Ranee Chatterjee

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.

African strains of hepatitis E virus that are distinct from Asian strains

Partial genomic sequences of four hepatitis E virus (HEV) strains from Africa (Morocco and Tunisia) and one from Central Asia (Tashkent, Uzbekistan) were obtained. The reverse transcriptase‐polymerase chain reaction was used to amplify 5′ and hypervariable regions of open reading frame 1 (ORF1) and a region overlapping all 3 ORFs. Sequence analysis of these regions revealed the African strains to be quite distinct from all known Asian strains but more similar to them than to the Mexican strain. Sequence analysis of the Tashkent strain revealed almost complete identity with another central Asian strain from Osh, Kirgizia. These results thus further confirm the geographical origin of HEV strain divergence. J. Med. Virol. 53:139–144, 1997.

Rate- and Rhythm-Control Therapies in Patients With Atrial Fibrillation: A Systematic Review

Atrial fibrillation (AF) is a major public health problem in the United States. More than 2.3 million Americans are estimated to have AF (1). The known association between AF and substantial mortality, morbidity, and health care costs compounds the effect of this condition. Not only is the risk for death in patients with AF twice that of patients without it, but AF can result in myocardial ischemia and infarction, exacerbate heart failure (HF), and cause tachycardia-induced cardiomyopathy if the ventricular rate is not well-controlled (25). The most dreaded complication of AF is thromboembolism, especially stroke (6). In some patients, AF or therapies to manage this condition can severely depreciate quality of life (710). Furthermore, the management of AF and its complications is responsible for nearly

Serum and dietary potassium and risk of incident type 2 diabetes mellitus: The Atherosclerosis Risk in Communities (ARIC) study.

