Mary Ellen Sweeney

The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study

Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Design Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A1C) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control. Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia. Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia. Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued. Trial registration NCT00000620.

Long-Term Effects of Incident Diabetes Mellitus on Cardiovascular Outcomes in People Treated for Hypertension: The ALLHAT Diabetes Extension Study

Background— Thiazide-type diuretics are associated with an increased incidence of diabetes compared with other antihypertensive medications. In this study, we determined the long-term cardiovascular disease (CVD) consequences of incident diuretic-associated diabetes compared with the effects of incident diabetes associated with calcium channel blocker and angiotensin-converting enzyme inhibitor use. Methods and Results— A total of 22 418 participants from the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) with baseline diabetes, incident diabetes (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril), or no diabetes at 2 years of in-trial follow-up were followed for a mean total of 6.9 years (2.9 years in-trial and 4 additional years posttrial) through the use of national databases. The primary outcome was CVD mortality (death from coronary heart disease [CHD], stroke, heart failure, or other CVD). Among other outcomes were all-cause mortality, non-CVD mortality, and CHD (nonfatal myocardial infarction or fatal CHD). Participants on chlorthalidone with incident diabetes versus no diabetes had consistently lower, nonsignificant risk for CVD mortality (hazard ratio [HR], 1.04; 95% CI, 0.74–1.47), all-cause mortality (HR, 1.04; 95% CI, 0.82–1.30), and non-CVD mortality (HR, 1.05; 95% CI, 0.77–1.42) than participants on amlodipine or lisinopril with incident diabetes (HR range, 1.22–1.53). Participants with incident diabetes had elevated CHD risk compared with those with no diabetes (HR, 1.46; 95% CI, 1.09–1.96), but those on chlorthalidone had significantly lower risk than those on lisinopril (HR, 1.18 versus 2.57; P=0.04 for interaction). Conclusions— The findings suggest that thiazide-related incident diabetes has less adverse long-term CVD impact than incident diabetes that develops while on other antihypertensive medications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

Ezetimibe: an update on the mechanism of action, pharmacokinetics and recent clinical trials

Elevated serum cholesterol is a known risk factor for the development of coronary artery disease. Circulating cholesterol is a product of both cholesterol absorption from the gut and cellular cholesterol production. Ezetimibe is a novel cholesterol-lowering drug that acts at the brush border of the small intestine. Recent studies have further identified the molecular target as the Niemann–Pick C1-like transporter. Ezetimibe blocks the absorption of dietary and biliary cholesterol and plant sterols resulting in intracellular cholesterol depletion. Clinical studies have demonstrated beneficial improvements in the lipid profile with ezetimibe as monotherapy, but dramatic effects are seen when ezetimibe is combined with other lipid-lowering drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Combination studies of ezetimibe with statins, bile acid sequestrants, fenofibrate and niacin all demonstrate significant total and low density lipoprotein cholesterol lowering. An excellent safety and tolerability profile combined with once-daily dosing make this attractive adjunct therapy for the treatment of hypercholesterolemia.

Exercise testing and training with β-adrenergic blockade: Role of the drug washout period in “unmasking” a training effect

To determine whether or not a training effect can be achieved with beta-adrenergic blockade and whether there is a difference between selective and nonselective therapy, we recruited 40 healthy subjects (16 women, 24 men) to participate in a 9-week exercise training program. After a baseline exercise treadmill test, subjects were randomized to oral therapy groups of atenolol, 50 mg daily (AT 50), atenolol, 100 mg daily (AT 100), propranolol, 80 mg twice a day (Prop), or placebo. Repeat exercise tests were performed at week 1, week 8, and at week 9, with week 8 to 9 being a 1-week drug-free washout period. At week 8, maximal oxygen consumption (Max VO2), when compared with baseline levels, was increased slightly in AT 50 (4.2%) and Prop (2.4%), decreased in AT 100 (5.3%), and increased significantly in the placebo group (12.7%). After washout, Max VO2 increased significantly compared with baseline in AT 50, AT 100, and Prop (9.8%, 10.8%, and 9.8%, respectively). We conclude that there is no significant difference between selective and nonselective beta-blockade therapy in the development of a training effect. This effect, however, may not become apparent until the drug is withdrawn.

