Effect of Intensive Versus 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.

Technosphere insulin: inhaled prandial insulin.

INTRODUCTION: Insulin therapy is a mainstay for treatment of diabetes mellitus; however, many barriers to insulin exist. Insulin human inhalation powder (technosphere insulin) is a new FDA-approved alternative to subcutaneous bolus insulin. AREAS COVERED: This is an overview of technosphere insulin (TI). Pharmacokinetics, clinical efficacy, safety and tolerability are discussed. EXPERT OPINION: TI is more quickly absorbed than subcutaneous insulin therapies and has a shorter duration of action. It appears to be noninferior compared with subcutaneous insulin regimens, and is associated with less hypoglycemia. Thus, it may serve as an alternative insulin agent in patients reluctant to administer multiple subcutaneous injections of insulin daily or in patients who experience late postprandial hypoglycemia with subcutaneous insulin. Cough is the most common side effect, but tends to be mild and transient. A small decrease in the forced expiratory volume has been demonstrated, but does not appear to progress and is reversible. Patients should have periodic pulmonary function tests. TI is contraindicated in patients with chronic lung disease. The long-term risk of lung cancer is being monitored but at this point does not appear to be higher than the expected incidence of lung cancer in this population.

The Effect of Blood Glucose Self-Monitoring Among Inmates With Diabetes.

The increasing prevalence and risk of complications from diabetes necessitate patient participation and attentiveness to select appropriate foods, perform regular physical activity, and be active in diabetes management and self-maintenance. Diabetes is often largely asymptomatic; consequently, early diagnosis and treatment are necessary. Inmates are a unique population challenged by the increased prevalence of chronic conditions including diabetes. Diabetes standards for inmates contain diagnostic and treatment management guidelines that incorporate personal glucose monitoring for insulin users. In December 2009, the Federal Bureau of Prisons initiated a program to distribute glucose meters to insulin-dependent inmates to facilitate self-monitoring blood glucose. The purpose of this study was to evaluate the effect of these glucose meters on hemoglobin A1c levels.

Education, glucose control, and mortality risks among U.S. older adults with diabetes.

AIMS: Studies have shown that diabetes mellitus disproportionately afflicts persons of low socioeconomic status and that the burden of disease is greatest among the disadvantaged. However, our understanding of educational differences in the control of diabetes and its impact on survival is limited. This study investigated the associations among education, hemoglobin A1c (HbA1c), and subsequent mortality in adults with diabetes. METHODS: Prospective cohort data from the 2006, 2008, and 2010 Health and Retirement Study were linked with biomarker data for U.S. older adults with diabetes (n=3312). Weighted distributions were estimated for all subjects at baseline and by the American Diabetes Association's general guidelines for HbA1c control (<7.0% [53 mmol/mol] vs. ≥7.0% [53 mmol/mol]). Proportional hazard models were used to estimate educational differences in all-cause mortality by HbA1c level with sequential adjustments for contributing risk factors. RESULTS: Mortality risks associated with HbA1c≥7.0% [53 mmol/mol] were significantly greater in lower-educated adults than higher-educated adults (P<0.001). We found that the hazard ratios (HR) associated with HbA1c ≥7.0% [53 mmol/mol] were highest among low-educated adults (HR=2.18, 95% CI: 1.62, 2.94) and that a combination of socioeconomic, psychosocial, and behavioral factors accounted for most, but not all, of the associations. CONCLUSIONS: Educational differences in HbA1c control have significant implications for mortality and efforts to reduce these disparities should involve more vigilant screening and monitoring of lower-educated adults with diabetes.

Methods and initial findings from the Durham Diabetes Coalition: Integrating geospatial health technology and community interventions to reduce death and disability.

