The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro.

Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.

Similar HbA1c reduction and hypoglycaemia with variable- vs fixed-time dosing of basal insulin peglispro in type 1 diabetes: IMAGINE 7 study.

AIMS: To compare 24-hour fixed-time basal insulin peglispro (BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin (HbA1c) change after 12-week treatment (margin = 0.4%). MATERIALS AND METHODS: This Phase 3, open-label, randomized, cross-over study (N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. RESULTS: During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [least-squares mean difference = 0.06%, 95% confidence interval (-0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia (10.4 ± 0.62 and 10.5 ± 0.67 events/patient/30 days, P = .947) and nocturnal hypoglycaemia (1.3 ± 0.11 and 1.5 ± 0.13 events/patient/30days, P = .060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. CONCLUSIONS: Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy (HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin.

Different effects of basal insulin peglispro and insulin glargine on liver enzymes and liver fat content in patients with type 1 and type 2 diabetes.

AIMS: To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). MATERIALS AND METHODS: Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naïve T2D patients and 163 T2D patients previously treated with basal insulin. RESULTS: Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine-treated patients at 4-78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P < .001), and decreased after discontinuation of BIL. More BIL patients had ALT ≥3× upper limit of normal (ULN) than glargine. No patient had ALT ≥3× ULN with bilirubin ≥2× ULN that was considered causally related to BIL. In insulin-naїve T2D patients, LFC decreased with glargine but was unchanged with BIL. In T1D and T2D patients previously treated with basal insulin, LFC was unchanged with glargine but increased with BIL. In all three populations, LFC was higher after treatment with BIL vs glargine (difference at 52 weeks: 2.2% to 5.3%, all P < .01). CONCLUSIONS: Compared to glargine, patients treated with BIL had higher ALT and LFC at 52-78 weeks. No severe drug-induced liver injury was apparent with BIL treatment for up to 78 weeks.

Metabolic outcomes of matched patient populations initiating exenatide BID vs. insulin glargine in an ambulatory care setting.

AIM: This observational study evaluated the clinical effectiveness of exenatide BID (exenatide) vs. insulin glargine (glargine) in patients with type 2 diabetes mellitus in ambulatory clinical practice. METHODS: Retrospective analyses were conducted using an electronic medical record (EMR) database among adult patients with type 2 diabetes mellitus initiating exenatide or glargine between 1 November 2006 and 30 April 2009. The cohorts were propensity-score matched to control baseline demographics, clinical measures, health status and medication use. The changes from baseline to a 12-month follow-up period for A1C (primary outcome), weight, body mass index (BMI), blood pressure and lipid levels were compared between the matched cohorts using paired tests. RESULTS: Propensity-score matching between the exenatide (n = 4494) and glargine (n = 5424) cohorts led to 2683 matched pairs with comparable characteristics, including age, gender and baseline clinical values. The exenatide cohort achieved a greater mean reduction in A1C (-0.6% vs. -0.4%, p < 0.01), weight (-2.6 kg vs. -0.2 kg, p < 0.01), BMI (-0.8 kg/m(2) vs. -0.04 kg/m(2) , p < 0.01) and systolic blood pressure (SBP) (-1.8 mmHg vs. -0.1 mmHg, p < 0.01) in the follow-up period. The changes in diastolic blood pressure and lipid levels were not significantly different between cohorts. CONCLUSIONS: Compared to glargine, exenatide-treated patients experienced significant reductions in A1C, weight, BMI and SBP. Acknowledging the limitations of observational research, exenatide showed greater clinical effectiveness than glargine from a large EMR database in the ambulatory care setting.

Addition of exenatide twice daily to basal insulin for the treatment of type 2 diabetes: clinical studies and practical approaches to therapy.