Effect of intensiveversus standard blood pressure treatment according to baseline prediabetes status: A post hoc analysis of a randomized trial

OBJECTIVE To determine whether the effects of intensive (<120 mmHg) compared with standard (<140 mmHg) systolic blood pressure (SBP) treatment are different among those with prediabetes versus those with fasting normoglycemia at baseline in the Systolic Blood Pressure Intervention Trial (SPRINT). RESEARCH DESIGN AND METHODS This was a post hoc analysis of SPRINT. SPRINT participants were categorized by prediabetes status, defined as baseline fasting serum glucose ≥100 mg/dL versus those with normoglycemia (fasting serum glucose <100 mg/dL). The primary outcome was a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Cox regression was used to calculate hazard ratios for study outcomes with intensive compared with standard SBP treatment among those with prediabetes and normoglycemia. RESULTS Among 9,361 participants randomized (age 67.9 ± 9.4 years; 35.5% female), 3,898 and 5,425 had baseline prediabetes and normoglycemia, respectively. After a median follow-up of 3.26 years, the hazard ratio for the primary outcome was 0.69 (95% CI 0.53, 0.89) and 0.83 (95% CI 0.66, 1.03) among those with prediabetes and normoglycemia, respectively (P value for interaction 0.30). For all-cause mortality, the hazard ratio with intensive SBP treatment was 0.77 (95% CI 0.55, 1.06) for prediabetes and 0.71 (95% CI 0.54, 0.94) for normoglycemia (P value for interaction 0.74). Effects of intensive versus standard SBP treatment on prespecified renal outcomes and serious adverse events were similar for prediabetes and normoglycemia (all interaction P > 0.05). CONCLUSIONS In SPRINT, the beneficial effects of intensive SBP treatment were similar among those with prediabetes and fasting normoglycemia.

Efficacy and compliance with cholestyramine bar versus powder in the treatment of hyperlipidemia

PURPOSE The purpose of the study was to compare the powder and the bar forms of cholestyramine to determine efficacy and patient compliance. SUBJECTS AND METHODS A prospective, randomized trial was conducted that included 83 healthy men and women with hyperlipidemia greater than the 90th percentile for low-density lipoprotein (LDL) or total cholesterol. Patients were randomly assigned to receive either cholestyramine powder, two packets (8 g), twice daily, or cholestyramine confectionery bar, in maple or mint flavors, two bars (8 g), twice daily. Fasting serum total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were measured at baseline, after 6 to 8 weeks of following the American Heart Association Step I diet alone, and after 8 weeks of taking either the cholestyramine bar or powder. RESULTS Total cholesterol decreased significantly (p less than 0.01) by 16% in the bar group and 17% in the powder group. LDL cholesterol decreased by 28% and 29% in the bar and powder groups, respectively (p less than 0.01). There was no significant change in HDL cholesterol. Triglycerides increased in both groups, by 29% in the bar group and by 25% in the powder group. There was no difference between bar and powder in the effect on blood lipids. The majority of the lipid-lowering effect was seen within 14 days. Mean patient endpoint compliance with the therapy was 91.8 +/- 3.6% in the bar group and 94.8 +/- 2.1% in the powder group. There was no difference between groups. CONCLUSION The cholestyramine confectionery bar is as effective as cholestyramine powder in the treatment of hyperlipidemia. The majority of the lipid-lowering effect is seen within 14 days of therapy. Although patient compliance is comparable between the two forms, gastrointestinal side effects were slightly greater with the bar form. Therefore, although the bar offers an alternative form of therapy, there appears to be no advantage with regard to patient compliance or palatability.

Cardiovascular risk assessment: addition of CKD and race to the Framingham equation

BACKGROUND/AIMS The value of the Framingham equation in predicting cardiovascular risk in African Americans and patients with chronic kidney disease (CKD) is unclear. The purpose of the study was to evaluate whether the addition of CKD and race to the Framingham equation improves risk stratification in hypertensive patients. METHODS Participants in the ALLHAT were studied. Those randomized to doxazosin, older than 74 years, and those with a history of coronary heart disease were excluded. Two risk stratification models were developed using Cox proportional hazards models in a two-thirds developmental sample. The first model included the traditional Framingham risk factors. The second model included the traditional risk factors plus CKD, defined by estimated glomerular filtration rate categories, and stratification by race (black vs non-black). The primary outcome was a composite of fatal coronary heart disease, nonfatal myocardial infarction, coronary revascularization, and hospitalized angina. RESULTS There were a total of 19,811 eligible subjects. In the validation cohort, there was no difference in C-statistics between the Framingham equation and the ALLHAT model including CKD and race. This was consistent across subgroups by race and sex and among those with CKD. One exception was among Non-Black women where the C-statistic was higher for the Framingham equation (0.68 vs 0.65, P = .02). In addition, net reclassification improvement was not significant for any subgroup based on race and sex, ranging from -5.5% to 4.4%. CONCLUSION The addition of CKD status and stratification by race does not improve risk prediction in high-risk hypertensive patients.

