Ajay Sood

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy. Design Post hoc epidemiological analysis of a double 2×2 factorial, randomised, controlled trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A1C concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese). Interventions Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control. Main outcome measures Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon. Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A1C concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A1C concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21). Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk. Trial registration ClinicalTrials.gov number NCT00000620.

Outcomes of Combined Cardiovascular Risk Factor Management Strategies in Type 2 Diabetes: The ACCORD Randomized Trial

OBJECTIVE To compare effects of combinations of standard and intensive treatment of glycemia and either blood pressure (BP) or lipids in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS ACCORD enrolled 10,251 type 2 diabetes patients aged 40–79 years at high risk for cardiovascular disease (CVD) events. Participants were randomly assigned to hemoglobin A1c goals of <6.0% (<42 mmol/mol; intensive glycemia) or 7.0–7.9% (53–63 mmol/mol; standard glycemia) and then randomized a second time to either 1) systolic BP goals of <120 mmHg (intensive BP) or <140 mmHg (standard BP) or 2) simvastatin plus fenofibrate (intensive lipid) or simvastatin plus placebo (standard lipid). Proportional hazards models were used to assess combinations of treatment assignments on the composite primary (deaths due to CVD, nonfatal myocardial infarction [MI], and nonfatal stroke) and secondary outcomes. RESULTS In the BP trial, risk of the primary outcome was lower in the groups intensively treated for glycemia (hazard ratio [HR] 0.67; 95% CI 0.50–0.91), BP (HR 0.74; 95% CI 0.55–1.00), or both (HR 0.71; 95% CI 0.52–0.96) compared with combined standard BP and glycemia treatment. For secondary outcomes, MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment; most other HRs were neutral or favored intensive treatment groups. In the lipid trial, the general pattern of results showed no evidence of benefit of intensive regimens (whether single or combined) compared with combined standard lipid and glycemia treatment. The mortality HR was 1.33 (95% CI 1.02–1.74) in the standard lipid/intensive glycemia group compared with the standard lipid/standard glycemia group. CONCLUSIONS In the ACCORD BP trial, compared with combined standard treatment, intensive BP or intensive glycemia treatment alone improved major CVD outcomes, without additional benefit from combining the two. In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.

Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data

BackgroundHypoglycemia is a common complication of diabetes treatment. This paper describes symptoms, predecessors, consequences and medications associated with the first episode of severe hypoglycemia among ACCORD participants with type 2 diabetes, and compares these between intensive (Int: goal A1C <6.0%) and standard (Std, goal A1C 7–7.9%) glycemia intervention groups.MethodsInformation about symptoms, antecedents, and consequences was collected at the time participants reported an episode of severe hypoglycemia. Data on medications prescribed during the clinical trial was used to determine the association of particular diabetes drug classes and severe hypoglycemia.ResultsThe most frequently reported symptoms in both glycemia group were weakness/fatigue (Int 29%; Std 30%) and sweating (Int 26%; Std 27%), followed by confusion/disorientation (Int 22%; Std 29%) and shakiness (Int 21%; Std 19%). Approximately half of all events were preceded by a variation in food intake (Int 48%; Std 58%). The most common consequences were confusion (Int 37%; Std 34%), loss of consciousness (Int 25%; Std 25%), and hospitalization (Int 18%; Std 24%). The highest rates of hypoglycemia were found among those participants treated with insulin only (Int 6.09/100 person yrs; Std 2.64/100 person yrs) while the lowest were among those prescribed oral agents only (Int 1.93/100 person yrs; Std 0.20/100 person yrs).ConclusionsSevere hypoglycemia episodes were frequently preceded by a change in food intake, making many episodes potentially preventable. Symptoms of confusion/disorientation and loss of consciousness were frequently seen. The highest rates of hypoglycemia were seen with prescription of insulin, either alone or in combination with other medications.Clinical Trial RegistrationNumber: NCT00000620

Effect of intensive glycemic lowering on health-related quality of life in type 2 diabetes: ACCORD trial.

