Spyridon S Marinopoulos

Meta-analysis: Glycosylated hemoglobin and cardiovascular disease in diabetes mellitus

Context The relationship between glycosylated hemoglobin and cardiovascular disease in diabetic persons is less clear than its relationship with microvascular disease. Contribution This meta-analysis of 13 observational studies estimates that, for every 1-percentage point increase in glycosylated hemoglobin, the relative risk for any cardiovascular disease event is 1.18 for patients with type 2 diabetes mellitus and 1.15 for patients with type 1 diabetes mellitus. Cautions Although this analysis suggests that improvements in glycosylated hemoglobin level might translate into reductions in cardiovascular events, confirmation from randomized trials is necessary. The Editors Persons with diabetes mellitus are at an increased risk for cardiovascular disease; they have more than a 2-fold increased risk for cardiovascular death compared with persons without diabetes (1-3). Cardiovascular death accounts for more than 75% of all deaths among persons with diabetes mellitus (3, 4). Because this excess risk is only partially explained by traditional risk factors, such as obesity, dyslipidemia, and hypertension, diabetes is often considered an independent risk factor for cardiovascular disease. A strong body of evidence links chronic hyperglycemia to microvascular complications, such as retinopathy, neuropathy, and nephropathy, in persons with diabetes (5-10). In randomized clinical trials, improving glycemic control substantially reduces the incidence of microvascular disease in persons with diabetes (5, 6, 11). However, few randomized trials have specifically been designed to examine the influence of glycemic control on macrovascular complications, such as coronary heart disease, stroke, and peripheral arterial disease. Results from clinical trials that collected information on cardiovascular outcomes have been equivocal. In interpreting recent clinical trial data in a position statement, the American Diabetes Association stated that the role of hyperglycemia in cardiovascular complications is still unclear (12). Fasting blood glucose levels in diabetic and nondiabetic persons have been linked to an excess risk for cardiovascular disease (13-15); this link suggests an association between glycemic control and cardiovascular risk. A meta-regression analysis that combined data from more than 95 000 persons without diagnosed diabetes found a graded relationship between fasting and postprandial blood glucose levels and subsequent risk for a cardiovascular event (15). An important clinical question is whether improving long-term glycemic control in persons with diabetes reduces the risk for cardiovascular disease events. Glycosylated hemoglobin reflects long-term glycemic control and is a more accurate and stable measure than fasting blood glucose levels (16). It tracks well over time in persons with diabetes and has less measurement error than fasting blood glucose (17-20). Glycosylated hemoglobin is at the center of the clinical management of hyperglycemia in persons with diabetes. However, clinical guidelines for glycosylated hemoglobin levels are based on cut-points relevant for the prevention of microvascular complications (21). The relationship between glycosylated hemoglobin and cardiovascular disease, the most deadly complication of diabetes mellitus, has not been adequately characterized. We performed a systematic review to characterize the risk relation between long-term glycemic control, as measured by glycosylated hemoglobin, and cardiovascular end points (peripheral arterial disease, coronary heart disease, and cerebrovascular disease) in persons with type 1 and type 2 diabetes mellitus. Methods Study Design We systematically reviewed prospective cohort studies of glycosylated hemoglobin and cardiovascular disease in persons with diabetes mellitus. This study was part of a larger project commissioned by the Agency for Healthcare Research and Quality, which was conducted by the Johns Hopkins Evidenced-based Practice Center (22). Study Selection We searched the MEDLINE database for articles published in English from 1966 to July 2003 by using Medical Subject Heading terms and text words related to cardiovascular disease (coronary heart disease, peripheral arterial disease, or cerebrovascular disease), diabetes mellitus, glycemic control, and glycosylated hemoglobin (the Appendix contains the full text of the search string). We reviewed all abstracts obtained from our search for relevance. We manually reviewed bibliographies and review articles for additional citations and obtained the full text of all potentially relevant articles. We also queried experts to identify any additional studies. Our prespecified inclusion criteria were as follows: 1) prospective cohort studies that examined the cardiovascular outcomes of interest (peripheral arterial disease, coronary heart disease, and stroke) and 2) studies that reported a measure of glycosylated hemoglobin and that were conducted in samples that included persons with type 1 or type 2 diabetes. Persons described as having insulin-dependent diabetes mellitus or younger- or juvenile-onset diabetes were classified as having type 1 diabetes. Individuals described as having noninsulin-dependent diabetes mellitus or older-onset diabetes were classified as having type 2 diabetes. We excluded studies if they 1) had no original data, 2) did not address persons with diabetes, 3) involved nonprospective studies (for example, cross-sectional and retrospective casecontrol studies), 4) had less than 1 year of follow-up, 5) assessed the effect of glycemic control on cardiovascular outcomes after admission to a hospital or after surgery, and 6) involved only patients receiving dialysis or transplants. We excluded 1 additional study (23) in which the outcome was self-reported and the authors did not use standard definitions for classifying cardiovascular outcomes. When several, sequentially published studies were performed in the same sample, the publication with the longest follow-up was selected for inclusion in our analysis. For multiple studies of the same sample with equivalent follow-up, the most recent publication was selected. Data Abstraction Two investigators independently reviewed each article that met the selection criteria and abstracted the data by using standardized data abstraction forms. Discrepancies were resolved by consensus. Data abstracted were age, percentage of male and female study participants, sample size, outcome or outcomes, duration of follow-up, method of measuring glycosylated hemoglobin, main results, statistical methods, number of study participants included in the final analysis, and variables included in the adjusted model or models. For each prospective cohort study that met our inclusion criteria, we abstracted adjusted effect estimates (odds ratios, relative risks, or relative hazards) for the association between cardiovascular risk (based on incident events during follow-up) and baseline or updated mean glycosylated hemoglobin values. Standard errors for the estimates were abstracted or derived by using data reported in the manuscript. The cardiovascular disease end points, defined a priori, were fatal and nonfatal coronary heart disease (myocardial infarction, angina, and ischemic heart disease); cerebrovascular disease (fatal and nonfatal stroke); peripheral arterial disease (lower-extremity peripheral arterial disease, amputation, and claudication); and a combined cardiovascular disease outcome that included studies of coronary heart disease and stroke (but not peripheral arterial disease). We conducted separate analyses for each cardiovascular end point and for samples of persons with type 1 and type 2 diabetes. Studies using a combined outcome that included both coronary heart disease and stroke (24-26) were excluded from the pooled effect estimates for stroke alone and coronary heart disease alone but were included in the combined coronary heart disease and stroke subgroup. Statistical Analysis We conducted separate meta-analyses of the prospective cohort studies for study samples of persons with type 1 and type 2 diabetes and for the different cardiovascular outcomes. Most studies reported glycosylated hemoglobin as percentage hemoglobin A1c or its equivalent, although some studies (27-32) measured hemoglobin A1 and 1 study (33) measured total glycosylated hemoglobin. Although the American Diabetes Association advises that all measurements of glycosylated hemoglobin be reported as percentage hemoglobin A1c or its equivalent (16), there are direct linear relationships between glycosylated hemoglobin subfractions (34); therefore, we did not consider the measured subfraction to be an important source of heterogeneity across studies. For 4 studies (27, 30-32) that reported relative risk estimates for participants in the highest tertile of glycosylated hemoglobin compared with participants in the 2 lowest tertiles, we assumed a normal distribution for glycosylated hemoglobin values and used the reported mean and SD to estimate the 33rd and 83rd percentiles of glycosylated hemoglobin (corresponding to the midpoints of the 2 lowest and the highest tertiles, respectively). Then, we divided the log relative risk by the difference of these 2 values to estimate the effect of a 1-unit change in glycosylated hemoglobin (35). For the study (36) that reported a dichotomous relative risk estimate (it compared glycosylated hemoglobin above and below the median), we used the same method to estimate the effect of a 1-unit change in glycosylated hemoglobin but calculated the 25th and 75th percentiles and divided the log relative risk by the difference of these 2 values. One study (29) did not report relative risks or odds ratios but reported the mean and SD of glycosylated hemoglobin in persons with and without cardiovascular disease events. In this case, we estimated the odds ratio and its 95% CI on the basis of a linear discriminant function model. This m