BACKGROUND: Type 2 diabetes is a progressive disease that requires stepwise additions of non-insulin and insulin therapies to meet recommended glycaemic goals. The final stage of intensification may require prandial insulin, adding complexity and increased risks of hypoglycaemia and weight gain. AIMS: This review assesses the benefits and risks of adding exenatide twice daily, a glucagon-like peptide 1 receptor agonist, in patients with type 2 diabetes who are currently treated with basal insulin, but have failed to reach their glycaemic goals. METHODS AND RESULTS: Based on data from published studies, exenatide has a number of actions that complement basal insulin therapy. Exenatide has been shown to increase glucose-dependent insulin production, suppress abnormal plasma glucagon production, slow gastric emptying, enhance liver uptake of glucose and promote satiety. A recently published randomised clinical trial reported that the addition of exenatide twice daily to titrated basal insulin provided greater glycaemic control than titrated basal insulin alone, and did so without an increase in hypoglycaemic events and with modest weight loss. Exenatide use was associated with gastrointestinal side effects. The recent randomised trial confirmed and extended data from a number of prior observational studies that demonstrated the efficacy and safety of insulin/exenatide combination therapy. Practical considerations for adding exenatide twice daily to ongoing basal insulin are discussed.

The relationship of glycaemic control and triglycerides in patients with diabetes mellitus: a PreCIS Database Study.

AIMS: A common therapeutic approach in patients with type 2 diabetes mellitus who have elevated triglycerides (TGs) is to treat the hyperglycaemia before specifically targeting high TG. The aims of the current study were (i) to determine whether there was a relationship between glycated haemoglobin (HgbA1c) and TG levels at the baseline visit and (ii) to analyse the relationship between DeltaHgbA1c and DeltaTG after treatment. METHODS: Among 650 consecutive diabetic patients seen in the Cleveland Clinic Preventive Cardiology Department, 372 had both baseline and post-treatment HgbA1c and TG values. We analysed the relationship between baseline HgbA1c and TG as well as between the change in HgbA1c and the change in TG. For analysis, patients were divided into nine groups by tertiles of HgbA1c (< or =6.6, 6.7-7.8 and >7.8%) and TG (< or =1.75, 1.76-3.89 and >3.89 mmol/l) at baseline. RESULTS: At baseline, there was a small correlation between HgbA1c and TG (r(2) = 0.051; p < 0.001). For the entire group, there was a significant correlation between DeltaHgbA1c and DeltaTG from baseline to follow-up (r(2) = 0.077; p < 0.001). Analyses by tertiles showed that DeltaTG were only associated with changes in two groups: HgbA1c tertile 3 (>7.8%) and TG tertiles 2 (r(2) = 0.24; p < 0.0001) and 3 (r(2) = 0.187; p = 0.003). For every 1% change in the top tertile HgbA1c, there was a 9.3% change in TG (tertile 2) and a 9.8% change in TG (tertile 3). CONCLUSIONS: These observations suggest that for patients with diabetes mellitus and elevated TG, the effect of HgbA1c reduction has limited effects on TG reduction. Patients may benefit from TG-specific therapy initiated earlier rather than waiting to see effects of glycaemic control.

All-cause mortality risk predictors in a preventive cardiology clinic cohort-examining diabetes and individual metabolic syndrome criteria: a PRECIS database study.

