Background: As newer oral diabetes agents continue to emerge on the market, comparative evidence is urgently required to guide appropriate therapy. Purpose: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and α-glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus. Data Sources: The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through January 2006 for original articles and through November 2005 for systematic reviews. Unpublished U.S. Food and Drug Administration and industry data were also searched. Study Selection: 216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States. Data Extraction: Using standardized protocols, 2 reviewers serially abstracted data for each article. Data Synthesis: Evidence from clinical trials was inconclusive on major clinical end points, such as cardiovascular mortality. Therefore, the review was limited mainly to studies of intermediate end points. Most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree as sulfonylureas (absolute decrease in hemoglobin A_1c level of about 1 percentage point). Nateglinide and α-glucosidase inhibitors may have slightly weaker effects, on the basis of indirect comparisons of placebo-controlled trials. Thiazolidinediones were the only class that had a beneficial effect on high-density lipoprotein cholesterol levels (mean relative increase, 0.08 to 0.13 mmol/L [3 to 5 mg/dL]) but a harmful effect on low-density lipoprotein (LDL) cholesterol levels (mean relative increase, 0.26 mmol/L [10 mg/dL]) compared with other oral agents. Metformin decreased LDL cholesterol levels by about 0.26 mmol/L (10 mg/dL), whereas other oral agents had no obvious effects on LDL cholesterol levels. Most agents other than metformin increased body weight by 1 to 5 kg. Sulfonylureas and repaglinide were associated with greater risk for hypoglycemia, thiazolidinediones with greater risk for heart failure, and metformin with greater risk for gastrointestinal problems compared with other oral agents. Lactic acidosis was no more common in metformin recipients without comorbid conditions than in recipients of other oral diabetes agents. Limitations: Data on major clinical end points were limited. Studies inconsistently reported adverse events other than hypoglycemia, and definitions of adverse events varied across studies. Some harms not assessed in trials or observational studies may have been overlooked. Conclusions: Compared with newer, more expensive agents (thiazolidinediones, α-glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.

Background: Diabetes mellitus is a risk factor for cardiovascular disease ( CVD ) and has been associated with 2‐ to 4‐fold higher mortality. Diabetes mellitus–related mortality has not been reassessed in individuals receiving routine care in the United States in the contemporary era of CVD risk reduction. Methods and Results: We retrospectively studied 963 648 adults receiving care in the US Veterans Affairs Healthcare System from 2002 to 2014; mean follow‐up was 8 years. We estimated associations of diabetes mellitus status and hemoglobin A1c (HbA1c) with all‐cause and CVD mortality using covariate‐adjusted incidence rates and multivariable Cox proportional hazards regression. Of participants, 34% had diabetes mellitus. Compared with nondiabetic individuals, patients with diabetes mellitus had 7.0 (95% CI , 6.7–7.4) and 3.5 (95% CI, 3.3–3.7) deaths/1000‐person‐years higher all‐cause and CVD mortality, respectively. The age‐, sex‐, race‐, and ethnicity‐adjusted hazard ratio for diabetes mellitus–related mortality was 1.29 (95% CI, 1.28–1.31), and declined with adjustment for CVD risk factors (hazard ratio, 1.18 [95% CI, 1.16–1.19]) and glycemia (hazard ratio, 1.03 [95% CI, 1.02–1.05]). Among individuals with diabetes mellitus, CVD mortality increased as HbA1c exceeded 7% (hazard ratios, 1.11 [95% CI, 1.08–1.14], 1.25 [95% CI, 1.22–1.29], and 1.52 [95% CI, 1.48–1.56] for HbA1c 7%–7.9%, 8%–8.9%, and ≥9%, respectively, relative to HbA1c 6%–6.9%). HbA1c 6% to 6.9% was associated with the lowest mortality risk irrespective of CVD history or age. Conclusions: Diabetes mellitus remains significantly associated with all‐cause and CVD mortality, although diabetes mellitus–related excess mortality is lower in the contemporary era than previously. We observed a gradient of mortality risk with increasing HbA1c >6% to 6.9%, suggesting HbA1c remains an informative predictor of outcomes even if causality cannot be inferred.