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

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.

The Charlson comorbidity index is adapted to predict costs of chronic disease in primary care patients

OBJECTIVE (1) To determine chronic illness costs for large cohort of primary care patients, (2) to develop prospective model predicting total costs over one year, using demographic and clinical information including widely used comorbidity index. STUDY DESIGN AND SETTING Data including diagnostic, medication, and resource utilization were obtained for 5,861 patients from practice-based computer system over a 1-year period beginning December 1, 1993, for retrospective analysis. Hospital cost data were obtained from hospital cost accounting system. RESULTS Average annual per patient cost was

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

2,655. Older patients and those with Medicare or Medicaid had higher costs. Hospital costs were

Systematic Review: Comparative Effectiveness and Safety of Premixed Insulin Analogues in Type 2 Diabetes

1,558, accounting for 58.7% of total costs. In the predictive model, individuals with higher comorbidity incurred exponentially higher annual costs, from

The Science of Continuing Medical Education: Terms, Tools, and Gaps: Effectiveness of Continuing Medical Education: American College of Chest Physicians Evidence-Based Educational Guidelines

4,317 with comorbidity score of two, to

The reported validity and reliability of methods for evaluating continuing medical education: A systematic review

5,986 with score of three, to

Factors Associated With Intensification of Oral Diabetes Medications in Primary Care Provider-Patient Dyads: A Cohort Study

13,326 with scores greater than seven. To use an adapted comorbidity index to predict total yearly costs, four conditions should be added to the index: hypertension, depression, and use of warfarin with a weight of one, skin ulcers/cellulitis, a weight of two. CONCLUSION The adapted comorbidity index can be used to predict resource utilization. Predictive models may help to identify targets for reducing high costs, by prospectively identifying those at high risk.

Methods and Definition of Terms: Effectiveness of Continuing Medical Education: American College of Chest Physicians Evidence-Based Educational Guidelines

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.