AIM: It is unclear if metabolic syndrome (MS) is equal to type 2 diabetes mellitus (DM) in predicting cardiovascular disease (CVD) risk and mortality, and its prognostic value compared to Framingham risk model is controversial. We assessed mortality, CVD risk and prevalence in patients with DM and those without DM who met National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) MS criteria compared to patients without DM or MS. We analysed which component(s) of NCEP MS criteria had greatest predictive value for mortality. METHODS: Retrospective cohort analysis of 1189 DM, 1241 MS (fasting glucose < 126 mg/dl and > or =3 components NCEP-ATP III criteria) and 3023 non-DM/non-MS patients presented for baseline visit to Preventive Cardiology clinic between 1995 and 2006, whose subsequent vital status was determined for a median of 5.2 years. The association with mortality was determined by Cox proportional hazards models. The incremental predictive value of MS components was performed by concordance indexes. RESULTS AND CONCLUSION: DM group had highest mortality and CVD prevalence vs. MS and non-DM/non-MS groups respectively (all p < or = 0.001). Patients with MS criteria had increased CVD prevalence and 1.5-fold increased mortality vs. non-DM/non-MS group (all p < 0.02). In NCEP MS criteria, only fasting glucose significantly predicted mortality in MS group (p = 0.05). MS criteria predicted CVD prevalence in a parallel manner to Framingham risk score assessment. In a cohort of patients at high risk for CVD whose risk factors are being treated, presence of diabetes in addition to plasma glucose within NCEP MS criteria strongly predicts all-cause mortality.

Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.

BACKGROUND: Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition. METHODS: 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. FINDINGS: At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01). INTERPRETATION: Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

Obesity and glycemic control in patients with diabetes mellitus: Analysis of physician electronic health records in the US from 2009-2011.

AIMS: Examine the association between obesity and glycemic control among patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). METHODS: Data from US physician electronic health records (Humedica®) from 2009-2011 were utilized. Patients were defined as having above-target glycemic control if they had an HbA1c ≥7% at any time during the study period. Multinomial logistic regressions were conducted separately for T1DM and T2DM patients, and examined associations between BMI categories and probability of having above-target glycemic control (≥7% and <8%, ≥8% and <9%, or ≥9%) while controlling for patient demographics, general health, comorbid conditions, and antihyperglycemic medication use. RESULTS: There were 14,028 T1DM and 248,567 T2DM patients; 47.8% of T1DM and 63.4% of T2DM were obese (BMI ≥30kg/m(2)). For T1DM, being overweight (BMI 25-<30), obese class I (30-<35), II (35-<40), or III (≥40) was associated with a significantly higher probability of having HbA1c≥8% and <9% or ≥9%, while being overweight was associated with a significantly higher probability of having HbA1c ≥7% and <8% compared to normal BMI (BMI≥18.5 and<25). For T2DM patients, being overweight, obese class I, II, or III was associated with a significantly higher probability of having HbA1c ≥7% and <8%, ≥8% and <9%, or ≥9%. CONCLUSIONS: For both T1DM and T2DM patients, there were positive and statistically significant associations between being overweight or obese and having suboptimal glycemic control. These findings quantify the associations between obesity and glycemic control, and highlight the potential importance of individual characteristics on glycemic control.

Risk factors for 30-day readmission following hypoglycemia-related emergency room and inpatient admissions.

OBJECTIVE: Hypoglycemia is a serious complication of diabetes treatment. This retrospective observational study characterized hypoglycemia-related hospital emergency room (ER) and inpatient (in-pt) admissions and identified risk factors for 30-day all-cause and hypoglycemia-related readmission. RESEARCH DESIGN AND METHODS: 4476 hypoglycemia-related ER and in-pt encounters with discharge dates from 1/1/2009 to 3/31/2014 were identified in a large, multicenter electronic health record database. Outcomes were 30-day all-cause ER/hospital readmission and hypoglycemia-related readmission. Multivariable logistic regression methods identified risk factors for both outcomes. RESULTS: 1095 (24.5%) encounters had ER/hospital all-cause readmission within 30 days and 158 (14.4%) of these were hypoglycemia-related. Predictors of all-cause 30-day readmission included recent exposure to a hospital/nursing home (NH)/skilled nursing facility (SNF; OR 1.985, p<0.001); age 25-34 and 35-44 (OR 2.334 and 1.996, respectively, compared with age 65-74, both p<0.001); and African-American (AA) race versus all other race categories (OR 1.427, p=0.011). Other factors positively associated with readmission include chronic obstructive pulmonary disease, cerebrovascular disease, cardiac dysrhythmias, congestive heart disease, hypertension, and mood disorders. Predictors of readmissions attributable to hypoglycemia included recent exposure to a hospital/NH/SNF (OR 2.299, p<0.001), AA race (OR 1.722, p=0.002), age 35-44 (OR 3.484, compared with age 65-74, p<0.001), hypertension (OR 1.891, p=0.019), and delirium/dementia and other cognitive disorders (OR 1.794, p=0.038). Obesity was protective against 30-day hypoglycemia-related readmission (OR 0.505, p=0.017). CONCLUSIONS: Factors associated with 30-day all-cause and hypoglycemia-related readmission among patients with diabetic hypoglycemia include recent exposure to hospital/SNF/NH, adults <45 years, AAs, and several cardiovascular and respiratory-related comorbid conditions.

Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of 2 lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol (LDL-C) levels to <100 mg/dL compared with a moderate reduction to 132 to 136 mg/dL decreased the progression of atherosclerosis in grafts. Low-dose anticoagulation did not significantly affect progression. METHODS AND RESULTS: Approximately 3 years after the last trial visit, Clinical Center Coordinators contacted each patient by telephone to ascertain the occurrence of cardiovascular events and procedures. The National Death Index was used to ascertain vital status for patients who could not be contacted. Vital status was established for all but 3 of 1351 patients. Information on nonfatal events was available for 95% of surviving patients. A 30% reduction in revascularization procedures and 24% reduction in a composite clinical end point were observed in patients assigned to aggressive strategy compared with patients assigned to moderate strategy during 7.5 years of follow-up, P=0. 0006 and 0.001, respectively. Reductions of 35% in deaths and 31% in deaths or myocardial infarctions with low-dose anticoagulation compared with placebo were also observed, P=0.008 and 0.003, respectively. CONCLUSIONS: -The long-term clinical benefit observed during extended follow-up in patients assigned to the aggressive strategy is consistent with the angiographic findings of delayed atherosclerosis progression in grafts observed during the trial. The apparent long-term benefit of low-dose warfarin remains unexplained.

Aggressive cholesterol lowering delays saphenous vein graft atherosclerosis in women, the elderly, and patients with associated risk factors. NHLBI post coronary artery bypass graft clinical trial. Post CABG Trial Investigators.

BACKGROUND: The NHLBI Post Coronary Artery Bypass Graft trial (Post CABG) showed that aggressive compared with moderate lowering of low-density lipoprotein-cholesterol (LDL-C) decreased obstructive changes in saphenous vein grafts (SVGs) by 31%.1 Using lovastatin and cholestyramine when necessary, the annually determined mean LDL-C level ranged from 93 to 97 mg/dL in aggressively treated patients and from 132 to 136 mg/dL in the others (P<0.001). METHODS AND RESULTS: The present study evaluated the treatment effect in subgroups defined by age, gender, and selected coronary heart disease (CHD) risk factors, ie, smoking, hypertension, diabetes mellitus, high-density lipoprotein cholesterol (HDL-C) <35 mg/dL, and triglyceride serum levels >/=200 mg/dL at baseline. As evidenced by similar odds ratio estimates of progression (lumen diameter decrease >/=0.6 mm) and lack of interactions with treatment, a similar beneficial effect of aggressive lowering was observed in elderly and young patients, in women and men, in patients with and without smoking, hypertension, or diabetes mellitus, and those with and without borderline high-risk triglyceride serum levels. The change in minimum lumen diameter was in the same direction for all subgroup categories, without significant interactions with treatment. CONCLUSIONS: Aggressive LDL-C lowering delays progression of atherosclerosis in SVGs irrespective of gender, age, and certain risk factors for CHD.

Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the post coronary artery bypass graft trial.

