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Objective: To estimate baseline cardiovascular risk of 1,123 participants in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study and to assess cardiac event rates and the effect of screening on outcomes in these higher-risk participants.Research Design and Methods: Baseline cardiovascular risk was assessed using four established methods: Framingham score, UK Prospective Diabetes Study (UKPDS) risk engine, criteria of the French-Speaking Association for the Study of Diabetes and Metabolic Diseases, and the presence or absence of metabolic syndrome. Cardiac events (cardiac death or nonfatal myocardial infarction) were assessed during the 4.8-year follow-up in participants with intermediate/high cardiovascular risk.Results: By various risk-stratification approaches, 53-75% of participants were defined as having intermediate or high cardiovascular risk. The prevalence of inducible ischemia on screening in these individuals ranged from 21 to 24%, similar to lower-risk participants (19-23%). Cardiac event rates were greater in intermediate-/high-risk versus low-risk groups, but this was only significant for the UKPDS risk engine (4.2 vs. 1.2%, P = 0.002). The annual cardiac event rate was <1% in all risk groups, except in the high-risk UKPDS group (∼2% per year). In intermediate-/high-risk participants randomized to screening versus no screening, 4.8-year cardiac event rates were similar (2.5-4.8% vs. 3.1-3.7%).Conclusions: A substantial portion of the DIAD population was defined as having intermediate/high baseline cardiovascular risk. Nevertheless, their annual cardiac event rate was low and not altered by routine screening for inducible ischemia. [ABSTRACT FROM AUTHOR]

Objective: 11-Beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) converts inactive cortisone into active cortisol, thereby amplifying intracellular glucocorticoid action. The efficacy and safety of the 11betaHSD1 inhibitor INCB13739 were assessed when added to ongoing metformin monotherapy in patients with type 2 diabetes exhibiting inadequate glycemic control (A1C 7-11%).Research Design and Methods: This double-blind placebo-controlled paralleled study randomized 302 patients with type 2 diabetes (mean A1C 8.3%) on metformin monotherapy (mean 1.5 g/day) to receive one of five INCB13739 doses or placebo once daily for 12 weeks. The primary end point was the change in A1C at study end. Other end points included changes in fasting glucose, lipids, weight, adverse events, and safety.Results: After 12 weeks, 200 mg of INCB13739 resulted in significant reductions in A1C (-0.6%), fasting plasma glucose (-24 mg/dl), and homeostasis model assessment-insulin resistance (HOMA-IR) (-24%) compared with placebo. Total cholesterol, LDL cholesterol, and triglycerides were all significantly decreased in hyperlipidemic patients. Body weight decreased relative to placebo after INCB13739 therapy. A reversible dose-dependent elevation in adrenocorticotrophic hormone, generally within the normal reference range, was observed. Basal cortisol homeostasis, testosterone in men, and free androgen index in women were unchanged by INCB13739. Adverse events were similar across all treatment groups.Conclusions: INCB13739 added to ongoing metformin therapy was efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic control with metformin alone. 11BetaHSD1 inhibition offers a new potential approach to control glucose and cardiovascular risk factors in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Thiazolidinediones (TZDs) and metformin are insulin-sensitizing antihyperglycemic agents with reported benefits on atherosclerosis. Despite extensive use in patients with diabetes and cardiovascular disease, there is a paucity of outcomes data with metformin and none yet with TZDs. We sought to determine the impact of these insulin sensitizers on outcomes in diabetic patients after hospitalization with acute myocardial infarction (AMI).Research Design and Methods: We conducted a retrospective cohort study of 24,953 Medicare beneficiaries with diabetes discharged after hospitalization with AMI between April 1998 and March 1999 or July 2000 and June 2001. The independent association between discharge prescription for metformin, TZD, or both agents and outcomes at 1 year was assessed in multivariable Cox proportional hazards models, adjusting for patient, physician, and hospital variables. The primary outcome was time to death within 1 year of discharge; secondary outcomes were time to first rehospitalization within 1 year of discharge for AMI, heart failure, and all causes.Results: There were 8,872 patients discharged on an antihyperglycemic agent, of which 819 were prescribed a TZD, 1,273 metformin, and 139 both drugs. After multivariable analysis, compared with patients prescribed an antihyperglycemic regimen that included no insulin sensitizer, mortality rates were not significantly different in patients treated with either metformin (hazard ratio [HR] 0.92 [95% CI 0.81-1.06]) or a TZD (0.92 [0.80-1.05]) but were lower in those prescribed both drugs (0.52 [0.34-0.82]). The results were similar among patients with heart failure. The prescription of a TZD was associated with a borderline higher risk of all-cause readmission (1.09[1.00-1.20]), predominately due to a higher risk for heart failure readmission (1.17 [1.05-1.30]).Conclusions: Individually, prescription of insulin-sensitizing drugs is not associated with a significantly different risk of death in older diabetic patients within 1 year following AMI compared with other antihyperglycemic agents. Combined, however, metformin and TZDs may exert benefit. TZD prescription is associated with a higher risk of readmission for heart failure after myocardial infarction. [ABSTRACT FROM AUTHOR]

