Hsin Chieh Yeh

Smoking, Smoking Cessation, and Risk for Type 2 Diabetes Mellitus: A Cohort Study

BACKGROUND Cigarette smoking is an established predictor of incident type 2 diabetes mellitus, but the effects of smoking cessation on diabetes risk are unknown. OBJECTIVE To test the hypothesis that smoking cessation increases diabetes risk in the short term, possibly owing to cessation-related weight gain. DESIGN Prospective cohort study. SETTING The ARIC (Atherosclerosis Risk in Communities) Study. PATIENTS 10,892 middle-aged adults who initially did not have diabetes in 1987 to 1989. MEASUREMENTS Smoking was assessed by interview at baseline and at subsequent follow-up. Incident diabetes was ascertained by fasting glucose assays through 1998 and self-report of physician diagnosis or use of diabetes medications through 2004. RESULTS During 9 years of follow-up, 1254 adults developed type 2 diabetes. Compared with adults who never smoked, the adjusted hazard ratio of incident diabetes in the highest tertile of pack-years was 1.42 (95% CI, 1.20 to 1.67). In the first 3 years of follow-up, 380 adults quit smoking. After adjustment for age, race, sex, education, adiposity, physical activity, lipid levels, blood pressure, and ARIC Study center, compared with adults who never smoked, the hazard ratios of diabetes among former smokers, new quitters, and continuing smokers were 1.22 (CI, 0.99 to 1.50), 1.73 (CI, 1.19 to 2.53), and 1.31 (CI, 1.04 to 1.65), respectively. Further adjustment for weight change and leukocyte count attenuated these risks substantially. In an analysis of long-term risk after quitting, the highest risk occurred in the first 3 years (hazard ratio, 1.91 [CI, 1.19 to 3.05]), then gradually decreased to 0 at 12 years. LIMITATION Residual confounding is possible even with meticulous adjustment for established diabetes risk factors. CONCLUSION Cigarette smoking predicts incident type 2 diabetes, but smoking cessation leads to higher short-term risk. For smokers at risk for diabetes, smoking cessation should be coupled with strategies for diabetes prevention and early detection.

Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus

The prevalence and morbidity associated with type 2 diabetes mellitus continue to increase in the United States and elsewhere (1, 2). Several studies of the treatment of type 2 diabetes suggest that improved glycemic control reduces microvascular risks (37). In contrast, the effects of treatment on macrovascular risk are more controversial (3, 4, 8, 9), and the comparative effects of oral diabetes agents on clinical outcomes are even less certain. As newer oral agents, such as thiazolidinediones and meglitinides, are increasingly marketed, clinicians and patients must decide whether they prefer these generally more costly medications over older agents, such as sulfonylureas and metformin. Systematic reviews and meta-analyses of oral diabetes agents have attempted to fill this gap (1019), but few have compared all agents with one another (18, 19). The few investigations that have compared all oral agents focused narrowly on individual outcomes, such as hemoglobin A1c level (18) or serum lipid levels (19). No systematic review has summarized all available head-to-head comparisons with regard to the full range of intermediate end points (including hemoglobin A1c level, lipid levels, and body weight) and other clinically important outcomes, such as adverse effects and macrovascular risks. Therefore, the Agency for Healthcare Research and Quality commissioned a systematic review to summarize the comparative benefits and harms of oral agents that are used to treat type 2 diabetes. Methods Data Sources and Selection We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from inception to January 2006 for original articles. We also searched these databases until November 2005 for systematic reviews. We reviewed reference lists of related reviews and original data articles, hand-searched recent issues of 15 medical journals, invited experts to provide additional citations, reviewed selected medications from the U.S. Food and Drug Administration (FDA) Web site, and reviewed unpublished data from several pharmaceutical companies and public registries of clinical trials. Our search strategy for the bibliographic databases combined terms for type 2 diabetes and oral diabetes agents and was limited to English-language articles and studies in adults. The search for systematic reviews was similar but included terms for study design as well. We selected studies that included original data on adults with type 2 diabetes and assessed benefits or harms of FDA-approved oral diabetes agents that were available in the United States as of January 2006. To facilitate head-to-head comparisons of drug classes, we included drugs not on the U.S. market if members of their class were in use and had not been banned (voglibose, gliclazide, and glibenclamide). We also included studies of combinations of therapies that are commonly used, such as combinations of metformin, second-generation sulfonylureas, and thiazolidinediones. We excluded studies that evaluated combinations of 3 oral diabetes agents, and we also excluded first-generation sulfonylureas, because few clinicians prescribe these medications. We sought studies that reported on major clinical outcomes (for example, all-cause mortality, cardiovascular morbidity and mortality, and microvascular outcomes) or any of the following intermediate end points or adverse events: hemoglobin A1c level, body weight, systolic and diastolic blood pressure, high-density lipoprotein (HDL) cholesterol level, low-density lipoprotein (LDL) cholesterol level, triglyceride level, hypoglycemia, gastrointestinal problems, congestive heart failure, edema or hypervolemia, lactic acidosis, elevated aminotransferase levels, liver failure, anemia, leukopenia, thrombocytopenia, allergic reactions requiring hospitalization or causing death, and other serious adverse events. For intermediate end points, we included only randomized, controlled trials, which were abundant. For major clinical end points and adverse events, we considered observational studies as well as trials, because fewer randomized trials assessed these end points. We excluded studies that followed patients for less than 3 months (the conventional threshold for determining effects on hemoglobin A1c) or had fewer than 40 patients. Figure 1 shows the search and selection process, and the full technical report (available at effectivehealthcare.ahrq.gov/repFiles/OralFullReport.pdf) provides a more detailed description of the study methods (20). Figure 1. Study flow diagram. Data Extraction and Quality Assessment One investigator used standardized forms to abstract data about study samples, interventions, designs, and outcomes, and a second investigator confirmed the abstracted data. Two investigators independently applied the Jadad scale to assess some aspects of the quality of randomized trials (21). We considered observational studies and nonrandomized trials to provide weaker evidence than randomized trials, and we did not use a standardized scoring system to assess their quality (22). We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group definitions to grade the overall strength of the evidence as high, moderate, low, very low, or insufficient (23). Data Synthesis and Analysis We first performed a qualitative synthesis based on scientific rigor and type of end point. In general, we described the UKPDS (United Kingdom Prospective Diabetes Study) separately, because this large randomized, controlled trial differed from other trials in design, end points, and duration. When data were sufficient (that is, obtained from at least 2 randomized, controlled trials) and studies were relatively homogeneous in sample characteristics, study duration, and drug dose, we conducted meta-analyses for the following intermediate outcomes and adverse effects: hemoglobin A1c level, weight, systolic blood pressure, LDL cholesterol level, HDL cholesterol level, triglyceride level, and hypoglycemia. For trials with more than 1 dosing group, we chose the dose that was most comparable with other trials and most clinically relevant. We combined drugs into drug classes only when similar results were found across individual drugs. We could not perform formal meta-analyses for microvascular or macrovascular outcomes, mortality, and adverse events other than hypoglycemia because of methodological diversity among the trials or insufficient numbers of trials. We used a random-effects model with the DerSimonian and Laird formula to derive pooled estimates (posttreatment weighted mean differences for intermediate outcomes and posttreatment absolute risk differences for adverse events) (24). We tested for heterogeneity among the trials by using a chi-square test with set to 0.10 or less and an I 2 statistic greater than 50% (25). If heterogeneity was found, we conducted meta-regression analyses by using study-level characteristics of double-blinding, study duration, and dose ratio (calculated as the dose given in the study divided by the maximum approved dose of drug). The full report contains data on indirect comparisons, in which 2 interventions are compared through their relative effect against a common comparator (20). We tested for publication bias by using the tests of Begg and Mazumdar (26) and Egger and colleagues (27). All statistical analyses were done by using STATA Intercooled, version 8.0 (Stata, College Station, Texas). Role of the Funding Source The Agency for Healthcare Research and Quality suggested the initial questions and provided copyright release for this manuscript but did not participate in the literature search, data analysis, or interpretation of the results. Results Comparative Effectiveness of Oral Diabetes Agents in Reducing the Risk for Microvascular and Macrovascular Outcomes and Death We found no definitive evidence about the comparative effectiveness of oral diabetes agents on all-cause mortality, cardiovascular mortality or morbidity, peripheral arterial disease, neuropathy, retinopathy, or nephropathy (Table 1). For each head-to-head comparison on specific outcomes, the number of randomized trials (3 trials) and the absolute number of events were small (20). The few observational studies were limited in quantity, consistency, and adjustment for key confounders. Table 1. Evidence of the Comparative Effectiveness of Oral Diabetes Medications on Mortality, Microvascular and Macrovascular Outcomes, and Intermediate End Points Since our review, 2 high-profile comparative randomized trials with about 4 years of follow-up have been published, providing data on cardiovascular outcomes (28, 29). In ADOPT (A Diabetes Outcome Progression Trial) (28), the incidence of cardiovascular events was lower with glyburide than with rosiglitazone or metformin (1.8%, 3.4%, and 3.2%, respectively; P< 0.05). This effect was mainly driven by fewer congestive heart failure events and a lower rate of nonfatal myocardial infarction events in the glyburide group. Loss to follow-up was high (40%) and was disproportionate among the groups and therefore may account for some differences among groups. The interim analysis of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) study reported that rosiglitazone plus metformin or a sulfonylurea compared with metformin plus a sulfonylurea had a hazard ratio of 1.08 (95% CI, 0.89 to 1.31) for the primary end point of hospitalization or death from cardiovascular disease (29). The hazard ratio was driven by more congestive heart failure in the rosiglitazone plus metformin or sulfonylurea group than in the control group of metformin plus sulfonylurea (absolute risk, 1.7% vs. 0.8%, respectively). In KaplanMeier curves, the risk for hospitalization or death from myocardial infarction was slightly lower in the control group than in the rosiglitazone group, but the difference was not statistically significant. A limitation of