OBJECTIVE To compare the effect of intensive versus standard glycemic control strategies on health-related quality of life (HRQL) in a substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS A randomly selected subsample of 2,053 ACCORD participants enrolled in the HRQL substudy was assessed at baseline and 12-, 36-, and 48-month visits. HRQL assessment included general health status (the 36-Item Short Form Health Survey [SF-36]), diabetes symptoms (the Diabetes Symptom Distress Checklist), depression (Patient Health Questionnaire [PHQ]-9), and treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire [DTSQ]). Repeated-measures ANOVA models were used to estimate change in HRQL outcomes by treatment group over 48 months adjusting for model covariates. The effects of early discontinuation of the ACCORD intensive glycemic control arm on study results were explored. RESULTS A total of 1,956 (95%) completed the self-report HRQL instrument(s) at baseline. The intensive arm had a larger decrease in SF-36 physical health component score than the standard arm (−1.6 vs. −1.1, P = 0.0345). Treatment satisfaction (DTSQ) showed larger improvement with intensive than standard (P = 0.0004). There were no differences in mean scores of the Diabetes Symptom Checklist and PHQ-9. Effects of participant transition following discontinuation of the intensive arm on HRQL were not significant. CONCLUSIONS The ACCORD trial strategy of intensive glycemic control did not lead to benefits in HRQL and was associated with modest improvement in diabetes treatment satisfaction. Thus patient acceptability was apparently not compromised with intensive and complex interventions such as those used in ACCORD.

Effects of TZD Use and Discontinuation on Fracture Rates in ACCORD Bone Study

CONTEXT In trials, thiazolidinediones (TZDs) increase fracture risk in women, but the effects of discontinuation are unknown. OBJECTIVE The objective was to investigate the effects of TZD use and discontinuation on fractures in women and men. DESIGN This was a longitudinal observational cohort study using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial bone ancillary study. Duration of TZD use and discontinuation during ACCORD, assessed every 2-4 months at clinic visits, were modeled as time-varying covariates in proportional hazards models for occurrence of first non-spine fracture. PARTICIPANTS We studied a total of 6865 participants in ACCORD BONE. MAIN OUTCOME MEASURES Main outcome measures were centrally adjudicated non-spine fracture. RESULTS Average age was 62.4 (SD, 6.6) years; average duration of diabetes was 11.1 (SD, 7.8) years. Rosiglitazone was used by 74% and pioglitazone by 13% of participants. During a mean follow-up of 4.8 (SD, 1.5) years, 262 men and 287 women experienced at least one non-spine fracture. The fracture rate was higher in women with 1-2 years of TZD use (hazard ratio [HR] = 2.32; 95% confidence interval [CI], 1.49, 3.62) or >2 years of TZD use (HR = 2.01; 95% CI, 1.35, 2.98), compared with no use. The fracture rate was reduced in women who had discontinued TZD use for 1-2 years (HR = 0.57; 95% CI, 0.35, 0.92) or > 2 years (HR = 0.42; 95% CI, 0.24, 0.74) compared with current users. TZD use and discontinuation were not associated with non-spine fractures in men. CONCLUSIONS TZD use was associated with increased non-spine fractures in women, but not men, with type 2 diabetes. When women discontinued TZD use, the fracture effects were attenuated.

Effect of thiazolidinediones and insulin on cognitive outcomes in ACCORD-MIND

OBJECTIVE To examine the relationship of cognitive performance to exposure to insulin (INS) and thiazolidinediones (TZD) in the ACCORD-MIND cohort. METHODS Participants (55-80years) with type 2 diabetes (T2D), hemoglobin A1c (HbA1c) >7.5% (>58mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive control targeting HbA1c to <6.0% (42mmol/mol) or a standard strategy targeting HbA1c to 7.0%-7.9% (53-63mmol/mol). The Digit Symbol Substitution Test (DSST) was assessed at baseline and at 20 and 40months. Exposure to INS was calculated as average daily dose/kg of body weight; exposure to rosiglitazone (ROS) was calculated as days of ROS prescription in the intervals preceding the 20- and 40-month DSSTs. RESULTS At baseline, INS use was associated with reduced DSST performance, but not after controlling for comorbidities and lab values. There was no relationship between use of a TZD and DSST performance on at baseline. ROS but not INS exposure was associated with greater decline in DSST performance over 40months in subjects randomized to the intensive but not the standard group. CONCLUSIONS Exposure to a TZD may increase cognitive decline in some patients with T2D. However, these results may be confounded by unexplained differences between participants.

Comparison of diabetes mellitus and insulin resistance screening methods for women with polycystic ovary syndrome

OBJECTIVE To compare screening strategies for type 2 diabetes mellitus (DM), impaired glucose tolerance (pre-DM), and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS). DESIGN Prospective study. SETTING Academic reproductive endocrinology practice. PATIENT(S) Adult women with PCOS (n = 111). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Subjects were screened for pre-DM and DM using a 2-hour glucose tolerance test (GTT), hemoglobin A1c (HbA1c), or fasting plasma glucose (FPG) and for IR using homeostasis model assessment (HOMA), insulin levels (fasting and 2 hours after 75 glucose load), or obesity. Screening approaches were compared using positive and negative percent agreement and Cohens kappa (κ). RESULT(S) DM and pre-DM were diagnosed by GTT in 4% and 20% of subjects, respectively. Screening with FPG failed to identify 41% of pre-DM and 20% of DM subjects. GTT and HbA1c had only fair agreement (κ = 0.29). IR was diagnosed in 24% of subjects with pre-DM or DM and in 56% of the remaining subjects using HOMA and insulin levels. HOMA and elevated insulin levels demonstrated substantial agreement for detecting IR (κ = 0.70-0.73). Obesity demonstrated fair to slight agreement (κ = 0.33-0.18). CONCLUSION(S) Women with PCOS should be screened for Pre-DM and DM using GTT or HbA1c, and those with Pre-DM or DM are presumed to have IR. In the rest, IR can be detected using either HOMA or insulin levels.

