo (nonaspirin group). The therapy, except in the aspirin group, was started 48 h before the operation. In all aspirin subgroups, one 325 mg aspirin dose was given 12 h before surgery and maintained thereafter according to the assigned regimen. Patients in the aspirin group had significantly more postoperative bleeding and received more packed blood cells and blood products than did patients in the nonaspirin group. Although total operative duration and cardiopulmonary bypass duration were not different, the interval between completion of cardiopulmonary bypass and wound closure was significantly longer (p = 0.035) in the aspirin group. Thirty-one (6.6%) of 471 patients in the aspirin group and 5 (1.7%) of 301 patients in the nonaspirin group also required reoperation for control of postoperative bleeding (p = 0.002). The site of bleeding found at reoperation was not different between the two groups. There was no difference in operative mortality rates, incidence of other bleeding complications or occurrence of other post-operative complications between the two groups. Thus, antiplatelet regimens involving preoperative initiation of aspirin therapy, which has been shown to improve graft patency, increase the risk of abnormal postoperative bleeding and the need for reoperation.(ABSTRACT TRUNCATED AT 250 WORDS)

Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial.

OBJECTIVES: The goal of this study was to compare long-term survival and valve-related complications between bioprosthetic and mechanical heart valves. BACKGROUND: Different heart valves may have different patient outcomes. METHODS: Five hundred seventy-five patients undergoing single aortic valve replacement (AVR) or mitral valve replacement (MVR) at 13 VA medical centers were randomized to receive a bioprosthetic or mechanical valve. RESULTS: By survival analysis at 15 years, all-cause mortality after AVR was lower with the mechanical valve versus bioprosthesis (66% vs. 79%, p = 0.02) but not after MVR. Primary valve failure occurred mainly in patients <65 years of age (bioprosthesis vs. mechanical, 26% vs. 0%, p < 0.001 for AVR and 44% vs. 4%, p = 0.0001 for MVR), and in patients > or =65 years after AVR, primary valve failure in bioprosthesis versus mechanical valve was 9 +/- 6% versus 0%, p = 0.16. Reoperation was significantly higher for bioprosthetic AVR (p = 0.004). Bleeding occurred more frequently in patients with mechanical valve. There were no statistically significant differences for other complications, including thromboembolism and all valve-related complications between the two randomized groups. CONCLUSIONS: At 15 years, patients undergoing AVR had a better survival with a mechanical valve than with a bioprosthetic valve, largely because primary valve failure was virtually absent with mechanical valve. Primary valve failure was greater with bioprosthesis, both for AVR and MVR, and occurred at a much higher rate in those aged <65 years; in those aged > or =65 years, primary valve failure after AVR was not significantly different between bioprosthesis and mechanical valve. Reoperation was more common for AVR with bioprosthesis. Thromboembolism rates were similar in the two valve prostheses, but bleeding was more common with a mechanical valve.

Six month postoperative hemodynamics of the Hancock heterograft and the Björk-Shiley prosthesis: results of a Veterans Administration cooperative prospective randomized trial.

In a Veterans Administration Cooperative Study involving 13 medical centers, 575 patients undergoing single valve replacement were prospectively randomized to receive either the standard Björk-Shiley prosthesis or the Hancock porcine heterograft (with a modified orifice for sizes 23 and smaller). The hemodynamic data in the 268 patients who underwent cardiac catheterization an average of 6 months (range 3 to 12) postoperatively are reported. Statistical analyses were performed on valve sizes 23, 25 and 27 in the aortic position, and 29, 31 and 33 in the mitral position. A wide variation was observed in mean pressure gradient and calculated orifice area in both valve types within all sizes in both the aortic and the mitral positions. In the aortic position, the Björk-Shiley prosthesis tended to have a lower pressure gradient and larger calculated orifice area than the Hancock heterograft, but the differences in gradient between the two valve types were significant only in the larger-sized valves. The difference in calculated area between the two valve types was not significant within each valve size. In the mitral position, there were no differences in gradient and calculated orifice area between the two types of prostheses. The postoperative cardiac index, regurgitant volume, pulmonary artery systolic and mean pressures, left ventricular end-diastolic pressure, left ventricular ejection fraction and left ventricular end-diastolic volume index did not differ in patients receiving the Björk-Shiley prosthesis from values in patients receiving the Hancock heterograft. Hence, the overall hemodynamic performance of both types of valves is remarkably similar. The choice between these two prostheses should, therefore, be governed not by the hemodynamic performance, but by other factors such as valve durability, risk of anticoagulation and incidence of valve-related complications.

