Deborah J. Wexler

Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects

Canagliflozin, a potent, selective sodium glucose co‐transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the renal threshold for glucose (RTG) and increasing urinary glucose excretion (UGE). An ascending single oral‐dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24‐h mean RTG with maximal reduction to approximately 60 mg/dl, and increased mean 24‐h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.

Correlates of health-related quality of life in type 2 diabetes

Aims/hypothesisWe assessed the impact of medical comorbidities, depression, and treatment intensity on quality of life in a large primary care cohort of patients with type 2 diabetes.MethodsWe used the Health Utilities Index-III, an instrument that measures health-related quality of life based on community preferences in units of health utility (scaled from 0=death to 1.0=perfect health), in 909 primary care patients with type 2 diabetes. Demographic and clinical correlates of health-related quality of life were assessed.ResultsThe median health utility score for this population was 0.70 (interquartile range 0.39–0.88). In univariate analyses, older age, female sex, low socioeconomic status, cardiovascular disease, microvascular complications, congestive heart failure, peripheral vascular disease, chronic lung disease, depression, insulin use and number of medications correlated with decreased quality of life, while obesity, hypertension and hypercholesterolaemia did not. In multiple regression analyses, microvascular complications, heart failure and depression were most strongly related to decreased health-related quality of life, independently of duration of diabetes; in these models, diabetes patients with depression had a utility of 0.59, while patients without symptomatic comorbidities did not have a significantly reduced quality of life. Treatment intensity remained a significant negative correlate of quality of life in multivariable models.Conclusions/interpretationPatients with type 2 diabetes have a substantially decreased quality of life in association with symptomatic complications. The data suggest that treatment of depression and prevention of complications have the greatest potential to improve health-related quality of life in type 2 diabetes.

Association of diabetes‐related emotional distress with diabetes treatment in primary care patients with Type 2 diabetes

Aims  To characterize the determinants of diabetes‐related emotional distress by treatment modality (diet only, oral medication only, or insulin).

Symptoms of Depression Prospectively Predict Poorer Self-Care in Patients with Type 2 Diabetes

Aims  To examine prospectively the association of depression symptoms with subsequent self‐care and medication adherence in patients with Type 2 diabetes mellitus.

A Randomized Controlled Trial of Cognitive Behavioral Therapy for Adherence and Depression (CBT-AD) in Patients With Uncontrolled Type 2 Diabetes

OBJECTIVE To test cognitive behavioral therapy for adherence and depression (CBT-AD) in type 2 diabetes. We hypothesized that CBT-AD would improve adherence; depression; and, secondarily, hemoglobin A1c (A1C). RESEARCH DESIGN AND METHODS Eighty-seven adults with unipolar depression and uncontrolled type 2 diabetes received enhanced treatment as usual (ETAU), including medication adherence, self-monitoring of blood glucose (SMBG), and lifestyle counseling; a provider letter documented psychiatric diagnoses. Those randomized to the intervention arm also received 9–11 sessions of CBT-AD. RESULTS Immediately after acute treatment (4 months), adjusting for baseline, CBT-AD had 20.7 percentage points greater oral medication adherence on electronic pill cap (95% CI −31.14 to −10.22, P = 0.000); 30.2 percentage points greater SMBG adherence through glucometer downloads (95% CI −42.95 to −17.37, P = 0.000); 6.44 points lower depression scores on the Montgomery-Asberg Depression Rating Scale (95% CI 2.33–10.56, P = 0.002); 0.74 points lower on the Clinical Global Impression (95% CI 0.16–1.32, P = 0.01); and 0.72 units lower A1C (95% CI 0.29–1.15, P = 0.001) relative to ETAU. Analyses of 4-, 8-, and 12-month follow-up time points indicated that CBT-AD maintained 16.3 percentage points higher medication adherence (95% CI −26.1 to −6.5, P = 0.001); 22.3 percentage points greater SMBG adherence (95% CI −36.1 to −8.6, P = 0.002); and 0.63 units lower A1C (95% CI 0.06–1.2, P = 0.03) after acute treatment ended. For depression, there was some evidence of continued improvement posttreatment, but no between-group differences. CONCLUSIONS CBT-AD is an effective intervention for adherence, depression, and glycemic control, with enduring and clinically meaningful benefits for diabetes self-management and glycemic control in adults with type 2 diabetes and depression.