Long-term All-Cause Mortality in Cancer Patients With Preexisting Diabetes Mellitus: A Systematic Review and Meta-analysis

CONTEXT Diabetes mellitus appears to be a risk factor for some cancers, but the effect of preexisting diabetes on all-cause mortality in newly diagnosed cancer patients is less clear. OBJECTIVE To perform a systematic review and meta-analysis comparing overall survival in cancer patients with and without preexisting diabetes. DATA SOURCES We searched MEDLINE and EMBASE through May 15, 2008, including references of qualifying articles. STUDY SELECTION English-language, original investigations in humans with at least 3 months of follow-up were included. Titles, abstracts, and articles were reviewed by at least 2 independent readers. Of 7858 titles identified in our original search, 48 articles met our criteria. DATA EXTRACTION One reviewer performed a full abstraction and other reviewers verified accuracy. We contacted authors and obtained additional information for 3 articles with insufficient reported data. RESULTS Studies reporting cumulative survival rates were summarized qualitatively. Studies reporting Cox proportional hazard ratios (HRs) or Poisson relative risks were combined in a meta-analysis. A random-effects model meta-analysis of 23 articles showed that diabetes was associated with an increased mortality HR of 1.41 (95% confidence interval [CI], 1.28-1.55) compared with normoglycemic individuals across all cancer types. Subgroup analyses by type of cancer showed increased risk for cancers of the endometrium (HR, 1.76; 95% CI, 1.34-2.31), breast (HR, 1.61; 95% CI, 1.46-1.78), and colorectum (HR, 1.32; 95% CI, 1.24-1.41). CONCLUSIONS Patients diagnosed with cancer who have preexisting diabetes are at increased risk for long-term, all-cause mortality compared with those without diabetes.