Left atrial dimension and risk of systemic embolism in patients with a prosthetic heart valve. Department of Veterans Affairs Cooperative Study on Valvular Heart Disease.

The relation between left atrial dimension measured by M-mode echocardiography and systemic embolization after valve replacement was examined prospectively among 397 patients with a prosthetic valve enrolled in the Department of Veterans Affairs Cooperative Study on Valvular Heart Disease. Baseline characteristics including several measures of left atrial enlargement were compared for 31 patients who developed systemic embolism and 366 who did not develop embolism during a 5 year follow-up period. Variables that were significantly related to left atrial dimension or systemic embolization in univariate analyses were included with several others in a multiple logistic regression model. The incidence rate of systemic embolism was more than three times higher after mitral valve replacement than after aortic valve replacement (4.4 and 1.3 per 100 patient-years, respectively); this difference persisted after adjustment for other factors. Univariate analysis indicated a threefold higher incidence of systemic embolism in patients with a left atrial dimension greater than or equal to 4 cm compared with that in patients with a dimension less than 4 cm (3 versus 1 per 100 patient-years, respectively). However, when the effect of valve location (mitral versus aortic) was taken into account using either univariate or multivariate techniques, left atrial dimension was found not to be associated with systemic embolism. In multivariate analysis, atrial fibrillation, age, ejection fraction and location of the prosthetic valve were significantly associated with embolism. Results of this multicenter study suggest that left atrial dimension is not independently related to the development of systemic embolism in patients undergoing valve replacement.

Comparison of outcome after valve replacement with a bioprosthesis versus a mechanical prosthesis: initial 5 year results of a randomized trial.

The Veterans Administration Cooperative Study on Valvular Heart Disease was organized to compare survival and incidence of valve-related complications between patients receiving a bioprosthesis (the Hancock porcine heterograft) and a mechanical prosthesis (the Björk-Shiley spherical disc valve). Five hundred seventy-five patients undergoing single aortic or mitral valve replacement were randomized at surgery to one of the two valve types. At an average follow-up of 5 years (range 3 to 8) there are no statistically significant differences in survival between patients with the two valve types in the aortic valve replacement group. There is a statistically nonsignificant trend toward improved survival in patients undergoing mitral valve replacement with a bioprosthesis compared with a mechanical prosthesis (5 year survival probability was 0.70 +/- 0.05 and 0.58 +/- 0.06, respectively). Fatal and nonfatal valve-related complications occurred significantly less frequently in patients with a bioprosthesis compared with a mechanical prosthesis for both mitral and aortic valve replacement. Five year complication-free probability was 0.67 +/- 0.05 and 0.45 +/- 0.06, respectively, for patients with mitral valve replacement and 0.63 +/- 0.04 and 0.53 +/- 0.04, respectively, for those with aortic valve replacement. The difference in overall complication rates was largely due to the increased number of clinically significant but nonfatal bleeding episodes in patients receiving a mechanical prosthesis. Adjustment for differences in baseline characteristics between patients receiving a mitral mechanical prosthesis and a mitral bioprosthesis reduced the statistical significance of the difference in both mortality and complications.

