OBJECTIVE-Cerebral microvascular disease associated with type 2 diabetes may exacerbate the effects of aging on cognitive function. A considerable homology exists between the retinal and cerebral microcirculations; a hypothesized association between diabetic retinopathy (DR) and cognitive decline was examined in older people with type 2 diabetes. RESEARCH DESIGN AND METHODS-In the population-based Edinburgh Type 2 Diabetes Study, 1,046 men and women aged 60-75 years with type 2 diabetes underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. A general cognitive ability score (g) was generated by principal components analysis. The Mill-Hill Vocabulary Scale was used to estimate premorbid cognitive ability. DR was graded using a modification of the Early Treatment of Diabetic Retinopathy Scale. RESULTS-After age and sex adjustment, a significant relationship was observed with increasing severity of DR (none, mild, and moderate to severe) for most cognitive measures. Participants with moderate-to-severe retinopathy had the worst g and the worst performances on the individual tests. There was a significant interaction between sex and retinopathy for g. In male subjects, the associations of retinopathy with g (and with tests of verbal fluency, mental flexibility, and processing speed but not memory and nonverbal reasoning) persisted (P < 0.05) when further adjusted for vocabulary (to estimate lifetime cognitive decline), depression, sociodemographic characteristics, cardiovascular risk factors, and macrovascular disease. CONCLUSIONS-DR was independently associated with estimated lifetime cognitive decline in older men with type 2 diabetes, supporting the hypothesis that cerebral microvascular disease may contribute to their observed accelerated age-related cognitive decline. A sex interaction with stronger findings in men requires further confirmation. Diabetes 59:2883-2889, 2010
R.M. Bergenstal: membership of scientific advisory boards and consultation for or clinical research support with Abbott Diabetes Care, Amylin, Bayer, Becton Dickinson, Boehringer Ingelheim, Calibra, DexCom, Eli Lilly, Halozyme, Helmsley Trust, Hygieia, Johnson & Johnson, Medtronic, NIH, Novo Nordisk, Roche, Sanofi, and Takeda (all under contracts with his employer). Inherited stock in Merck (held by family) J.B. Buse: research and consulting with Amylin Pharmaceuticals, Inc.; AstraZeneca; Biodel Inc.; Boehringer Ingelheim; BristolMyers Squibb Company; Diartis Pharmaceuticals, Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd; Halozyme Therapeutics; Johnson & Johnson; Medtronic MiniMed; Merck & Co., Inc.; Novo Nordisk; Pfizer Inc.; Sanofi; and TransPharma Medical Ltd (all under contracts with his employer) M. Diamant: member of advisory boards of Abbott Diabetes Care, Eli Lilly, Merck Sharp &r Dohme (MSD), Novo Nordisk, Poxel Pharma.
Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs. Purpose: To assess the efficacy and safety of SGLT2 inhibitors in adults with type 2 diabetes. Data Sources: MEDLINE, EMBASE, and the Cochrane Library from inception through April 2013 without language restrictions; regulatory authorities' reports; and gray literature. Study Selection: Randomized trials comparing SGLT2 inhibitors with placebo or other medication for type 2 diabetes. Data Extraction: Three reviewers extracted or checked data for study characteristics, outcomes of interest, and risk of bias, and 3 reviewers summarized strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Data Synthesis: Sodium-glucose cotransporter 2 inhibitors were compared with placebo in 45 studies (n = 11 232) and with active comparators in 13 studies (n = 5175). They had a favorable effect on hemoglobin A(1c) level (mean difference vs. placebo, -0.66% [95% CI, -0.73% to -0.58%]; mean difference vs. active comparators, -0.06% [CI, -0.18% to 0.05%]). Sensitivity analyses incorporating unpublished data showed similar effect estimates. Compared with other agents, SGLT2 inhibitors reduced body weight (mean difference, -1.80 kg [CI, -3.50 to -0.11 kg]) and systolic blood pressure (mean difference, -4.45 mm Hg [CI, -5.73 to -3.18 mm Hg]). Urinary and genital tract infections were more common with SGLT2 inhibitors (odds ratios, 1.42 [CI, 1.06 to 1.90] and 5.06 [CI, 3.44 to 7.45], respectively). Hypoglycemic risk was similar to that of other agents. Results for cardiovascular outcomes and death were inconclusive. An imbalance in incidence of bladder and breast cancer was noted with dapagliflozin compared with control. Limitation: Most trials were rated as high risk of bias because of missing data and last-observation-carried-forward methods. Conclusion: Sodium-glucose cotransporter 2 inhibitors may improve short-term outcomes in adults with type 2 diabetes, but effects on long-term outcomes and safety are unclear.
This study ascertained cases of type 1 and type 2 diabetes among youths from 2002 through 2012 at five U.S. study centers. After adjustment for age, sex, and race or ethnic group, there were relative annual increases in the incidences of type 1 and type 2 diabetes. Diagnoses of type 1 and type 2 diabetes in youths present a substantial clinical and public health burden owing to the challenges of disease management and the risks of acute and chronic complications. 1 The SEARCH for Diabetes in Youth study (hereafter, the SEARCH study) previously showed increases in the prevalences of both diseases in the 2001–2009 period. 2 However, data on the trends in incidence are needed to understand the current and potential burden of diabetes more fully. Previous reports have shown that the incidence of type 1 diabetes has increased worldwide over the past three decades. 3 – 8 Data from Australia . . .