16 billion in additional costs to the U.S. health care system per year (11). Despite the substantial public health effect of AF, uncertainties around its management remain. In particular, the comparative safety and effectiveness of different rate- and rhythm-control therapies for patients with AF are unclear. We conducted this systematic review to evaluate the comparative safety and effectiveness of rate- versus rhythm-control strategies; medications used for ventricular rate control; strict versus more lenient rate-control strategies; nonpharmacologic rate-control therapies versus medications; electrical cardioversion and antiarrhythmic medications for restoration of sinus rhythm; and catheter ablation, surgical ablation, and antiarrhythmic medications for maintenance of sinus rhythm. Methods We developed and followed a standard protocol for our review. Full details of our methods, search strategies, results, and conclusions are presented in a comparative effectiveness review commissioned by the Agency for Healthcare Research and Quality (AHRQ) and are available at www.effectivehealthcare.ahrq.gov (12). Data Sources and Searches We searched PubMed, EMBASE, and the Cochrane Database of Systematic Reviews for studies published between 1 January 2000 and 12 November 2013. Data before 2000 have been summarized in an AHRQ report on the management of new-onset AF published in 2001 (1315). Study Selection We identified randomized, controlled trials (RCTs) published in English that were comparative assessments of pharmacologic or nonpharmacologic rate- or rhythm-control therapies aimed at treating adults with AF. Observational studies were also allowed for comparisons of strict versus lenient rate control or cardiac resynchronization therapy versus other rhythm-control therapies. The following outcomes were considered: restoration of sinus rhythm (conversion), maintenance of sinus rhythm, recurrence of AF at 12 months, development of cardiomyopathy, death (all-cause and cardiac), myocardial infarction, cardiovascular hospitalizations, HF symptoms, control of AF symptoms, quality of life, functional status, stroke and other embolic events, bleeding events, and adverse effects of therapy. Data Extraction and Quality Assessment One investigator abstracted and another confirmed data related to study setting and design, patient characteristics, details of treatment, comparators, and relevant outcomes. The quality of individual studies was evaluated using the approach described in AHRQs Methods Guide for Effectiveness and Comparative Effectiveness Reviews (16). Investigators also assessed factors that limited applicability of the evidence. Data Synthesis and Analysis For each treatment comparison and outcome of interest, we determined the feasibility of completing a quantitative synthesis (meta-analysis) based on the volume of relevant literature, conceptual homogeneity of the studies (both in terms of study population and outcomes), and completeness of the reporting of results. We considered meta-analysis for outcomes that at least 3 studies reported. For our evaluation of rate- versus rhythm-control strategies, we grouped all rate-control strategies together and all rhythm-control strategies together, regardless of the specific medication or procedure. We grouped pharmacologic interventions by class, considering rate-controlling calcium-channel blockers and all -blockers each to be similar enough to be grouped together. We categorized procedures into electrical cardioversion, atrioventricular node (AVN) ablation, AF ablation by pulmonary vein isolation (PVI) (by open surgical, minimally invasive, or transcatheter procedures), and different types of surgical maze procedures and explored comparisons among these categories. In addition, for the comparisons focusing on medications versus procedures, we also explored grouping all medications together and comparing them with all procedures. When a meta-analysis was appropriate, we used a random-effects model to synthesize the available evidence quantitatively using Comprehensive Meta-Analysis, version 2 (Biostat, Englewood, New Jersey). We used a standardized approach to rank the overall strength of evidence (SOE) for each outcome (16). Role of the Funding Source Primary funding was provided by AHRQ. Neither the technical experts nor AHRQ representatives had a role in the literature search, data analysis, interpretation of the data, or decision to submit the manuscript for publication. Results We screened 10495 abstracts, evaluated 570 full-text articles, and included 200 articles representing 162 studies involving 28836 patients (Figure 1). Tables 1 to 6 of the Supplement provide details about these studies and their populations for each topic described here. Table 7 of the Supplement lists identified and potential limitations of the studies. The full AHRQ report highlights additional findings (12). Figure 1. Summary of evidence search and selection. AAD = antiarrhythmic drug; CRT = cardiac resynchronization therapy; RCT = randomized, controlled trial. * Some studies were relevant to more than 1 topic. Supplement. Tables Rate- Versus Rhythm-Control Strategies We included 16 RCTs in this analysis: 13 compared pharmacologic rhythm-control versus rate-control strategies (1729) and 3 compared a rhythm-control strategy with PVI versus a rate-control strategy that involved AVN ablation and implantation of a pacemaker in 1 study (30) and rate-controlling medications in the other 2 (31, 32). Ten RCTs (17, 18, 2022, 2428) provided information on outcomes of interest and were combined quantitatively (Figure 2). Of these, 5 included only patients with persistent AF (2022, 25, 28), 1 included only patients with paroxysmal AF (17), and 4 included patients with paroxysmal or persistent AF (18, 24, 26, 27). Two studies (17, 22) compared a single-chamber pacemaker plus AVN ablation versus a dual-chamber pacemaker plus AVN ablation plus an antiarrhythmic medication; all others compared largely unspecified rate-control with rhythm-control strategies. Figure 2. Meta-analysis forest plots. AAD = antiarrhythmic drug; PVI = pulmonary vein isolation. A. All-cause mortality for rate- vs. rhythm-control strategies. B. Cardiovascular mortality for rate- vs. rhythm-control strategies. C. Stroke for rate- vs. rhythm-control strategies. D. Restoration of sinus rhythm for monophasic vs. biphasic waveforms. E. Maintenance of sinus rhythm for PVI vs. AAD therapy. Figure 2. Continued. Data from the included studies showed moderate SOE that pharmacologic rate- and rhythm-control strategies are of comparable efficacy with regard to their effect on all-cause mortality (odds ratio [OR], 1.34 [95% CI, 0.89 to 2.02]; Q= 21.71; P= 0.003) (Figure 2, A) (18, 2022, 24, 2628), cardiac mortality (OR, 0.96 [CI, 0.77 to 1.20]; Q= 3.55; P= 0.47) (Figure 2, B) (18, 21, 22, 24, 25), and stroke (OR, 0.99 [CI, 0.76 to 1.30]; Q= 7.02; P= 0.43) (Figure 2, C) (17, 18, 2022, 24, 27, 28). Although the meta-analysis for all-cause mortality showed a potential benefit, it did not reach statistical significance and 6 of the 8 studies (6069 patients [95%]) had ORs that crossed 1, resulting in a final moderate SOE. For cardiac mortality (Figure 2, B), point estimates were inconsistent and CIs were wide for 2 of the 5 studies (18, 21), but there was no evidence of heterogeneity; therefore, our SOE rating was not affected. For the outcome of stroke, there was no evidence of heterogeneity, but the findings were mostly driven by 1 large, good-quality RCT (4060 patients), which was inconsistent with several of the smaller studies, reducing our confidence in the finding and in the SOE. These studies largely included older patients with mild AF symptoms. Three RCTs compared pharmacologic rate-control strategies with rhythm-control strategies using antiarrhythmic medications (17, 18, 22). These RCTs showed fewer cardiovascular hospitalizations with the rhythm-control strategies (17, 18, 22). Although data from 5 RCTs suggest that there is no difference between pharmacologic rate- and rhythm-control strategies in their effect on HF symptoms (17, 22, 24, 26, 46) (Table 1), a prespecified substudy of the Atrial Fibrillation and Congestive Heart Failure study showed that a higher proportion of time spent in sinus rhythm was associated with a greater improvement in New York Heart Association class (29). Table 1. Summary of SOE and Effect Estimates for Rate- Versus Rhythm-Control Strategies Three studies compared a rhythm-control strategy involving catheter ablation with a rate-control strategy involving rate-controlling medications (32) or AVN ablation combined with implantation of a pacemaker (30) or rate-controlling medications (31). One study showed that catheter ablation was better than pharmacologic rate control at improving symptoms, neurohormonal status, and objective physiologic exercise capacity (32). Another study showed that PVI isolation was superior to AVN ablation and pacemaker implantation in improving quality of life, 6-minute walk distance, and ejection fraction (30). Another study showed that PVI resulted in long-term restoration o