Importance of obesity, race and age to the cardiac structural and functional effects of hypertension. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

OBJECTIVES: The purpose of this study was to determine the effects of obesity and its interaction with age, race and the magnitude of blood pressure elevation in a large cohort of patients with mild to moderate hypertension and a high prevalence of left ventricular hypertrophy. BACKGROUND: Obesity, race and age each have important effects on the incidence and severity of hypertension and may contribute to the effects of blood pressure elevation on the cardiac manifestations of hypertension. METHODS: Left ventricular structure and function were assessed with two-dimensional targeted M-mode echocardiography in 692 men with mild to moderate hypertension (average blood pressure 153/100 mm Hg), and the data were compared in relation to obesity (determined from body mass index), age, race, blood pressure, physical activity, plasma renin activity, urinary sodium excretion, hematocrit, heart rate and serum lipids. RESULTS: Left ventricular hypertrophy was common (63% with increased left ventricular mass, 22% with left ventricular hypertrophy on the electrocardiogram [ECG]). On multivariable regression analysis, body mass index was the strongest predictor of left ventricular mass and magnified the slope relation of blood pressure to left ventricular mass. Despite a greater prevalence of ECG left ventricular hypertrophy in blacks (31%) than in whites (10%), left ventricular mass and echocardiographic prevalence of left ventricular hypertrophy did not differ by race. However, septal, posterior left ventricular and relative wall thickness were greater in black than in white men. CONCLUSIONS: Obesity is the strongest clinical predictor of left ventricular mass and left ventricular hypertrophy in men, even in those with mild to moderate hypertension of sufficient severity to be associated with a high prevalence of left ventricular hypertrophy. Moreover, independent effects of systolic blood pressure on left ventricular mass are amplified by obesity. Although race does not affect left ventricular mass or the prevalence of left ventricular hypertrophy, black race is associated with greater relative wall thickness, itself a predictor of unfavorable cardiovascular outcome.

Cigarette smoking interferes with treatment of hypertension.

We retrospectively analyzed two studies to determine whether smoking affected the treatment of hypertension. In a study of the effects of propranolol hydrochloride (a hepatically metabolized beta-blocker) vs hydrochlorothiazide, 108 smokers and 232 nonsmokers were randomized to the propranolol treatment group. The propranolol-treated smokers tended to be younger, taller, thinner, and wre more likely to be black. This group also had an initial blood pressure reduction (+/- SD) of -7.9 +/- 12.9/-8.7 +/- 8.4 mm Hg compared with -10.7 +/- 13.0/-10.9 +/- 7.1 mm Hg for the nonsmokers. Blood pressure increased less during the one-year maintenance period for the nonsmokers. However, when analyzed by race, this effect was seen in blacks, but not in whites. Diastolic blood pressure tended to be reduced more in nonsmokers (vs smokers) receiving hydrochlorothiazide (-12.1 +/- 6.7 vs -10.7 +/- 6.7 mm Hg, respectively). The second study compared the effects of nadolol (a renally excreted beta-blocker) with bendroflumethiazide. There were no significant effects on blood pressure for either of these drugs. In both studies, there was a greater tendency for smokers to be terminated from the study irrespective of drug group. We conclude that cigarette smoking does interfere with the treatment of hypertension in general, and especially with reduction of blood pressure by propranolol in black patients.

Racial comparison of outcomes of male Department of Veterans Affairs patients with lung and colon cancer.