A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus. With the addition of newer oral therapies to the market in the late 1990s (eg, thiazolidinediones and meglitinides), it is critical to evaluate how these agents compare with older medications. This is particularly important in light of the expense of many of the newer therapies. Clinical trials examining the efficacy of these different therapies have largely focused on intermediate clinical outcomes such as changes in levels of hemoglobin A_1c (HbA_1c) or serum lipids and in blood pressure. Improvements in control of glucose levels per se have been shown to reduce the incidence of microvascular disease,¹ and there is accumulating evidence of potential macrovascular benefits.^2-5 Nonetheless, the specific effects of oral diabetes agents on cardiovascular risks remain unclear.

Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS–disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.75 (95% CI: 1.57–1.95) for type 2 diabetes to 2.38 (95% CI: 2.07–2.73) for breast cancer). After confirming the high performance and robustness of the pipeline for use as a clinical assay for individual patients, we analyzed the first 227 prospective samples from the GenoVA Study and found that the frequency of PRS corresponding to published OR > 2 ranged from 13/227 (5.7%) for colorectal cancer to 23/150 (15.3%) for prostate cancer. In addition to the PRS laboratory report, we developed physician- and patient-oriented informational materials to support decision-making about PRS results. Our work illustrates the generalizable development of a clinical PRS assay for multiple conditions and the technical, reporting and clinical workflow challenges for implementing PRS information in the clinic.

Multivitamin and mineral supplements are the most commonly used dietary supplements in the United States. To synthesize studies on the efficacy and safety of multivitamin/mineral supplement use in primary prevention of cancer and chronic disease in the general population. English-language literature search of the MEDLINE, EMBASE, and Cochrane databases through February 2006 and hand-searching of pertinent journals and articles. Randomized, controlled trials in adults were reviewed to assess efficacy, and randomized, controlled trials and observational studies in adults or children were reviewed to assess safety. Paired reviewers extracted data and independently assessed study quality. 12 articles from 5 randomized, controlled trials that assessed efficacy and 8 articles from 4 randomized, controlled trials and 3 case reports on adverse effects were identified. Study quality was rated fair for the studies on cancer, cardiovascular disease, cataracts, or age-related macular degeneration and poor for the studies on hypertension. In a poorly nourished Chinese population, combined supplementation with β-carotene, α-tocopherol, and selenium reduced the incidence of and mortality rate from gastric cancer and the overall mortality rate from cancer by 13% to 21%. In a French trial, combined supplementation with vitamin C, vitamin E, β-carotene, selenium, and zinc reduced the rate of cancer by 31% in men but not in women. Multivitamin and mineral supplements had no significant effect on cardiovascular disease or cataracts, except that combined β-carotene, selenium, α-tocopherol, retinol, and zinc supplementation reduced the mortality rate from stroke by 29% in the Linxian study and that a combination of 7 vitamins and minerals stabilized visual acuity loss in a small trial. Combined zinc and antioxidants slowed the progression of advanced age-related macular degeneration in high-risk persons. No consistent adverse effects of multivitamin and mineral supplements were evident. Only randomized, controlled trials were considered for efficacy assessment. Special nutritional needs, such as use of folic acid by pregnant women to prevent birth defects, were not addressed. Findings may not apply to use of commercial multivitamin supplements by the general U.S. population. Evidence is insufficient to prove the presence or absence of benefits from use of multivitamin and mineral supplements to prevent cancer and chronic disease.

The clinical value of whole-genome sequencing (WGS) in asymptomatic adults is uncertain. This pilot trial describes the effects on care of adding WGS to standardized family history assessment in pr... Background: Whole-genome sequencing (WGS) in asymptomatic adults might prevent disease but increase health care use without clinical value. Objective: To describe the effect on clinical care and ou...