Cardiovascular Outcomes in Trials of Oral Diabetes Medications: A Systematic Review

BACKGROUND A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus, but it is unclear how these agents compare with respect to long-term cardiovascular risk. Our objective was to systematically examine the peer-reviewed literature on the cardiovascular risk associated with oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides) for treating adults with type 2 diabetes. METHODS We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception through January 19, 2006. Forty publications of controlled trials that reported information on cardiovascular events (primarily myocardial infarction and stroke) met our inclusion criteria. Using standardized protocols, 2 reviewers serially abstracted data from each article. Trials were first described qualitatively. For comparisons with 4 or more independent trials, results were pooled quantitatively using the Mantel-Haenszel method. Results are presented as odds ratios (ORs) and corresponding 95% confidence intervals (CIs). RESULTS Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular mortality (pooled OR, 0.74; 95% CI, 0.62-0.89) compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity and all-cause mortality were similar but not statistically significant. No other significant associations of oral diabetes agents with fatal or nonfatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity or mortality, but this result was not statistically significant (OR, 1.68; 95% CI, 0.92-3.06). CONCLUSIONS Meta-analysis suggested that, compared with other oral diabetes agents and placebo, metformin was moderately protective and rosiglitazone possibly harmful, but lack of power prohibited firmer conclusions. Larger, long-term studies taken to hard end points and better reporting of cardiovascular events in short-term studies will be required to draw firm conclusions about major clinical benefits and risks related to oral diabetes agents.

Comparative Effectiveness and Safety of Methods of Insulin Delivery and Glucose Monitoring for Diabetes Mellitus: A Systematic Review and Meta-analysis

BACKGROUND Patients with diabetes mellitus need information about the effectiveness of innovations in insulin delivery and glucose monitoring. PURPOSE To review how intensive insulin therapy (multiple daily injections [MDI] vs. rapid-acting analogue-based continuous subcutaneous insulin infusion [CSII]) or method of monitoring (self-monitoring of blood glucose [SMBG] vs. real-time continuous glucose monitoring [rt-CGM]) affects outcomes in types 1 and 2 diabetes mellitus. DATA SOURCES MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through February 2012 without language restrictions. STUDY SELECTION 33 randomized, controlled trials in children or adults that compared CSII with MDI (n=19), rt-CGM with SMBG (n=10), or sensor-augmented insulin pump use with MDI and SMBG (n=4). DATA EXTRACTION 2 reviewers independently evaluated studies for eligibility and quality and serially abstracted data. DATA SYNTHESIS In randomized, controlled trials, MDI and CSII showed similar effects on hemoglobin A1c (HbA1c) levels and severe hypoglycemia in children or adults with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. In adults with type 1 diabetes mellitus, HbA1c levels decreased more with CSII than with MDI, but 1 study heavily influenced these results. Compared with SMBG, rt-CGM achieved a lower HbA1c level (between-group difference of change, 0.26% [95% CI, 0.33% to 0.19%]) without any difference in severe hypoglycemia. Sensor-augmented insulin pump use decreased HbA1c levels more than MDI and SMBG did in persons with type 1 diabetes mellitus (between-group difference of change, 0.68% [CI, 0.81% to 0.54%]). Little evidence was available on other outcomes. LIMITATION Many studies were small, of short duration, and limited to white persons with type 1 diabetes mellitus. CONCLUSION Continuous subcutaneous insulin infusion and MDI have similar effects on glycemic control and hypoglycemia, except CSII has a favorable effect on glycemic control in adults with type 1 diabetes mellitus. For glycemic control, rt-CGM is superior to SMBG and sensor-augmented insulin pumps are superior to MDI and SMBG without increasing the risk for hypoglycemia. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Diabetes Mellitus and Breast Cancer Outcomes: A Systematic Review and Meta-Analysis