OBJECTIVE: The Durham Diabetes Coalition (DDC) was established in response to escalating rates of disability and death related to type 2 diabetes mellitus, particularly among racial/ethnic minorities and persons of low socioeconomic status in Durham County, North Carolina. We describe a community-based demonstration project, informed by a geographic health information system (GHIS), that aims to improve health and healthcare delivery for Durham County residents with diabetes. MATERIALS AND METHODS: A prospective, population-based study is assessing a community intervention that leverages a GHIS to inform community-based diabetes care programs. The GHIS integrates clinical, social, and environmental data to identify, stratify by risk, and assist selection of interventions at the individual, neighborhood, and population levels. RESULTS: The DDC is using a multifaceted approach facilitated by GHIS to identify the specific risk profiles of patients and neighborhoods across Durham County. A total of 22,982 patients with diabetes in Durham County were identified using a computable phenotype. These patients tended to be older, female, African American, and not covered by private health insurance, compared with the 166,041 persons without diabetes. Predictive models inform decision-making to facilitate care and track outcomes. Interventions include: 1) neighborhood interventions to improve the context of care; 2) intensive team-based care for persons in the top decile of risk for death or hospitalization within the coming year; 3) low-intensity telephone coaching to improve adherence to evidence-based treatments; 4) county-wide communication strategies; and 5) systematic quality improvement in clinical care. CONCLUSIONS: To improve health outcomes and reduce costs associated with type 2 diabetes, the DDC is matching resources with the specific needs of individuals and communities based on their risk characteristics.

Barriers to care for patients with diabetes in Durham, North Carolina, why are we withholding life-sustaining medications from the patients who need them the most?

The diabetes epidemic and its complications disproportionately affect minorities and the poor. Medical treatments that can prevent or delay diabetes complications are widely available but poverty underlies much of why there are disparities in diabetes care and outcomes. Lack of access to care, food insecurity and inability to pay for medications prevents adherence to a medication and lifestyle regimen that can be life-sustaining. At the very least, US policies should be changed to provide life-sustaining medications that prevent costly complications to patients who cannot afford them. Adopting value-based insurance design would benefit patients with diabetes who cannot afford to pay for medications but would also reduce healthcare costs in the long run.

HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin.

OBJECTIVE: To compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes receiving metformin were randomized to albiglutide (30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined hyperglycemia criteria. The primary end point was change in HbA1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue. RESULTS: Baseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA1c was 8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104, albiglutide significantly reduced HbA1c compared with placebo (-0.9% [-9.8 mmol/mol]; P < 0.0001), sitagliptin (-0.4% [-4.4 mmol/mol]; P = 0.0001), and glimepiride (-0.3% [-3.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA1c were similar. Weight change from baseline for each were as follows: albiglutide -1.21 kg (95% CI -1.68 to -0.74), placebo -1.00 kg (95% CI -1.81 to -0.20), sitagliptin -0.86 kg (95% CI -1.32 to -0.39), glimepiride 1.17 kg (95% CI 0.70-1.63). The difference between albiglutide and glimepiride was statistically significant (P < 0.0001). Hyperglycemic rescue rate at week 104 was 25.8% for albiglutide compared with 59.2% (P < 0.0001), 36.4% (P = 0.0118), and 32.7% (P = 0.1504) for placebo, sitagliptin, and glimepiride, respectively. Rates of serious adverse events in the albiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%, other groups 8.6-10.9%) and nausea (albiglutide 10.3%, other groups 6.2-10.9%) were generally the most frequently reported gastrointestinal events. CONCLUSIONS: Added to metformin, albiglutide was well tolerated; produced superior reductions in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.

Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study.

BACKGROUND: As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs. METHODS: We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ≥18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m(2) were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0·6 mg once daily titrated to 1·2 mg at week 1 and 1·8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0·3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894. FINDINGS: 422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was -0·78% (95% CI -0·87 to -0·69) in the albigludite group and -0·99% (-1·08 to -0·90) in the liraglutide group; treatment difference was 0·21% (0·08-0·34; non-inferiority p value=0·0846). Injection-site reactions occurred in more patients given albiglutide than in those given liraglutide (12·9% vs 5·4%; treatment difference 7·5% [95% CI 3·6-11·4]; p=0·0002), whereas the opposite was the case for gastrointestinal events, which occurred in 49·0% of patients in the liraglutide group versus 35·9% in the albiglutide group (treatment difference -13·1% [95% CI -19·9 to -6·4]; p=0·00013). INTERPRETATION: Patients who received once-daily liraglutide had greater reductions in HbA1c than did those who received once-weekly albiglutide. Participants in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than did those in the liraglutide group. FUNDING: GlaxoSmithKline.

Missing signposts on the roadmap to quality: a call to improve medication adherence indicators in data collection for population research.