Screening Adults for Pre-Diabetes and Diabetes May Be Cost-Saving

BACKGROUND Serum potassium levels affect insulin secretion by pancreatic β-cells, and hypokalemia associated with diuretic use has been associated with dysglycemia. We hypothesized that adults with lower serum potassium levels and lower dietary potassium intake are at higher risk for incident diabetes mellitus (DM), independent of diuretic use. METHODS We analyzed data from 12 209 participants from the Atherosclerosis Risk in Communities (ARIC) Study, an ongoing prospective cohort study, beginning in 1986, with 9 years of in-person follow-up and 17 years of telephone follow-up. Using multivariate Cox proportional hazard models, we estimated the hazard ratio (HR) of incident DM associated with baseline serum potassium levels. RESULTS During 9 years of in-person follow-up, 1475 participants developed incident DM. In multivariate analyses, we found an inverse association between serum potassium and risk of incident DM. Compared with those with a high-normal serum potassium level (5.0-5.5 mEq/L), adults with serum potassium levels lower than 4.0 mEq/L, 4.0 to lower than 4.5 mEq/L, and 4.5 to lower than 5.0 mEq/L had an adjusted HR (95% confidence interval [CI]) of incident DM of 1.64 (95% CI, 1.29-2.08), 1.64 (95% CI, 1.34-2.01), and 1.39 (95% CI, 1.14-1.71), respectively. An increased risk persisted during an additional 8 years of telephone follow-up based on self-report with HRs of 1.2 to 1.3 for those with a serum potassium level lower than 5.0 mEq/L. Dietary potassium intake was significantly associated with risk of incident DM in unadjusted models but not in multivariate models. CONCLUSIONS Serum potassium level is an independent predictor of incident DM in this cohort. Further study is needed to determine if modification of serum potassium could reduce the subsequent risk of DM.

Potassium and risk of Type 2 diabetes

OBJECTIVE The economic costs of hyperglycemia are substantial. Early detection would allow management to prevent or delay development of diabetes and diabetes-related complications. We investigated the economic justification for screening for pre-diabetes/diabetes. RESEARCH DESIGN AND METHODS We projected health system and societal costs over 3 years for 1,259 adults, comparing costs associated with five opportunistic screening tests. All subjects had measurements taken of random plasma and capillary glucose (RPG and RCG), A1C, and plasma and capillary glucose 1 h after a 50 g oral glucose challenge test without prior fasting (GCT-pl and GCT-cap), and a subsequent diagnostic 75 g oral glucose tolerance test (OGTT). RESULTS Assuming 70% specificity screening cutoffs, Medicare costs for testing, retail costs for generic metformin, and costs for false negatives as 10% of reported costs associated with pre-diabetes/diabetes, health system costs over 3 years for the different screening tests would be GCT-pl

Patient and provider interventions for managing osteoarthritis in primary care: protocols for two randomized controlled trials.

180,635; GCT-cap

Serum potassium and the racial disparity in diabetes risk: the Atherosclerosis Risk in Communities (ARIC) Study

182,980; RPG

Screening for diabetes and prediabetes should be cost-saving in patients at high risk.

182,780; RCG

Prioritization of patient-centered comparative effectiveness research for osteoarthritis.

186,090; and A1C