PURPOSE The goal of this study was to perform a systematic review and meta-analysis to examine the effect of pre-existing diabetes on breast cancer-related outcomes. METHODS We searched EMBASE and MEDLINE databases from inception through July 1, 2009, using search terms related to diabetes mellitus, cancer, and prognostic outcome. Studies were included if they reported a prognostic outcome by diabetes status, evaluated a cancer population, and contained original data published in the English language. We performed a meta-analysis of pre-existing diabetes and its effect on all-cause mortality in patients with breast cancer and qualitatively summarized other prognostic outcomes. RESULTS Of 8,828 titles identified, eight articles met inclusion/exclusion criteria and described outcomes in patients with breast cancer and diabetes. Pre-existing diabetes was significantly associated with all-cause mortality in six of seven studies. In a meta-analysis, patients with breast cancer and diabetes had a significantly higher all-cause mortality risk (pooled hazard ratio [HR], 1.49; 95% CI, 1.35 to 1.65) compared with their nondiabetic counterparts. Three of four studies found pre-existing diabetes to be associated with more advanced stage at presentation. Diabetes was also associated with altered regimens for breast cancer treatment and increased toxicity from chemotherapy. CONCLUSION Compared with their nondiabetic counterparts, patients with breast cancer and pre-existing diabetes have a greater risk of death and tend to present at later stages and receive altered treatment regimens. Studies are needed to investigate pathophysiologic interactions between diabetes and breast cancer and determine whether improvements in diabetes care can reduce mortality in patients with breast cancer.

Trends in the Prevalence of Type 2 Diabetes in Asians Versus Whites: Results from the United States National Health Interview Survey, 1997–2008

OBJECTIVE To examine trends in the prevalence of type 2 diabetes and related conditions in Asian Americans compared with non-Hispanic whites. RESEARCH DESIGN AND METHODS We analyzed data from the National Health Interview Survey (NHIS) from 1997 to 2008 to construct a nationally representative sample of 230,503 U.S. adults aged ≥18 years. Of these adults, 11,056 identified themselves as Asian Americans and 219,447 as non-Hispanic whites. RESULTS The age- and sex-adjusted prevalence of type 2 diabetes was higher in Asian Americans than in whites throughout the study period (4.3–8.2% vs. 3.8–6.0%), and there was a significant upward trend in both ethnic groups (P < 0.01). BMI also was increased in both groups, but age- and sex-adjusted BMI was consistently lower in Asian Americans. In fully adjusted logistic regression models, Asian Americans remained 30–50% more likely to have diabetes than their white counterparts. In addition, Asian Indians had the highest odds of prevalent type 2 diabetes, followed by Filipinos, other Asians, and Chinese. CONCLUSIONS Compared with their white counterparts, Asian Americans have a significantly higher risk for type 2 diabetes, despite having substantially lower BMI. Additional investigation of this disparity is warranted, with the aim of tailoring optimal diabetes prevention strategies to Asian Americans.

Effect of the 2011 vs 2003 duty hour regulation-compliant models on sleep duration, trainee education, and continuity of patient care among internal medicine house staff: a randomized trial.

IMPORTANCE On July 1, 2011, the Accreditation Council for Graduate Medical Education implemented further restrictions of its 2003 regulations on duty hours and supervision. It remains unclear if the 2003 regulations improved trainee well-being or patient safety. OBJECTIVE To determine the effects of the 2011 Accreditation Council for Graduate Medical Education duty hour regulations compared with the 2003 regulations concerning sleep duration, trainee education, continuity of patient care, and perceived quality of care among internal medicine trainees. DESIGN AND SETTING Crossover study design in an academic research setting. PARTICIPANTS Medical house staff. INTERVENTION General medical teams were randomly assigned using a sealed-envelope draw to an experimental model or a control model. MAIN OUTCOME MEASURES We randomly assigned 4 medical house staff teams (43 interns) using a 3-month crossover design to a 2003-compliant model of every fourth night overnight call (control) with 30-hour duty limits or to one of two 2011-compliant models of every fifth night overnight call (Q5) or a night float schedule (NF), both with 16-hour duty limits. We measured sleep duration using actigraphy and used admission volumes, educational opportunities, the number of handoffs, and satisfaction surveys to assess trainee education, continuity of patient care, and perceived quality of care. RESULTS The study included 560 control, 420 Q5, and 140 NF days that interns worked and 834 hospital admissions. Compared with controls, interns on NF slept longer during the on call period (mean, 5.1 vs 8.3 hours; P = .003), and interns on Q5 slept longer during the postcall period (mean, 7.5 vs 10.2 hours; P = .05). However, both the Q5 and NF models increased handoffs, decreased availability for teaching conferences, and reduced intern presence during daytime work hours. Residents and nurses in both experimental models perceived reduced quality of care, so much so with NF that it was terminated early. CONCLUSIONS AND RELEVANCE Compared with a 2003-compliant model, two 2011 duty hour regulation-compliant models were associated with increased sleep duration during the on-call period and with deteriorations in educational opportunities, continuity of patient care, and perceived quality of care.