Association of diet with glycated hemoglobin during intensive treatment of type 1 diabetes in the Diabetes Control and Complications Trial

BACKGROUND Persons with type 1 diabetes have received widely varying dietary advice based on putative effects on glycemic control. OBJECTIVE The objective was to determine whether diet composition was associated with subsequent glycated hemoglobin (Hb A1c) concentrations during intensive therapy for type 1 diabetes. DESIGN We examined associations between quantiles of dietary intake and Hb A1c adjusted for age and sex in 532 intensively treated participants in the Diabetes Control and Complications Trial (DCCT) who had complete dietary data through 5 y of follow-up. Multivariate macronutrient density linear regression models tested the association of Hb A1c at year 5 with macronutrient composition and were adjusted for age, sex, exercise, triglyceride concentration, body mass index (BMI), baseline Hb A1c, and concurrent insulin dose. RESULTS Higher insulin dose, lower carbohydrate intake, and higher saturated, monounsaturated, and total fat intakes were associated with higher Hb A1c concentrations at year 5. In age- and sex-adjusted multivariate macronutrient models, substitution of fat for carbohydrate was associated with higher Hb A1c concentrations (P = 0.01); this relation remained significant after adjustment for exercise level, serum triglycerides, and BMI (P = 0.02) but was no longer significant (P = 0.1) after adjustment for baseline Hb A1c and concurrent insulin dose. CONCLUSION Among intensively treated patients with type 1 diabetes, diets higher in fat and saturated fat and lower in carbohydrate are associated with worse glycemic control, independent of exercise and BMI.

How Doctors Choose Medications to Treat Type 2 Diabetes A national survey of specialists and academic generalists

OBJECTIVE—Glycemic control remains suboptimal despite the wide range of available medications. More effective medication prescription might result in better control. However, the process by which physicians choose glucose-lowering medicines is poorly understood. We sought to study the means by which physicians choose medications for type 2 diabetic patients. RESEARCH DESIGN AND METHODS—We surveyed 886 physician members of either the Society of General Internal Medicine (academic generalists, response rate 30%) or the American Diabetes Association (specialists, response rate 23%) currently managing patients with type 2 diabetes. Respondents weighed the importance of 15 patient, physician, and nonclinical factors when deciding which medications to prescribe for type 2 diabetic subjects at each of three management stages (initiation, use of second-line oral agents, and insulin). RESULTS—Respondents reported using a median of five major considerations (interquartile range 4–6) at each stage. Frequently cited major considerations included overall assessment of the patients health/comorbidity, A1C level, and patients adherence behavior but not expert guidelines/hospital algorithms or patient age. For insulin initiation, academic generalists placed greater emphasis on patient adherence (76 vs. 60% of specialists, P < 0.001). These generalists also identified patient fear of injections (68%) and patient desire to prolong noninsulin therapy (68%) as major insulin barriers. Overall, qualitative factors (e.g., adherence, motivation, overall health assessment) were somewhat more highly considered than quantitative factors (e.g., A1C, age, weight) with mean aggregate scores of 7.3 vs. 6.9 on a scale of 0–10, P < 0.001. CONCLUSIONS—The physicians in our survey considered a wide range of qualitative and quantitative factors when making medication choices for hyperglycemia management. The apparent complexity of the medication choice process contrasts with current evidence-based treatment guidelines.

Prevalence of Elevated Hemoglobin A1c among Patients Admitted to the Hospital without a Diagnosis of Diabetes

CONTEXT One in four hospitalized patients has diagnosed diabetes. The prevalence of unrecognized, or undiagnosed, diabetes among hospitalized patients is not well established. OBJECTIVE Our objective was to determine the prevalence of unrecognized probable diabetes in this patient population determined by elevated hemoglobin A1c (HbA1c) level. DESIGN We conducted a prospective observational cohort trial with retrospective follow-up of patients with elevated HbA1c levels and no diagnosis of diabetes. HbA1c levels were obtained for all patients. SETTING The study was conducted at an acute care general hospital. PATIENTS Patients included 695 adult, nonobstetric patients admitted on 11 d in 2006. MAIN OUTCOME MEASURES Outcome measures included rate of unrecognized probable diabetes, defined as admission HbA1c of more than 6.1% and no diagnosis of diabetes or treatment with antidiabetic medications before or during their admission and rate of unrecognized diabetes 1 yr after discharge. RESULTS Eighteen percent of hospitalized patients had elevated HbA1c levels without a diagnosis of diabetes. Random glucose levels poorly predicted elevated HbA1c levels (area under receiver operating characteristic curve, 0.60). Neither diagnosed diabetes nor HbA1c level was associated with length of stay or costs (P>0.1 for all comparisons). Only 15% of patients with elevated HbA1c levels who continued to receive care within the system studied had diabetes diagnosed in the year after the index admission. CONCLUSIONS Nearly one in five adult patients admitted to a large general hospital had unrecognized probable diabetes, based on elevated HbA1c levels. Random glucose levels during the hospital stay were poorly predictive of this condition. Few hospitalized patients with elevated HbA1c levels were diagnosed within the year after admission.

Food Insecurity and Metabolic Control Among U.S. Adults With Diabetes

OBJECTIVE We sought to determine whether food insecurity is associated with worse glycemic, cholesterol, and blood pressure control in adults with diabetes. RESEARCH DESIGN AND METHODS We conducted a cross-sectional analysis of data from participants of the 1999–2008 National Health and Nutrition Examination Survey. All adults with diabetes (type 1 or type 2) by self-report or diabetes medication use were included. Food insecurity was measured by the Adult Food Security Survey Module. The outcomes of interest were proportion of patients with HbA1c >9.0% (75 mmol/mol), LDL cholesterol >100 mg/dL, and systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg. We used multivariable logistic regression for analysis. RESULTS Among the 2,557 adults with diabetes in our sample, a higher proportion of those with food insecurity (27.0 vs. 13.3%, P < 0.001) had an HbA1c >9.0% (75 mmol/mol). After adjustment for age, sex, educational attainment, household income, insurance status and type, smoking status, BMI, duration of diabetes, diabetes medication use and type, and presence of a usual source of care, food insecurity remained significantly associated with poor glycemic control (odds ratio [OR] 1.53 [95% CI 1.07–2.19]). Food insecurity was also associated with poor LDL control before (68.8 vs. 49.8, P = 0.002) and after (1.86 [1.01–3.44]) adjustment. Food insecurity was not associated with blood pressure control. CONCLUSIONS Food insecurity is significantly associated with poor metabolic control in adults with diabetes. Interventions that address food security as well as clinical factors may be needed to successfully manage chronic disease in vulnerable adults.

Validity of Medication Adherence Self-Reports in Adults With Type 2 Diabetes

OBJECTIVE To assess the validity of self-report measures of diabetes medication adherence and evaluate the effect of depression on the validity of these reports. RESEARCH DESIGN AND METHODS Adults with type 2 diabetes, treated with oral medications, completed a set of medication adherence self-reports that varied response scales and time frames, were administered structured clinical interviews for depression, and provided blood samples for HbA1c as part of a screening for an intervention study. A subsample of participants with HbA1c ≥7.0% and clinically significant depression received Medication Event Monitoring System (MEMS) bottle caps to record adherence. Analyses examined relationships between adherence measures and HbA1c and, in the subsample, MEMS. Moderated linear regression evaluated whether depression severity modified relationships with HbA1c. RESULTS Participant (n = 170, 57% men, 81% white, mean HbA1c 8.3% [SD, 1.7]) adherence self-reports were significantly (r = −0.18 to −0.28; P < 0.03) associated with lower HbA1c. In the subsample (n = 88), all self-reports were significantly (r = 0.35 to 0.55; P ≤ 0.001) associated with MEMS-measured adherence. Depression significantly moderated the relationship between three of six self-reports and HbA1c; at high levels of depression, associations with HbA1c became nonsignificant. CONCLUSIONS Results support the validity of easily administered self-reports for diabetes medication adherence. One-month, percentage-based ratings of adherence had the strongest associations with MEMS and HbA1c; those requiring the report of missed doses had weaker associations. One-week self-ratings and measures that require respondents to record the number of missed doses appear to be vulnerable to bias from depression severity.