BACKGROUND: The Post Coronary Artery Bypass Graft Trial, designed to compare the effects of two lipid-lowering regimens and low-dose anticoagulation versus placebo on progression of atherosclerosis in saphenous vein grafts of patients who had had CABG surgery, demonstrated that aggressive lowering of LDL cholesterol levels to a mean yearly cholesterol level from 93 to 97 mg/dL compared with a moderate reduction to a level of 132 to 136 mg/dL decreased the progression of atherosclerosis in saphenous vein grafts. Low-dose anticoagulation did not affect progression. This secondary analysis tested the hypothesis that a similar decrease in progression of atherosclerosis would also be present in native coronary arteries as measured in the left main coronary artery (LMCA). METHODS AND RESULTS: A sample of 402 patients was randomly selected from 1102 patients who had baseline and follow-up views of the LMCA suitable for analysis. Patients treated with the aggressive lipid-lowering strategy had less progression of atherosclerosis in the LMCA as measured by changes in minimum (P=0.0003) lumen diameter or the maximum percent stenosis (P=0.001), or the presence of substantial progression (P=0.008), or vascular occlusion (P=0.005) when compared with the moderate strategy. CONCLUSIONS: A strategy of aggressive lipid lowering results in significantly less atherosclerosis progression than a moderate approach in LMCAs.

Meal-stimulated C-peptide and insulin antibodies in type I diabetic subjects and their nondiabetic siblings characterized by HLA-DR antigens.

We studied serum C-peptide (CP) response 90 min after a breakfast meal and insulin antibody titers in 171 type I diabetic (IDDM) patients and 272 of their nondiabetic siblings from 169 unrelated families. HLA typing was performed in all participants. In IDDM patients, there was a decline in CP response with increased duration of disease. CP responses of greater than or equal to 1.8 ng/ml were seen significantly less often in patients who were less than 10 yr old at the time of diagnosis of IDDM than in patients who were greater than 10 yr old at the time of diagnosis (8% versus 21%, P less than 0.05). More patients with HLA-DR4 had a CP response greater than or equal to 1.8 ng/ml than did patients who lacked this antigen whether duration of IDDM was less than 10 yr (30% versus 18%, P greater than 0.05) or greater than or equal to 10 yr (15% versus 0%, P less than 0.05). Mean C-peptide was also higher in HLA-DR4-positive patients compared with HLA-DR4-negative patients both when duration of disease was less than 10 yr (1.7 +/- 1.9 versus 1.4 +/- 1.0, P less than 0.01) and greater than or equal to 10 yr (1.2 +/- 1.5 versus 1.0 +/- 0.4, P less than 0.0001). Insulin antibody binding was slightly higher in patients with HLA-DR4 compared with patients lacking this antigen (5.96 +/- 7.20 versus 4.89 +/- 4.74, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Skeletal muscle basement membrane in maturity-onset diabetes in the young.

We have studied skeletal muscle capillary basement membrane width (CBMW) and intensity of skeletal muscle extracellular basement membrane staining for albumin and IgG in eight families with maturity-onset diabetes in the young (MODY). Ninety-two MODY patients were identified. Sixty-three of these patients, 33 relatives with nondiagnostic oral glucose tolerance studies, and 61 normoglycemic relatives were studied for glucose and insulin. Twenty-six of these MODY patients, 20 normoglycemic relatives, and 16 unrelated normal controls had skeletal muscle capillary morphologic studies. The muscle capillary basement membrane was significantly increased in MODY patients younger than 40 yr when compared with unrelated normal subjects and relatives of the same age (P less than 0.001). However, in these families, the CBMW of MODY patients showed no significant thickening with age (slope = 0.45, P less than 0.14), as expected and seen in the normal subjects and in the normoglycemic relatives of the patients (slope = 1.21, P less than 0.001). The slope derived from the linear regression of age and CBMW in MODY patients (0.45 +/- 0.29) was significantly less (P less than 0.05) than that of the nondiabetic subjects (1.21 +/- 0.19). The mean intensity of skeletal muscle extracellular basement membrane staining for albumin was higher in MODY patients (1.1 +/- 0.15) than in unrelated normal subjects (0.7 +/- 0.1, P less than 0.025) and normal MODY family members (0.6 +/- 0.08, P less than 0.01). The unexpected absence of basement membrane thickening with age in the MODY patients may explain the paucity of vascular complications that have been reported by some.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of aggressive cholesterol lowering and low-dose anticoagulation on clinical and angiographic outcomes in patients with diabetes: the Post Coronary Artery Bypass Graft Trial.