BACKGROUND: A study was performed to distinguish between genetic vs socioeconomic factors or artifacts inherent in retrospective studies to discover explanations for the apparent shorter survival of blacks than whites with lung and colon cancer. METHODS: Detailed biological and socioeconomic data were collected prospectively from a large cohort of patients with advanced lung and colon cancer who had not previously received chemotherapy and who consented to be entered in the clinical trial. Twelve medical centers within the Department of Veterans Affairs hospital system (Veterans Affairs Cooperative Study 188) entered patients between May 1981 and May 1986. These patients were evaluated and treated in a uniform manner within this hospital system and followed up to death. Outcome measures included time to tumor progression, tumor response, and survival. RESULTS: A total of 719 patients were entered in the study, 704 of whom were either black or white men. Blacks were found to have a significantly lower socioeconomic status than whites as measured by marital and educational status, occupation, income, housing, and number of individuals residing in household. Blacks had a significantly lower frequency of prior tumor resection and a significantly increased frequency of mediastinal lymph node involvement and of metastasis than whites. Trends existed toward a shorter time interval from original diagnosis to entry and a lower frequency of prior radiation therapy among blacks in comparison with whites at the time of entry to the study. However, no differences in intensity of treatment or follow-up, time to progression, response to treatment, or overall survival (measured from entry to the study to death) were observed for blacks vs whites. CONCLUSIONS: Lung and colon cancer are not necessarily more aggressive diseases in blacks than in whites. Based on a comparison of these data with those reported from other practice settings, we postulate that lung and colon cancer outcomes may be similar among black and white patients who receive equal access to comparable medical care in spite of socioeconomic differences. Findings suggest that future studies might focus profitably on racial factors that may exist at the time of patient entry to the health care system.

A four-year prospective trial of unmeasured diet in lean diabetic adults.

Fifty-one adult male outpatients at or below ideal body weight (IBW) with no history of weighing more than 15% over IBW in the past 5 yr and no more than 25% in the past 15 yr were randomly assigned to a traditional calorically defined exchange-type diet (EXCH) or an unmeasured diet emphasizing avoidance of refined sugar and balance of food consumption throughout the day. All but 4 patients were insulin treated. With the exception of one patient in each group, all patients were classified as having type II diabetes. Subjects were followed in a single-blind design for 4 yr in the Diabetes Outpatient Clinic every 3 mo. The average mean fasting glycemia (FBS), coefficient of FBS variation, number of reported hypoglycemic reactions, mean fasting serum triglyceride and cholesterol levels, and mean total daily insulin dosage were similar in both groups. Each patient's mean daily caloric intake did vary over time, but there was no difference in mean caloric intake between diet groups. There was a significant correlation between a patient's mean FBS rating and his serum triglyceride level: patients with lower mean FBS had a significantly lower mean triglyceride level than patients with higher FBS. Overall body weights remained stable throughout the study. However, there was a significant difference in the number of patients in the EXCH group whose actual weight was 3% or more above IBW on 50% or more of their visits.(ABSTRACT TRUNCATED AT 250 WORDS)

Response to intensive therapy steps and to glipizide dose in combination with insulin in type 2 diabetes. VA feasibility study on glycemic control and complications (VA CSDM).

OBJECTIVE: The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes (VA CSDM) prospectively studied 153 insulin-requiring type 2 diabetes patients, randomized between an intensively treated arm and a standard treatment arm during a mean follow-up of 27 months. The glycemic response to each of the progressive, sequential phases of insulin treatment was assessed, along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin. RESEARCH DESIGN AND METHODS: Five medical centers participated; half of the patients were assigned to the intensive treatment arm aiming for normal HbA1c levels. Age of patients was 60 +/- 6 years, duration of diabetes 8 +/- 3 years, and BMI 30.7 +/- 4 kg/m2. A four-step management technique was used, with patients moving to the next step if the operational goals were not met: Phase I, evening intermediate or long-acting insulin; phase II, added day-time glipizide; phase III, two injections of insulin alone; and phase IV, multiple daily insulin injections. Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week. Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases. RESULTS: Baseline HbA1c was 9.3 +/- 1.8%, and fasting plus serum glucose was 11.4 +/- 3.3 mmol/1. Fasting serum glucose fell to near normal in phase I, and remained so in the other treatment phases. An HbA1c separation of 2.1% between the arms was maintained during the course of the study, while the intensive arm kept HbA1c levels below 7.3% (P = 0.001). Most of the decrease in HbA1c occurred with one injection of insulin alone (phase I, -1.4%) or adding day-time glipizide (phase II, -1.9% compared with baseline). HbA1c did not decrease further after substituting two injections of insulin alone, with twice the insulin dose. Multiple daily injections resulted in an additional HbA1c fall (-2.4% compared with baseline). However, two-thirds of the patients were still on one or two injections a day at the end of the study. Changes in home glucose monitoring levels paralleled those of the HbA1c, as did the increments in number of reported hypoglycemic reactions, virtually all either "mild" or "moderate" in character. For the combination of glipizide and insulin (phase II), the only significant effect was obtained with daily doses up to 10 mg a day; there were no significant additional benefits with up to fourfold higher daily doses, and HbA1c levels had an upward trend with doses > 20 mg/day. CONCLUSIONS: A simple regime of a single injection of insulin, alone or with glipizide, seemed sufficient to obtain clinically acceptable levels of HbA1c for most obese, insulin-requiring type 2 diabetes patients. Further decrease of HbA1c demanded multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events. In combination therapy, doses of glipizide > 20 mg/day offered no additional benefit.