PURPOSE: Poor adherence to prescribed medicines is associated with increased rates of poor outcomes, including hospitalization, serious adverse events, and death, and is also associated with increased healthcare costs. However, current approaches to evaluation of medication adherence using real-world electronic health records (EHRs) or claims data may miss critical opportunities for data capture and fall short in modeling and representing the full complexity of the healthcare environment. We sought to explore a framework for understanding and improving data capture for medication adherence in a population-based intervention in four U.S. counties. APPROACH: We posited that application of a data model and a process matrix when designing data collection for medication adherence would improve identification of variables and data accessibility, and could support future research on medication-taking behaviors. We then constructed a use case in which data related to medication adherence would be leveraged to support improved healthcare quality, clinical outcomes, and efficiency of healthcare delivery in a population-based intervention for persons with diabetes. Because EHRs in use at participating sites were deemed incapable of supplying the needed data, we applied a taxonomic approach to identify and define variables of interest. We then applied a process matrix methodology, in which we identified key research goals and chose optimal data domains and their respective data elements, to instantiate the resulting data model. CONCLUSIONS: Combining a taxonomic approach with a process matrix methodology may afford significant benefits when designing data collection for clinical and population-based research in the arena of medication adherence. Such an approach can effectively depict complex real-world concepts and domains by "mapping" the relationships between disparate contributors to medication adherence and describing their relative contributions to the shared goals of improved healthcare quality, outcomes, and cost.

A comparison of phenotype definitions for diabetes mellitus.

OBJECTIVE: This study compares the yield and characteristics of diabetes cohorts identified using heterogeneous phenotype definitions. MATERIALS AND METHODS: Inclusion criteria from seven diabetes phenotype definitions were translated into query algorithms and applied to a population (n=173 503) of adult patients from Duke University Health System. The numbers of patients meeting criteria for each definition and component (diagnosis, diabetes-associated medications, and laboratory results) were compared. RESULTS: Three phenotype definitions based heavily on ICD-9-CM codes identified 9-11% of the patient population. A broad definition for the Durham Diabetes Coalition included additional criteria and identified 13%. The electronic medical records and genomics, NYC A1c Registry, and diabetes-associated medications definitions, which have restricted or no ICD-9-CM criteria, identified the smallest proportions of patients (7%). The demographic characteristics for all seven phenotype definitions were similar (56-57% women, mean age range 56-57 years).The NYC A1c Registry definition had higher average patient encounters (54) than the other definitions (range 44-48) and the reference population (20) over the 5-year observation period. The concordance between populations returned by different phenotype definitions ranged from 50 to 86%. Overall, more patients met ICD-9-CM and laboratory criteria than medication criteria, but the number of patients that met abnormal laboratory criteria exclusively was greater than the numbers meeting diagnostic or medication data exclusively. DISCUSSION: Differences across phenotype definitions can potentially affect their application in healthcare organizations and the subsequent interpretation of data. CONCLUSIONS: Further research focused on defining the clinical characteristics of standard diabetes cohorts is important to identify appropriate phenotype definitions for health, policy, and research.

Risk vs benefit in diabetes pharmacotherapy: a rational approach to choosing pharmacotherapy in type 2 diabetes.

Type 2 diabetes now affects more than 1 in 10 US adults and is a leading cause of morbidity, mortality, and healthcare expense. There are increasing numbers of available pharmacotherapies, with established agents as well as newer drugs developed from hormones in the incretin pathway, among others. New data are accumulating continuously with respect to potential benefits of both long-standing and new agents, as well as risks identified through post-marketing surveillance. Here we review the commonly prescribed pharmacotherapy options with attention to recently published information and provide a rational approach to choice of therapy.

Injectable protease-operated depots of glucagon-like peptide-1 provide extended and tunable glucose control.