Diabetic patients have greater risk for coronary heart disease (CHD) events after coronary artery bypass graft (CABG) surgery than nondiabetic patients. The Post CABG trial studied the effects of aggressive cholesterol lowering and low-dose anticoagulation in diabetic patients compared with nondiabetic patients. A double-blind, randomized clinical trial in 1,351 patients (1-11 years after CABG), the Post CABG trial consisted of two interventions (aggressive cholesterol-lowering versus moderate lowering and low-dose warfarin versus placebo) on angiographic end points. Angiographic changes in saphenous vein graft conduits 4.3 years after entry were compared in 116 diabetic and 1,235 nondiabetic patients. Seven clinical centers participated in the trial, as well as the National Institutes of Health project office (National Heart, Lung, and Blood Institute), the coordinating center (Maryland Medical Research Institute), and the Angiogram Reading Center (University of Minnesota). Baseline characteristics of the diabetic patients differed from the nondiabetic patients in the following ways: percentage of women participants, 15 vs. 7%, P = 0.002; mean baseline weight, 87.4 vs. 82.8 kg, P = 0.006; mean BMI, 29.5 vs. 27.6 kg/m2, P = 0.0002; mean systolic blood pressure, 141.7 vs. 133.6, P < 0.0001; mean triglyceride concentrations, 2.09 vs. 1.77 mmol/l, P < 0.0001; and mean HDL cholesterol concentrations, 0.93 vs. 1.02 mmol, P = 0.0001. The percentage of clinical events was higher in diabetic than nondiabetic patients (20.6 vs. 13.4, P = 0.033) and angiographic outcomes were not different. The benefits of aggressive cholesterol lowering were comparable in diabetic and nondiabetic patients for the angiographic end points. Warfarin use was not associated with clinical or angiographic benefit. Diabetic patients in the Post CABG trial had more CHD risk factors at study entry and higher clinical event rates during the study than nondiabetic patients. The benefits of aggressive cholesterol lowering in diabetic patients were comparable to those in nondiabetic patients for both angiographic and clinical end points. The small number of diabetic patients provided limited power to detect significant differences between diabetic and nondiabetic patients or between diabetic patients in the aggressive versus moderate cholesterol treatment strategies.

Prognostic factors for atherosclerosis progression in saphenous vein grafts: the postcoronary artery bypass graft (Post-CABG) trial. Post-CABG Trial Investigators.

OBJECTIVES: The study was done to assess patients in the Post-Coronary Artery Bypass Graft (Post-CABG) trial to determine prognostic factors for atherosclerosis progression. BACKGROUND: Saphenous vein grafts (SVGs) are effective in relieving angina and, in certain patient subsets, in prolonging life. However, the progression of atherosclerosis in many of these grafts limits their usefulness. METHODS: The Post-CABG trial studied moderate versus aggressive lipid-lowering and low-dose warfarin versus placebo in patients with a history of coronary artery bypass surgery and found that more aggressive lipid lowering was effective in preventing progression of atherosclerosis in SVGs, but warfarin had no effect. Using variables measured at baseline, we sought the independent prognostic factors for atherosclerosis progression in SVGs, employing the statistical method of generalized estimating equations with a logit-link function. RESULTS: Twelve independent prognostic factors for atherosclerosis progression were found. In the order of their importance they were: maximum stenosis of the graft at baseline angiography, years post-SVG placement; the moderate low-density lipoprotein-cholesterol (LDL-C) lowering strategy; prior myocardial infarction; high triglyceride level; small minimum graft diameter; low high-density lipoprotein-cholesterol (HDL-C); high LDL-C; high mean arterial pressure; low ejection fraction; male gender; and current smoking. CONCLUSIONS: This study identified Post-CABG patient and SVG characteristics associated with saphenous vein graft atherosclerosis progression. These data provide a basis for rational risk factor management to prevent progression of SVG atherosclerosis.