Evaluations of retinopathy in the VA Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM). A feasibility study.

OBJECTIVE: The main goal of the study of 153 male veterans was to determine whether a statistically and clinically significant difference in HbA1c could be achieved between a standard therapy and an intensively treated group of patients with type II diabetes. A second major goal was to assess the feasibility of collecting reliable high-quality endpoint data, including microvascular and macrovascular events. Retinopathy was defined as a key microvascular endpoint. RESEARCH DESIGN AND METHODS: This was a randomized prospective trial of 153 men between the ages of 40 and 69 years, with type II diabetes for 15 years or less. Of the patients, 78 were assigned to the standard therapy arm and 75 to the intensive therapy arm. The goal of standard therapy was good general medical care and well-being and avoiding excessive hyperglycemia, glycosuria, ketonuria, or hypoglycemia. This was generally accomplished with one shot of insulin per day. The goal of intensive therapy was to obtain an HbA1c within two standard deviations of the mean of nondiabetic subjects (4.0-6.1%). This was obtained by a four-step management technique, with patients moving to the next step only if operational goals were not met. The steps were as follows: step 1: evening intermediate or long-acting insulin only; step 2: evening insulin with daytime glipizide; step 3: insulin, twice a day, no glipizide; and step 4: more than two injections of insulin, no glipizide. Retinopathy was assessed at baseline, 12, and 24 months by seven-field stereo fundus photography done at each of the five participating VA medical centers and read at the Central Reading Center at the Department of Ophthalmology, University of Wisconsin Medical School, Madison. Visual acuity was determined by ophthalmologists at each of the participating hospitals. RESULTS: After the 6th month of the 24-month study, an average HbA1c of approximately 7.1% in the intensively treated group was sustained for the full study and was significantly lower than that seen in the standard group (9.2%, P < 0.001). Compliance in obtaining fundus photographs was excellent. Near normalization of glycemia did not cause transient worsening of retinal morphology nor did it prevent the onset or delay the progression of retinopathy. There was no effect on visual acuity. CONCLUSIONS: 1) A glycemic control intervention study in people with type II diabetes is feasible and safe; 2) intensive control did not cause transient deterioration of retinopathy; and 3) although no improvement was seen in retinopathy, the follow-up was 24 months, an interval shorter than the 3 years or more of intensive therapy before improvement is seen in type 1 diabetic studies. This does not rule out the possibility that longer periods of intensive therapy would have improved retinopathy. A full-scale intervention trial in type II diabetes is needed to resolve this issue.

Effect of intensive glycemic control on microalbuminuria in type 2 diabetes. Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes Feasibility Trial Investigators.