Cross-Sectional and Prospective Study of Lung Function in Adults With Type 2 Diabetes The Atherosclerosis Risk in Communities (ARIC) Study

OBJECTIVE—The aim of this study was to test the hypothesis that diabetes is independently associated with reduced lung function, both cross-sectionally and longitudinally. RESEARCH DESIGN AND METHODS—We conducted cross-sectional and prospective analyses of diabetes status and lung function decline using baseline and 3-year follow-up data on 1,100 diabetic and 10,162 nondiabetic middle-aged adults from the Atherosclerosis Risk in Communities (ARIC) Study. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were measured at baseline and at the 3-year follow-up using standard spirometry. RESULTS—At baseline, adults with diabetes had significantly lower predicted FVC (96 vs. 103%, P < 0.001) and predicted FEV1 (92 vs. 96%, P < 0.001) than those without diabetes. These differences remained significant after adjustment for demographic characteristics, adiposity, smoking, physical activity index, education, and ARIC field center. Graded, inverse associations were observed between hyperglycemia, diabetes severity (i.e., duration of diabetes and types of antidiabetes medications), and FVC and FEV1 (all Ptrend < 0.001). In prospective analyses, FVC declined faster in diabetic adults than in their nondiabetic counterparts (64 vs. 58 ml/year, P = 0.01). Diabetes severity as indicated by intensity of antidiabetic treatment also showed graded relationships with the rate of FVC decline (P < 0.01). CONCLUSIONS—These data support the notion that the lung is a target organ for diabetic injury. Additional research is required to identify pathophysiologic mechanisms and to determine clinical significance.

The Effects of a Nurse Case Manager and a Community Health Worker Team on Diabetic Control, Emergency Department Visits, and Hospitalizations Among Urban African Americans With Type 2 Diabetes Mellitus: A Randomized Controlled Trial

BACKGROUND Although African American adults bear a disproportionate burden from diabetes mellitus (DM), few randomized controlled trials have tested culturally appropriate interventions to improve DM care. METHODS We randomly assigned 542 African Americans with type 2 DM enrolled in an urban managed care organization to either an intensive or minimal intervention group. The intensive intervention group consisted of all components of the minimal intervention plus individualized, culturally tailored care provided by a nurse case manager (NCM) and a community health worker (CHW), using evidence-based clinical algorithms with feedback to primary care providers (eg, physicians, nurse practitioners, or physician assistants). The minimal intervention consisted of mailings and telephone calls every 6 months to remind participants about preventive screenings. Data on diabetic control were collected at baseline and at 24 months by blind observers; data emergency department (ER) visits and hospitalizations were assessed using administrative data. RESULTS At baseline, participants had a mean age of 58 years, 73% were women, and 50% were living in poverty. At 24 months, compared with the minimal intervention group, those in the intensive intervention group were 23% less likely to have ER visits (rate difference [RD], -14.5; adjusted rate ratio [RR], 0.77; 95% confidence interval [CI], 0.59-1.00). In on-treatment analyses, the rate reduction was strongest for patients who received the most NCM and CHW visits (RD, -31.0; adjusted RR, 0.66; 95% CI, 0.43-1.00; rate reduction downward arrow 34%). CONCLUSION These data suggest that a culturally tailored intervention conducted by an NCM/CHW team reduced ER visits in urban African Americans with type 2 DM. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00022750.