Objective: To assess the prevalence and clinical predictors of silent myocardial ischemia in asymptomatic patients with type 2 diabetes and to test the effectiveness of current American Diabetes Association screening guidelines.Research Design and Methods: In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 1,123 patients with type 2 diabetes, aged 50-75 years, with no known or suspected coronary artery disease, were randomly assigned to either stress testing and 5-year clinical follow-up or to follow-up only. The prevalence of ischemia in 522 patients randomized to stress testing was assessed by adenosine technetium-99m sestamibi single-photon emission-computed tomography myocardial perfusion imaging.Results: A total of 113 patients (22%) had silent ischemia, including 83 with regional myocardial perfusion abnormalities and 30 with normal perfusion but other abnormalities (i.e., adenosine-induced ST-segment depression, ventricular dilation, or rest ventricular dysfunction). Moderate or large perfusion defects were present in 33 patients. The strongest predictors for abnormal tests were abnormal Valsalva (odds ratio [OR] 5.6), male sex (2.5), and diabetes duration (5.2). Other traditional cardiac risk factors or inflammatory and prothrombotic markers were not predictive. Ischemic adenosine-induced ST-segment depression with normal perfusion (n = 21) was associated with women (OR 3.4). Selecting only patients who met American Diabetes Association guidelines would have failed to identify 41% of patients with silent ischemia.Conclusions: Silent myocardial ischemia occurs in greater than one in five asymptomatic patients with type 2 diabetes. Traditional and emerging cardiac risk factors were not associated with abnormal stress tests, although cardiac autonomic dysfunction was a strong predictor of ischemia. [ABSTRACT FROM AUTHOR]

Objective: To assess the efficacy and tolerability of alogliptin plus pioglitazone for initial combination therapy in drug-naïve type 2 diabetic patients.Research Design and Methods: This 26-week, double-blind, parallel-group study randomized 655 patients with inadequately controlled type 2 diabetes to four arms: 25 mg alogliptin (A25) q.d. monotherapy, 30 mg pioglitazone (P30) q.d. monotherapy, or 12.5 (A12.5) or 25 mg alogliptin q.d. plus pioglitazone (P30) q.d. combination therapy. Primary efficacy was A1C change from baseline with the high-dose combination (A25+P30) versus each monotherapy.Results: Combination therapy with A25+P30 resulted in greater reductions in A1C (-1.7±0.1% from an 8.8% mean baseline) vs. A25 (-1.0±0.1%, P<0.001) or P30 (-1.2±0.1%, P<0.001) and in fasting plasma glucose (-2.8±0.2 mmol/l) vs. A25 (-1.4±0.2 mmol/l, P<0.001) or P30 (-2.1±0.2 mmol/l, P=0.006). The A25+P30 safety profile was consistent with those of its component monotherapies.Conclusions: Alogliptin plus pioglitazone combination treatment appears to be an efficacious initial therapeutic option for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: We investigated sex and racial differences in insulin sensitivity, β-cell function, and glycated hemoglobin (HbA 1c ) and the associations with selected phenotypic characteristics., Research Design and Methods: This is a cross-sectional analysis of baseline data from 3,108 GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) participants. All had type 2 diabetes diagnosed <10 years earlier and were on metformin monotherapy. Insulin sensitivity and β-cell function were evaluated using the HOMA of insulin sensitivity and estimates from oral glucose tolerance tests, including the Matsuda Index, insulinogenic index, C-peptide index, and oral disposition index (DI)., Results: The cohort was 56.6 ± 10 years of age (mean ± SD), 63.8% male, with BMI 34.2 ± 6.7 kg/m 2 , HbA 1c 7.5 ± 0.5%, and type 2 diabetes duration 4.0 ± 2.8 years. Women had higher DI than men but similar insulin sensitivity. DI was the highest in Black/African Americans, followed by American Indians/Alaska Natives, Asians, and Whites in descending order. Compared with Whites, American Indians/Alaska Natives had significantly higher HbA 1c , but Black/African Americans and Asians had lower HbA 1c . However, when adjusted for glucose levels, Black/African Americans had higher HbA 1c than Whites. Insulin sensitivity correlated inversely with BMI, waist-to-hip ratio, triglyceride-to-HDL-cholesterol ratio (TG/HDL-C), and the presence of metabolic syndrome, whereas DI was associated directly with age and inversely with BMI, HbA 1c , and TG/HDL-C., Conclusions: In the GRADE cohort, β-cell function differed by sex and race and was associated with the concurrent level of HbA 1c . HbA 1c also differed among the races, but not by sex. Age, BMI, and TG/HDL-C were associated with multiple measures of β-cell function and insulin sensitivity., (© 2020 by the American Diabetes Association.)