OBJECTIVE: Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes. The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated. RESEARCH DESIGN AND METHODS: We randomly assigned 153 male patients to either intensive treatment (INT) (goal HbA(1c) 7.1%) or to standard treatment (ST) (goal HbA(1c) 9.1%; P = 0.001), and data were obtained during a 2-year period. Mean duration of known diabetes was 8 years, mean age of the patients was 60 years, and patients were well matched at baseline. We obtained 3-h urine samples for each patient at baseline and annually and defined microalbuminuria as an albumin:creatinine ratio of 0.03-0.30. All patients were treated with insulin and received instructions regarding diet and exercise. Hypertension and dyslipidemia were treated with similar goals in each group. RESULTS: A total of 38% of patients had microalbuminuria at entry and were evenly assigned to both treatment groups. INT retarded the progression of microalbuminuria during the 2-year period: the changes in albumin:creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141, respectively (P = 0.046). Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were randomized to INT. Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control. In the group entering without microalbuminuria, the subgroup receiving ST had a lower percentage of patients with a macrovascular event (17%) than the subgroup receiving INT (36%) (P = 0.03). Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups. CONCLUSIONS: Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function. Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening, as observed with microvascular disease in the Diabetes Control and Complications Trial.

Ethnic differences in the glycemic response to exogenous insulin treatment in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus was conducted in NIDDM patients to determine if a significant difference in HbA1c could be achieved between groups receiving standard and intensive treatment. We observed differences in the response to exogenous insulin between African-Americans and other intensively treated patients. Therefore, we assessed the variations of response and correlated factors that might explain such differences. RESEARCH DESIGN AND METHODS: One hundred fifty-three men aged 40-69 years with NIDDM for < or = 15 years were randomized to either the standard therapy (n = 78) or the intensive therapy (n = 75) arm. Of the 75 patients in the intensive therapy group, 57 completed the study on insulin therapy alone. Of these, 18 were African-Americans and 39 were non-African-Americans. We conducted an analysis of the data collected to determine differences in baseline characteristics, glycemic response, insulin requirement, body weight, exercise, and basal C-peptide level, factors that may explain a difference in response to insulin therapy. RESULTS: Glycemic control improved in all patients with intensive insulin therapy. African-Americans achieved a greater improvement in HbA1c compared with non-African-Americans with a similar increment in insulin. This difference could not be explained by differences in body weight, activity, concomitant use of other medicines, or insulin-secretory capacity of the pancreas. CONCLUSIONS: We conclude that ethnic differences may exist in the response to insulin therapy. A knowledge of such differences may aid in achieving good glycemic control, especially since minorities have a greater prevalence of and burden from the microvascular complications of diabetes.

The Veterans Affairs Implantable Insulin Pump Study: effect on cardiovascular risk factors.

OBJECTIVE: To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. RESULTS: No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. CONCLUSIONS: IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.

Two years of intensive glycemic control and left ventricular function in the Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM).

OBJECTIVE: The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus (VA CSDM) was a multicenter randomized prospective study of 153 male type 2 diabetic patients to assess the ability to sustain clinically significant glycemic separation between intensive and standard treatment arms. A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier. The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular (LV) function. RESEARCH DESIGN AND METHODS: The patients were randomized to intensive step treatment with insulin alone or with sulfonylurea (intensive treatment arm [INT], n = 75) or to standard once-daily insulin injection (standard treatment arm [STD], n = 78) treatment. A total of 136 patients (standard treatment arm [STD], n = 70; INT, n = 66) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function. RESULTS: There was no difference in the mean LV ejection fraction (at entry: STD 57.1+/-9.51%; INT 58.1+/-8.7%; at 24 months: STD 57.3+/-10.8%, INT 59.5+/-10.7%), peak filling rate (at entry: STD 2.6+/-0.7 end diastolic volume per second, INT 2.4+/-0.8 end diastolic volume per second; at 24 months: STD 2.7+/-1.0 end diastolic volume per second, INT 2.5+/-0.7 end diastolic volume per second), or time to peak filling rate (at entry: STD 195.3+/-69.5 ms, INT 185.6 +/-62.4 ms; at 24 months: STD 182.6+/-64.8 ms, INT 179.2+/-61.2 ms) between the 2 treatment arms. A subgroup analysis of 104 patients (STD, n = 53; INT, n = 51) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups. Abnormal LV ejection fraction at baseline predicted cardiac events (interval between cardiac beats [RR] = 2.5). CONCLUSIONS: Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes.