Wendy L Bennett

Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations.

BACKGROUND Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices. PURPOSE To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes. DATA SOURCES MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes. STUDY SELECTION Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms. DATA EXTRACTION Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality. DATA SYNTHESIS Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A(1c) level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about -2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones. LIMITATIONS Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits. CONCLUSION Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A(1c) levels, but some increased risk for hypoglycemia and other adverse events. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Barriers to and Facilitators of Postpartum Follow-Up Care in Women with Recent Gestational Diabetes Mellitus: A Qualitative Study

OBJECTIVES Women with a history of gestational diabetes mellitus (GDM) have an increased risk of developing type 2 diabetes (T2DM) but often do not return for follow-up care. We explored barriers to and facilitators of postpartum follow-up care in women with recent GDM. METHODS We conducted 22 semistructured interviews, 13 in person and 9 by telephone, that were audiotaped and transcribed. Two investigators independently coded transcripts. We identified categories of themes and subthemes. Atlas.ti qualitative software (Berlin, Germany) was used to assist data analysis and management. RESULTS Mean age was 31.5 years (standard deviation) [SD] 4.5), 63% were nonwhite, mean body mass index (BMI) was 25.9 kg/m(2) (SD 6.2), and 82% attended a postpartum visit. We identified four general themes that illustrated barriers and six that illustrated facilitators to postpartum follow-up care. Feelings of emotional stress due to adjusting to a new baby and the fear of receiving a diabetes diagnosis at the visit were identified as key barriers; child care availability and desire for a checkup were among the key facilitators to care. CONCLUSIONS Women with recent GDM report multiple barriers and facilitators of postpartum follow-up care. Our results will inform the development of interventions to improve care for these women to reduce subsequent diabetes risk.

Impact of bariatric surgery on hypertensive disorders in pregnancy: retrospective analysis of insurance claims data.

Objective To determine whether women who had a delivery after bariatric surgery have lower rates of hypertensive disorders in pregnancy compared with women who had a delivery before bariatric surgery. Design Retrospective cohort study. Setting Claims data for 2002-6 from seven insurance plans in the United States. Participants 585 women aged 16-45 who had undergone bariatric surgery, had at least one pregnancy and delivery, and had continuous insurance coverage during pregnancy plus two weeks after delivery. Main outcome measure Hypertensive disorders in pregnancy defined with ICD-9 codes. The independent variable was the timing of delivery in relation to bariatric surgery, classified as deliveries before and after surgery. We used logistic regression to calculate odds ratios and confidence intervals for each type of hypertensive disorder in pregnancy. Results Among the 585 women who had undergone bariatric surgery and had a delivery, 269 delivered before surgery and 316 delivered after surgery. Gastric bypass was the surgery in 82% (477) of all women. Women who delivered before surgery were younger at the time of delivery (mean age 31.3 v 32.5) but had higher rates of pre-existing diabetes and gestational diabetes mellitus. Compared with women who delivered before surgery, women who delivered after surgery had substantially lower rates of pre-eclampsia and eclampsia (odds ratio 0.20, 95% confidence interval 0.09 to 0.44), chronic hypertension complicating pregnancy (0.39, 0.20 to 0.74), and gestational hypertension (0.16, 0.07 to 0.37), even after adjustment for age at delivery, multiple pregnancy (that is, twins or more), surgical procedure, pre-existing diabetes, and insurance plan. Conclusion In this retrospective analysis of US women, bariatric surgery was associated with lower rates of hypertensive disorders in subsequent pregnancy.

Evaluation of Guideline Recommendations on Oral Medications for Type 2 Diabetes Mellitus: A Systematic Review

BACKGROUND Clinical practice guidelines have an important role in guiding choices among the numerous medications available to treat type 2 diabetes mellitus, but little is known about their quality. PURPOSE To assess whether guidelines on oral medications for type 2 diabetes are consistent with a systematic review of the current evidence and whether the consistency of the guidelines depends on the quality of guideline development. DATA SOURCES MEDLINE, CINAHL, and guideline-specific databases were searched between July 2007 and August 2011, after the 2007 publication of a peer-reviewed systematic review on oral diabetes medications. STUDY SELECTION Two reviewers independently screened citations to identify English-language guidelines on oral medications to treat type 2 diabetes that were applied in the United States, United Kingdom, and Canada. DATA EXTRACTION Reviewers assessed whether the guidelines addressed and agreed with 7 evidence-based conclusions from the 2007 systematic review. Two reviewers independently rated guideline quality by using 2 domains from the Appraisal of Guidelines Research and Evaluation instrument. DATA SYNTHESIS Of the 1000 screened citations, 11 guidelines met the inclusion criteria. Seven guidelines agreed with the conclusion that metformin is favored as the first-line agent. Ten guidelines agreed that thiazolidinediones are associated with higher rates of edema and congestive heart failure compared with other oral medications to treat type 2 diabetes. One guideline addressed no evidence-based conclusions, and 5 guidelines agreed with all 7 conclusions. The summary scores of the rigor of development (median, 28.6% [range, 16.7% to 100.0%]) and editorial independence (median, 75.0% [range, 8.3% to 100.0%]) domains varied greatly across guidelines. Guidelines that received higher quality scores contained more recommendations that were consistent with the evidence-based conclusions. LIMITATION Only English-language guidelines targeting users in the United States, United Kingdom, and Canada that contained recommendations on oral medications were included. CONCLUSION Not all practice guidelines on oral treatment of type 2 diabetes were consistent with available evidence from a systematic review. Guidelines judged to be of higher quality contained more recommendations consistent with evidence-based conclusions. The quality of guideline development processes varied substantially. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

The Pharmacogenetics of Type 2 Diabetes: A Systematic Review

OBJECTIVE We performed a systematic review to identify which genetic variants predict response to diabetes medications. RESEARCH DESIGN AND METHODS We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance. RESULTS Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication–gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis. CONCLUSIONS We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.

Reduced Incidence of Gestational Diabetes with Bariatric Surgery

BACKGROUND Obesity is a risk factor for gestational diabetes mellitus (GDM), and bariatric surgery is an effective treatment for obesity. Our objective was to determine the association of bariatric surgery with the incidence of GDM and related complications. STUDY DESIGN We performed a retrospective study comparing rates of GDM and related outcomes (including cesarean section, large-for-gestational-age infant, shoulder dystocia, and infection) between a group of women with a delivery before bariatric surgery and a group with a delivery after bariatric surgery. We used a private insurance claims database with information on 23,594 women who had bariatric surgery between 2002 and 2006. The dataset was searched to identify women with codes for bariatric surgery and a pregnancy resulting in a delivery at greater than 22 weeks gestation. Incidences of GDM and selected delivery complications for delivery before versus after bariatric surgery were compared using Fisher exact test and logistic regression. RESULTS There were 346 women who had a delivery before bariatric surgery, and 354 had a delivery after bariatric surgery. Women with delivery after bariatric surgery had lower incidences of GDM (8% vs 27%, odds ratio (OR) 0.23, (95% CI 0.15 to 0.36) and cesarean section (28% vs 43%, OR0.53, 95% CI 0.39 to 0.72) than those with delivery before bariatric surgery. CONCLUSIONS Bariatric surgery is associated with a decreased incidence of GDM and cesarean section in subsequent pregnancies. This potential effect of bariatric surgery should be considered in the management of obese women of childbearing age. Prospective studies are needed to confirm these findings.

National survey of US primary care physicians’ perspectives about causes of obesity and solutions to improve care

Objective To describe physician perspectives on the causes of and solutions to obesity care and identify differences in these perspectives by number of years since completion of medical school. Design National cross-sectional online survey from 9 February to 1 March 2011. Setting USA. Participants 500 primary care physicians. Main Measures We evaluated physician perspectives on: (1) causes of obesity, (2) competence in treating obese patients, (3) perspectives on the health professional most qualified to help obese patients lose or maintain weight and (4) solutions for improving obesity care. Results Primary care physicians overwhelmingly supported additional training (such as nutrition counselling) and practice-based changes (such as having scales report body mass index) to help them improve their obesity care. They also identified nutritionists/dietitians as the most qualified providers to care for obese patients. Physicians with fewer than 20 years since completion of medical school were more likely to identify lack of information about good eating habits and lack of access to healthy food as important causes of obesity. They also reported feeling relatively more successful helping obese patients lose weight. The response rate for the survey was 25.6%. Conclusions Our results indicate a perceived need for improved medical education related to obesity care.

Antepartum Glucose Tolerance Test Results as Predictors of Type 2 Diabetes Mellitus in Women With a History of Gestational Diabetes Mellitus : A Systematic Review

BACKGROUND Women with a history of gestational diabetes mellitus (GDM) are at high risk for type 2 diabetes mellitus (T2DM). OBJECTIVE We reviewed prospective studies of antepartum glucose tolerance test results as risk factors for development of T2DM among women with a history of GDM. METHODS We searched 4 electronic databases and hand-searched 13 journals for literature published through January 2007. The search strategy consisted of medical subject headings and text words for GDM, T2DM, and other relevant terms. Articles were excluded for the following reasons: (1) not written in English; (2) no human data; (3) no original data; (4) <90% of sample was diagnosed with GDM without a separate analysis for women with GDM; (5) case report or series; (6) diagnosis of GDM not based on 3-hour 100-g oral glucose tolerance test (OGTT) or 2-hour 75-g OGTT; (7) T2DM not evaluated as outcome; (8) no relative measure of association or incidence reported; or (9) design did not address antepartum OGTT as a predictor of T2DM. Two investigators independently reviewed citations, performed serial data abstraction on full articles, and assessed the quality of each article. Data were abstracted for study participants and characteristics, T2DM diagnosis, length of follow-up, regression model covariates, and measures of association and variability. RESULTS Of 11,400 unique citations, we identified 11 articles that evaluated antepartum glucose testing and risk of T2DM in women with a history of GDM. Five studies found that the fasting blood glucose (FBG) on the antepartum diagnostic OGTT was a significant predictor of T2DM (odds ratio [OR] range: 11.1-21.0; relative risk [RR] range: 1.37-1.5; relative hazard [RH] = 2.47). Risk of incident T2DM was predicted by the antepartum 2-hour OGTT plasma glucose in 3 studies (OR range: 1.02-1.03; RR = 1.3) and by the antepartum OGTT glucose AUC in 3 other studies (OR range: 3.64-15; RH = 2.13). Overall, study quality was limited by high losses to follow-up (>20% in 6 studies) and short duration. Few studies adjusted for adiposity, an established diabetes risk factor. CONCLUSION FBG, OGTT 2-hour blood glucose, and OGTT glucose AUC appeared to be strong and consistent predictors of subsequent T2DM among women who met diagnostic criteria for GDM using the OGTT.

Performance Characteristics of Postpartum Screening Tests for Type 2 Diabetes Mellitus in Women with a History of Gestational Diabetes Mellitus: A Systematic Review

BACKGROUND Women with a history of gestational diabetes mellitus are at high risk for type 2 diabetes mellitus. We systematically reviewed and synthesized the literature on the sensitivity, specificity, and reproducibility of postpartum screening tests for type 2 diabetes in women with prior gestational diabetes to inform screening guidelines. METHODS We searched electronic databases through October 1, 2008. Two investigators independently reviewed titles, abstracts, and articles, performed serial data abstraction, and independently assessed quality. We calculated standard errors and confidence intervals for sensitivity and specificity using the exact binomial formula. RESULTS Eleven studies contained 13 evaluations of a comparison screening test with the 2-h 75-g oral glucose tolerance test (OGTT) reference. All studies used a cross-sectional study design. There were ten comparisons of a single fasting blood glucose (FBG) >=7.0 mmol/L (>=126 mg/dL) with the OGTT. The sensitivity ranged from 14%-100% in five studies using the 1985 World Health Organizations (WHO) criteria as the reference and from 16%-89% in five studies using the 1999 WHO criteria as the reference. Variation in the sensitivities may be due to the limited number of comparisons, differences in populations, and timing of screening. There were high losses to follow-up, limiting generalizability. CONCLUSIONS When compared with the OGTT, the single FBG alone was not consistently reported to be a sensitive screening test for type 2 diabetes in women with a history of gestational diabetes. Longitudinal studies are needed to address the natural history of glucose metabolism in women with a history of gestational diabetes, the optimal approach to diagnostic testing for type 2 diabetes in this population, and the short-term and long-term outcomes of testing.

Effectiveness of an Activity Tracker- and Internet-Based Adaptive Walking Program for Adults: A Randomized Controlled Trial

Background The benefits of physical activity are well documented, but scalable programs to promote activity are needed. Interventions that assign tailored and dynamically adjusting goals could effect significant increases in physical activity but have not yet been implemented at scale. Objective Our aim was to examine the effectiveness of an open access, Internet-based walking program that assigns daily step goals tailored to each participant. Methods A two-arm, pragmatic randomized controlled trial compared the intervention to no treatment. Participants were recruited from a workplace setting and randomized to a no-treatment control (n=133) or to treatment (n=132). Treatment participants received a free wireless activity tracker and enrolled in the walking program, Walkadoo. Assessments were fully automated: activity tracker recorded primary outcomes (steps) without intervention by the participant or investigators. The two arms were compared on change in steps per day from baseline to follow-up (after 6 weeks of treatment) using a two-tailed independent samples t test. Results Participants (N=265) were 66.0% (175/265) female with an average age of 39.9 years. Over half of the participants (142/265, 53.6%) were sedentary (<5000 steps/day) and 44.9% (119/265) were low to somewhat active (5000-9999 steps/day). The intervention group significantly increased their steps by 970 steps/day over control (P<.001), with treatment effects observed in sedentary (P=.04) and low-to-somewhat active (P=.004) participants alike. Conclusions The program is effective in increasing daily steps. Participants benefited from the program regardless of their initial activity level. A tailored, adaptive approach using wireless activity trackers is realistically implementable and scalable. Trial Registration Clinicaltrials.gov NCT02229409, https://clinicaltrials.gov/ct2/show/NCT02229409 (Archived by WebCite at http://www.webcitation.org/6eiWCvBYe)