Peptide drugs are an exciting class of pharmaceuticals increasingly used for the treatment of a variety of diseases; however, their main drawback is a short half-life, which dictates multiple and frequent injections and an undesirable "peak-and-valley" pharmacokinetic profile, which can cause undesirable side-effects. Synthetic prolonged release formulations can provide extended release of biologically active native peptide, but their synthetic nature can be an obstacle to production and utilization. Motivated by these limitations, we have developed a new and entirely genetically encoded peptide delivery system--Protease Operated Depots (PODs)--to provide sustained and tunable release of a peptide drug from an injectable s.c. depot. We demonstrate proof-of-concept of PODs, by fusion of protease cleavable oligomers of glucagon-like peptide-1, a type-2 diabetes drug, and a thermally responsive, depot-forming elastin-like-polypeptide that undergoes a thermally triggered inverse phase transition below body temperature, thereby forming an injectable depot. We constructed synthetic genes for glucagon-like peptide-1 PODs and demonstrated their high-yield expression in Escherichia coli and facile purification by a nonchromatographic scheme we had previously developed. Remarkably, a single injection of glucagon-like peptide-1 PODs was able to reduce blood glucose levels in mice for up to 5 d, 120 times longer than an injection of the native peptide drug. These findings demonstrate that PODs provide the first genetically encoded alternative to synthetic peptide encapsulation schemes for sustained delivery of peptide therapeutics.

Pilot Study of Caffeine Abstinence for Control of Chronic Glucose in Type 2 Diabetes.

BACKGROUND: A growing body of evidence suggests that caffeinated beverages may impair chronic glucose control in type 2 diabetes. This pilot study tested the chronic effects of caffeine abstinence on glucose control in type 2 diabetic patients who were daily coffee drinkers. METHODS: Twelve coffee drinkers (six males) with established type 2 diabetes participated. Seven (five males) completed 3 months of total caffeine abstinence. Measures of chronic glucose control, long-term (hemoglobin A1c [HbA1c]) and short-term (1,5-anhydroglucitol [1,5-AG]), were collected at baseline and during follow-up. Abstinence was established by diaries confirmed by saliva caffeine assays. RESULTS: Abstinence produced significant decreases in HbA1c and increases in 1,5-AG, both indicating improvements in chronic glucose control. Fasting glucose and insulin did not change, nor were changes in body weight observed. CONCLUSIONS: Although preliminary, these results suggest that caffeine abstinence may be beneficial for patients with type 2 diabetes. This hypothesis should be confirmed in larger controlled clinical trials.

Robertsite, Ca(2)Mn(III) (3)O(2)(PO(4))(3)·3H(2)O.

Robertsite, ideally Ca(2)Mn(3)O(2)(PO(4))(3)·3H(2)O [calcium manganese(III) tris-(orthophosphate) trihydrate], can be associated with the arseniosiderite structural group characterized by the general formula Ca(2)A(3)O(2)(TO(4))(3)·nH(2)O, with A = Fe, Mn; T = As, P; and n = 2 or 3. In this study, single-crystal X-ray diffraction data were used to determine the robertsite structure from a twinned crystal from the type locality, the Tip Top mine, Custer County, South Dakota, USA, and to refine anisotropic displacement parameters for all atoms. The general structural feature of robertsite resembles that of the other two members of the arseniosiderite group, the structures of which have previously been reported. It is characterized by sheets of [MnO(6)] octa-hedra in the form of nine-membered pseudo-trigonal rings. Located at the center of each nine-membered ring is a PO(4) tetra-hedron, and the other eight PO(4) tetra-hedra sandwich the Mn-oxide sheets. The six different Ca(2+) ions are seven-coordinated in form of distorted penta-gonal bipyramids, [CaO(5)(H(2)O)(2)], if Ca-O distances less than 2.85 Šare considered. Along with hydrogen bonding involving the water mol-ecules, they hold the manganese-phosphate sheets together. All nine [MnO(6)] octa-hedra are distorted by the Jahn-Teller effect.

Physician reasons for nonpharmacologic treatment of hyperglycemia in older patients newly diagnosed with type 2 diabetes mellitus.