Artifactual elevation of serum creatinine level due to fasting.

Abnormal serum creatinine (1.6 mg/dL) and creatinine clearance (33 mL/min) levels found in a 50-year-old woman during fasting were corrected with refeeding. Five healthy subjects who fasted for 96 hours demonstrated an increase in their mean serum creatinine level from 1.0 +/- 0.08 to 1.7 +/- 0.11 mg/dL as determined by Jaffé's method. This increase was probably an artifact caused by the rise in the serum acetoacetate level during fasting. The serum creatinine level determined by an enzymatic method and serum urea nitrogen level did not change substantially during the fast. We conclude that fasting may cause an artifactual increase in the serum creatinine level determined by Jaffé's method, the method used by most clinical laboratories.

Influence of frequency, time interval from initial instruction, and method of instruction on performance competency for blood glucose monitoring.

In a sample of 178 nurses who had been instructed in the performance of fingerstick monitoring of blood glucose (MBG), we investigated variables that may predict their proficiency at subsequent MBG performance. All nurses were given initial instruction in a classroom-type setting or via a self-instructional packet, and initial proficiency was documented by initial testing. All nurses were retested 1-8 mo later. To address whether actual frequency of performing MBG at work affected proficiency, the nurses were categorized based on the frequency of performing MBG groups: greater than 1 test/day (n = 53), greater than 1 test/wk (n = 51), greater than 1 test/mo (n = 52), and less than 1 test/mo (n = 22). No differences in test and retest scores were detected. To address whether the time interval from the original instruction and test to the retest affected proficiency, the nurses were divided into groups who had initial test less than 6 mo (n = 108) and greater than 6 mo (n = 70) before the retest. Mean change in test scores was less in the greater than 6-mo group than in the less than 6-mo group (P less than 0.01), and they had a lower retest fail rate (3 vs. 12%, P = 0.03). To explain this unexpected finding, test scores were analyzed by groups based on the type of original instruction. Nurses who attended class (n = 79) were compared with those who had self-instruction (n = 99). The classroom-trained group had less change in test-to-retest score (P = 0.0002) and a lower retest failure rate (3 vs. 12%, P less than 0.05).

Urinary C-peptide as a measure of beta-cell function after a mixed meal in healthy subjects: comparison of four-hour urine C-peptide with serum insulin and plasma C-peptide.

Urinary C-peptide (UCP) is a noninvasive measure of integrated insulin production, and the usefulness of 24-h collections has been previously reported. Only small numbers of subjects have been studied using shorter urine collections. To see how well 4-h urine collections for C-peptide (UCP) correlate with serum immunoreactive insulin (SI) and plasma C-peptide (PCP), we studied 41 healthy subjects (19 men, 22 women) using as a stimulus a 600-kcal mixed meal and the same mixed meal after oral prednisone. UCP values correlated best with the area under the curves for SI (r = 0.457, P less than 0.001) and PCP (r = 0.557, P less than 0.001). UCP was also significantly correlated with peak SI (r = 0.382, P less than 0.001), peak PCP (r = 0.496, P less than 0.001), fasting SI (r = 0.297, P = 0.007), and fasting PCP (r = 0.341, P = 0.007) values. Urinary C-peptide was significantly correlated with SI and PCP concentrations in a broad range of physiologic values for SI and PCP supporting the usefulness of UCP as a simple, noninvasive measure of beta-cell function. Four-hour collections for UCP may be useful in further studies of beta-cell function.