Improved glycemic control in veterans with poorly controlled diabetes mellitus using a Specialty Care Access Network-Extension for Community Healthcare Outcomes model at primary care clinics

Introduction An increasing number of patients with diabetes mellitus has created a need for innovative delivery of specialized care not only by diabetes specialists but also by primary care providers (PCPs) as well. A potential avenue to address this need is training of PCPs by specialists via telehealth. The Veteran Affairs (VA) Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN-ECHO) program includes education and case-based learning for PCPs by a multidisciplinary specialty team utilizing videoconferencing technology. Methods Two PCPs completed a year of SCAN-ECHO diabetes training. These two PCPs set up “diabetes mini-clinics” to treat difficult-to-control high-risk patients with diabetes mellitus from their own panel and from their colleagues in the same community-based outpatient clinic (CBOC). We utilized a retrospective program evaluation by t-test using pre/post glycated hemoglobin (HbA1c) lab values after being seen by the two PCPs. Results A total of 39 patients, all with HbA1c > 9.0%, were seen in the two PCP mini-clinics over 15 months. The mean HbA1c improved from 10.2 ± 1.4% to 8.4 ± 1.8% (p < 0.001) over the average follow-up period of five months. This was not explained by system-wide changes or improvements. Discussion Care of veteran patients with poorly controlled diabetes by PCPs who participated in SCAN-ECHO program leads to improvement in glycemic control. This model of health care delivery can be effective in remote or rural areas with limited availability of specialists.

Effect of dexamethasone on insulin secretion: examination of underlying mechanisms.

OBJECTIVE To study the mechanism of increased insulin secretion in response to short-term administration of dexamethasone. METHODS Male Wistar rats were injected intraperitoneally with dexamethasone (dexamethasone; 200 mcg/kg body weight per day) or saline for 3 consecutive days. Insulin secretion in response to glucose, ionomycin, and KCl was quantified in islets isolated from the animals, and the amount of glucokinase was measured by Western blot. RESULTS Dexamethasone-treated animals had 1.18-fold higher fasting blood glucose concentration and 6.5-fold increase in fasting serum insulin concentration compared with findings from animals injected with saline. Compared with islets isolated from control rats, islets from dexamethasone-treated rats secreted more insulin at 60 minutes in response to 5.5 mM glucose (416.4 vs 115.6 fmoles/10 islets, P = .011) and in response to 16.6 mM glucose (985.5 vs 520.6 fmoles/10 islets, P = .014); no change in insulin secretion was observed at 10 minutes. Insulin secretion from islets of dexamethasone-treated rats and control rats was not differentially augmented in response to either ionomycin or potassium chloride. Glucokinase expression was not altered by treatment with dexamethasone. CONCLUSIONS Augmentation of insulin secretion in response to glucose in the pancreatic islets from dexamethasone-treated rats is preserved in islets studied in vitro. The increase in glucose-stimulated insulin secretion appears to be mediated by steps upstream to β-cell membrane depolarization and the attended increase in intracellular calcium in the signaling pathway of insulin secretion.

Diabetes nurse case management: Improving glucose control: 10 years of quality improvement follow-up data

UNLABELLED The purpose of this retrospective case-control review is to determine the effectiveness of a registered nurse case managers (RNCMs) certified diabetes educator (CDE) quality improvement case management program. RNCMs have a long tradition of providing chronic care intervention, particularly for the high-risk diabetes population with glycosylated hemoglobin (A1C) of 9% or more. However, limited data are available with regard to evaluation of such programs in a Veterans Health Administration population. RESULTS A large population (N=3956) of high-risk veterans with a baseline A1C of 9% or more (mean=10.6%) was seen by the RNCMs. Paired T-tests of A1C after the last RNCM visit showed a statistically significant A1C reduction (p<0.001) (mean=8.5%), after 14-26 months of intervention. CONCLUSIONS RNCMs clinical intervention demonstrated significant A1C reduction (~2%). This is an important finding for health care policy makers for planning interventions with respect to long-term management of diabetes mellitus.