Background: Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices. Purpose: To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes. Data Sources: English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015). Study Selection: Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. Data Extraction: Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. Data Synthesis: Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors. Limitation: Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes. Conclusion: The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies.
Background: Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. Objective: To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea. Design: 26-week multicenter, open-label, randomized, controlled trial. Setting: 82 outpatient study centers in 13 countries. Patients: 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A(1c) level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea. therapy. Intervention: Exenaticle, 10 mu g twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (< 100 mg/dL). Measurements: Hemoglobin A(1c) level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. Results: Baseline mean hemoglobin A(1c) level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin Ale levels by 1.11% (difference, 0.017 percentage point [95% Cl, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenaticle and increased 1.8 kg with insulin glargine (difference, -4.1 kg [Cl, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenaticle (0.9 event/patient-year versus 2.4 events/ patient-year; difference, -1.6 events/patient-year [Cl, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenaticle group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%). Limitations: The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenaticle and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenaticle group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (< 100 mg/dL). Conclusions: Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.
Aims Glucagon‐like peptide‐1 (GLP‐1) receptor agonists improve blood glucose control by enhancing glucose‐sensitive insulin release, delaying gastric emptying and reducing postprandial glucagon secretion. The studies reported here investigated the insulin response to an intravenous (iv) glucose challenge after injection of lixisenatide (LIXI) 20 µg or placebo. Methods Two single‐centre, double‐blind, randomized, placebo‐controlled, single‐dose, crossover studies were performed in healthy subjects (HS) and people with type 2 diabetes mellitus (T2DM). Participants received subcutaneous LIXI or placebo 2 h before an iv glucose challenge. Study endpoints included first‐ and second‐phase insulin response, insulin concentration (INS), glucagon response and glucose disposal rate (Kglucose). LIXI exposure was measured over 12 h. Results LIXI 20 µg reached maximum concentration after 2 h and resensitized first‐phase insulin secretion by 2.8‐fold in T2DM to rates comparable with those in HS on placebo, and raised second‐phase insulin secretion by 1.6‐fold in T2DM. INS rose correspondingly and glucose disposal was accelerated by 1.8‐fold in T2DM. First‐phase insulin secretion and glucose disposal were also augmented by LIXI in HS, whereas second‐phase insulin secretion reduced blood glucose concentrations to below fasting levels and then ceased, accompanied by a rapid, short‐lasting rise in glucagon. Otherwise, suppression of glucagon release subsequent to augmentation of insulin release was unaffected in T2DM and in HS. Conclusions LIXI resensitized the insulin response to an iv glucose challenge in people with T2DM, thereby accelerating glucose disposal to nearly physiological intensity, and did not impair counter‐regulation to low glucose levels by glucagon.
OBJECTIVE - Diabetes is associated with cognitive decline and dementia. However, the relationship between the degree of hyperglycemia and cognitive status remains unclear. This was explored using baseline cognitive measures collected in the ongoing Memory ill Diabetes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS - The relationship of AIC and fasting plasma glucose (FPG) levels to performance on four cognitive tests was assessed, adjusting lot age and Other determinants of cognitive status. The tests were the Digit Symbol Substitution Test (DSST), Mini Mental Status Examination (MMSE), Rey Auditory Verbal Learning Test, and Stroop Test. RESULTS - A Statistically significant age-adjusted association was observed between the A1C level and the score on all four Cognitive tests. Specifically, a 1% higher A1C value was associated with a significant 1.75-point lower DSST score (95% CI -1.22 to -2.28; P < 0.0001), a 0.20-point lower MMSE score (-0.11 to -0.28 P < 0.0001), a 0.11-point lower memory score (-0.02 to -0.1.9, P = 0.0142),and a worse score (i.e., 0.75 s more) on the Stroop Test(1.31-0.19, P = 0.0094). The association between the DSST score and A1C persisted in all multiple linear regression models. FPG was not associated With test performance. CONCLUSIONS- Higher A1C levels are associated With lower cognitive function in individuals with diabetes. The effect of glucose lowering on cognitive function will be determined by the ongoing ACCORD-MIND trial.
The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues Surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.
To forecast the number of U.S. individuals aged <20 years with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) through 2050, accounting for changing demography and diabetes incidence. We used Markov modeling framework to generate yearly forecasts of the number of individuals in each of three states (diabetes, no diabetes, and death). We used 2001 prevalence and 2002 incidence of T1DM and T2DM from the SEARCH for Diabetes in Youth study and U.S. Census Bureau population demographic projections. Two scenarios were considered for T1DM and T2DM incidence: 1) constant incidence over time; 2) for T1DM yearly percentage increases of 3.5, 2.2, 1.8, and 2.1% by age-groups 0-4 years, 5-9 years, 10-14 years, and 15-19 years, respectively, and for T2DM a yearly 2.3% increase across all ages. Under scenario 1, the projected number of youth with T1DM rises from 166,018 to 203,382 and with T2DM from 20,203 to 30,111, respectively, in 2010 and 2050. Under scenario 2, the number of youth with T1DM nearly triples from 179,388 in 2010 to 587,488 in 2050 (prevalence 2.13/1,000 and 5.20/1,000 [+144% increase]), with the greatest increase in youth of minority racial/ethnic groups. The number of youth with T2DM almost quadruples from 22,820 in 2010 to 84,131 in 2050; prevalence increases from 0.27/1,000 to 0.75/1,000 (+178% increase). A linear increase in diabetes incidence could result in a substantial increase in the number of youth with T1DM and T2DM over the next 40 years, especially those of minority race/ethnicity.