Blood magnesium and potassium alterations with maximal treadmill exercise testing: Effects of β-adrenergic blockade

To test alterations in plasma potassium and magnesium levels with maximal exercise, 15 sedentary, healthy men (mean age 29 years) participated in a double-blind crossover study for 11 weeks with propranolol, atenolol, and placebo. Maximal exercise tests were done at baseline and after placebo and beta-blockade phases. Blood for analysis was collected via indwelling brachial vein angiocatheters at baseline and during and after testing. Plasma potassium and magnesium levels increased at peak exercise with atenolol, propranolol, and placebo. There was no difference among groups in baseline recovery for magnesium (mean 28 minutes, range 24 to 30 minutes). Potassium levels returned to baseline more rapidly (compared with magnesium) in the placebo and atenolol groups (mean 10 minutes); however, recovery time was prolonged with propranolol (26 minutes) compared with placebo and atenolol (p less than 0.01). In conclusion, plasma magnesium and potassium levels increased significantly with maximal exercise and are unaffected by atenolol or propranolol beta-blockade. Propranolol, however (compared with atenolol and placebo), prolongs the time of return to baseline of plasma potassium after exercise.

VAMONOS (Veterans Affairs' Metabolism, Obstructed and Non-Obstructed Sleep) Study: Effects of CPAP Therapy on Glucose Metabolism in Patients with Obstructive Sleep Apnea.

STUDY OBJECTIVES Obstructive sleep apnea (OSA) and type 2 diabetes mellitus (T2DM) are prevalent disorders that pose increased risk of cardiovascular disease and death. The objective of this study was to clarify if continuous positive airway pressure (CPAP) therapy for OSA affects T2DM control and emergence. METHODS Point-of-care, comparative effectiveness study; cross-sectional and longitudinal analyses. RESULTS Our cohort included 928 consecutive patients; 13% were women; 36% were Caucasians and 61% African-Americans. OSA was diagnosed in approximately 738 patients and CPAP was initiated in 718 patients; median duration of therapy was 5 mo (25% to 75% interquartile range [IQR] 3-14). Patients with OSA used CPAP therapy for a median duration of 4.8 h, 34.5% of the nights. Adherence to CPAP was prespecified as follows: good (≥ 70% nights and ≥ 4 h/night), excellent (≥ 80% nights and ≥ 6 h/night) or outstanding (≥ 90% of nights and 8 h/night). Based on objective data, good, excellent, and outstanding compliance were found in only 30%, 20%, and 6%, respectively. Three percent of subjects without CPAP follow-up and less than 4% of those nonadherent to CPAP therapy (based on the established criteria) developed incident T2DM. Incident T2DM developed in only 0.8% of those with good compliance and in none (0%) of those in the excellent and outstanding groups. During follow-up, median weight change was +0.3 kg (IQR -1.8 to 2.7). CONCLUSIONS We found that an outstanding compliance to CPAP reduced fasting blood glucose in patients with OSA. Longitudinally, higher levels of therapeutic adherence may affect the rate of incident impaired fasting glucose, prediabetes, and T2DM, despite the observed weight gains. COMMENTARY A commentary on this article appears in this issue on page 365.

Constructing common cohorts from trials with overlapping eligibility criteria: Implications for comparing effect sizes between trials

Background Comparing findings from separate trials is necessary to choose among treatment options, however differences among study cohorts may impede these comparisons. Purpose As a case study, to examine the overlap of study cohorts in two large randomized controlled clinical trials that assess interventions to reduce risk of major cardiovascular disease events in adults with type 2 diabetes in order to explore the feasibility of cross-trial comparisons Methods The Action for Health in Diabetes (Look AHEAD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials enrolled 5145 and 10,251 adults with type 2 diabetes, respectively. Look AHEAD assesses the efficacy of an intensive lifestyle intervention designed to produce weight loss; ACCORD tests pharmacological therapies for control of glycemia, hyperlipidemia, and hypertension. Incidence of major cardiovascular disease events is the primary outcome for both trials. A sample was constructed to include participants from each trial who appeared to meet eligibility criteria and be appropriate candidates for the other trial’s interventions. Demographic characteristics, health status, and outcomes of members and nonmembers of this constructed sample were compared. Results Nearly 80% of Look AHEAD participants were projected to be ineligible for ACCORD; ineligibility was primarily due to better glycemic control or no early history of cardiovascular disease. Approximately 30% of ACCORD participants were projected to be ineligible for Look AHEAD, often for reasons linked to poorer health. The characteristics of participants projected to be jointly eligible for both trials continued to reflect differences between trials according to factors likely linked to retention, adherence, and study outcomes. Limitations Accurate ascertainment of cross-trial eligibility was hampered by differences between protocols. Conclusions Despite several similarities, the Look AHEAD and ACCORD cohorts represent distinct populations. Even within the subsets of participants who appear to be eligible and appropriate candidates for trials of both modes of intervention, differences remained. Direct comparisons of results from separate trials of lifestyle and pharmacologic interventions are compromised by marked differences in enrolled cohorts. Clinical Trials 2009; 6: 416—429. http://ctj.sagepub.com