INTRODUCTION: To identify reasons why primary care physicians (PCPs) do not treat older patients newly diagnosed with type 2 diabetes mellitus (T2DM) with antihyperglycemic agents following diagnosis. METHODS: US PCPs were surveyed via the internet regarding their reasons for not treating patients aged >65 years diagnosed with T2DM and had not yet initiated antihyperglycemic therapy for ≥6 months after diagnosis. PCPs were requested to provide relevant clinical information for untreated older patients and select applicable reasons for not initiating treatment from a list of 35 possibilities, grouped into five categories. RESULTS: A total of 508 PCPs completed the online survey and provided complete clinical data for 770 patients. The reasons provided by the first-ranked physician for not initiating antihyperglycemic therapy were related to diet and exercise (57.5%); mild hyperglycemia (23.8%); patient's concerns (13.4%); concerns about antihyperglycemic agents (3.0%); and comorbidities and polypharmacy (2.3%). The "diet and exercise" category was the most common first-ranked non-treatment reason, regardless of recent hemoglobin A(1c) (HbA(1c)) stratum. Reasons within the "patient's concerns," "concerns related to antihyperglycemic agents," and "comorbidities and polypharmacy" categories tended to be selected more often as first-ranked reasons by physicians for patients with higher HbA(1c) values. Of the 158 patients whose physicians planned to initiate antihyperglycemic therapy within the next month, 54.4% already had a most recent HbA(1c) value above their physician-stated threshold for treatment initiation. CONCLUSION: In the PCPs studied, there was a tendency to select appropriate reasons for non-treatment with antihyperglycemic agents given their patients' glycemic status. However, there was inertia related to the initiation of pharmacological therapy in some older patients with newly diagnosed T2DM. Important factors included physicians' perceptions of "mild" hyperglycemia and the HbA(1c) threshold for using antihyperglycemic agents.

Receipt of care and reduction of lower extremity amputations in a nationally representative sample of U.S. Elderly.

OBJECTIVE: To determine effectiveness of receipt of care from podiatrist and lower extremity clinician specialists (LEC specialists) on diabetes mellitus (DM)-related lower extremity amputation. DATA SOURCES: Medicare 5 percent sample claims, 1991-2007. STUDY DESIGN: Individuals with DM-related lower extremity complications (LECs) were followed 6 years. Visits with podiatrists, LEC specialists, and other health professionals were tracked to ascertain whether receipt of such care reduced the hazards of an LEC amputation. DATA COLLECTION: Individuals were stratified based on disease severity, Stage 1--neuropathy, paresthesia, pain in feet, diabetic amyotrophy; Stage 2--cellulitis, charcot foot; Stage 3--ulcer; Stage 4--osteomyelitis, gangrene. PRINCIPAL FINDINGS: Half the LEC sample died within 6 years. More severe lower extremity disease increased risk of death and amputation. Persons visiting a podiatrist and an LEC specialist within a year before developing all stage complications were between 31 percent (ulceration) and 77 percent (cellulitis and charcot foot) as likely to undergo amputation compared with individuals visiting other health professionals. CONCLUSIONS: Individuals with an LEC had high mortality. Visiting both a podiatrist and an LEC specialist in the year before LEC diagnosis was protective of undergoing lower extremity amputation, suggesting a benefit from multidisciplinary care.

Plasma epinephrine predicts fasting glucose in centrally obese African-American women.

The high prevalence of diabetes in African-American (AA) women has been widely assumed to be related to the greater prevalence of obesity in this group. Catecholamine release acting on central adipose tissue has been proposed to be a contributing factor. The aim of this article was to examine the interaction of plasma catecholamines and central adiposity on fasting and nonfasting glucose levels in two separate samples. In both studies, the women were healthy, nondiabetic of similar age. In addition, both studies assessed plasma epinephrine (EPI) and norepinephrine (NOREPI) levels collected at three time points. In study 1, catecholamines were measured during a standardized laboratory mental stress task and in study 2, they were measured during the initial phase (10 min) of an intravenous glucose tolerance test (IVGTT). Results from both studies revealed significant effects of EPI on fasting glucose in the obese women. In study 1, mean EPI levels were significantly related to fasting glucose in AA women with high trunk fat (beta = 0.60, P < 0.001). Because high BMI was associated with high trunk fat in women, we used BMI >30 as a proxy for high trunk fat (>32%) in study 2. In study 2, EPI response to the glucose bolus was a strong predictor of fasting glucose in AA women with BMI >30 (beta = 0.75, P < 0.003). We conclude that the effect of central adiposity on fasting glucose may be moderated by plasma EPI. This suggests that adrenal medullary activity could play a role in the pathophysiology of type 2 diabetes.

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 A(1C)) achieved during therapy. DESIGN: Post hoc epidemiological analysis of a double 2x2 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 A(1C) 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 A(1C) <6.0%) or standard (haemoglobin A(1C) 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 A(1C) 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 A(1C) 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 A(1C) 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.