Objective: The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial., Research Design and Methods: The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA 1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA 1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model., Results: At baseline, the mean HbA 1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebo group and 64 of 1,298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50-0.94; P = 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA 1c 5.7-6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not., Conclusions: In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure., (© 2020 by the American Diabetes Association.)

Objective: To explore the effects of empagliflozin on the incidence of obstructive sleep apnea (OSA) and its effects on metabolic, cardiovascular (CV), and renal outcomes among participants with or without OSA in the EMPA-REG OUTCOME trial., Research Design and Methods: Participants with diabetes and CV disease were randomized to empagliflozin (10 and 25 mg) or placebo daily in addition to standard of care. OSA was assessed by investigator report using Medical Dictionary for Regulatory Activities version 18.0, and CV outcomes were independently adjudicated. Analyses were performed using multivariable-adjusted Cox regression models., Results: OSA was reported in 391 of 7,020 (5.6%) participants at baseline. Those with OSA were more likely to be male (83% vs. 71%) and to have moderate to severe obesity (BMI ≥35 kg/m 2 ; 55% vs. 18%). Over a median of 3.1 years, empagliflozin had similar placebo-adjusted reductions in HbA 1c , waist circumference, and systolic blood pressure, regardless of OSA status, but a larger effect on weight (adjusted mean ± SE difference at week 52: OSA vs. no OSA -2.9 ± 0.5 vs. -1.9 ± 0.1 kg). Incidence of 3-point major adverse CV events, CV death, heart failure hospitalization, and incident or worsening nephropathy in the placebo group was 1.2- to 2.0-fold higher for those with baseline OSA compared with those without. Empagliflozin significantly reduced the risk for outcomes regardless of OSA status ( P -interaction all >0.05). Fifty patients reported a new diagnosis of OSA through 7 days after medication discontinuation, and this occurred less often with empagliflozin treatment (hazard ratio 0.48 [95% CI 0.27, 0.83])., Conclusions: In EMPA-REG OUTCOME, participants with OSA had greater comorbidity and higher frequency of CV and renal events. Empagliflozin had favorable effects on risk factors and CV and renal outcomes regardless of preexisting OSA and may also reduce the risk for new-onset OSA., (© 2020 by the American Diabetes Association.)

Objective: To determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT)., Research Design and Methods: We examined the effect of study treatment by the use or not of GLT and by GLT classes and combinations. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death., Results: In the 2,139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use or no use (hazard ratio 0.72 [95% CI 0.58-0.88] vs. 0.86 [0.60-1.23]; interaction P = 0.39) and across GLT classes., Conclusions: In DAPA-HF, dapagliflozin improved outcomes irrespective of use or no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF., (© 2020 by the American Diabetes Association.)

Objective: In 2016, the U.S. Food and Drug Administration (FDA) revised metformin's label to permit use in patients with mild-moderate chronic kidney disease. We sought to determine whether this change was associated with increased reports of metformin-associated lactic acidosis (MALA) to the FDA's Adverse Event Reporting System (FAERS)., Research Design and Methods: Publicly available FAERS reports were analyzed., Results: MALA reports increased from 521 in 2015 to 1,939 in 2018. After restriction to U.S. reports, absolute and relative increase in MALA reports was less, from 111 to 243. The proportionate reporting ratio (PRR), a measure adjusted for rates of other adverse event reports, was stable., Conclusions: The increased reports deserve attention, but the PRR's stability and FAERS's known limitations, including lack of a denominator or control group, do not permit the conclusion that U.S. MALA rates have increased. Further study with more robust data sources is needed., (© 2019 by the American Diabetes Association.)

Objective: In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial involving 7,020 patients with type 2 diabetes and established cardiovascular (CV) disease, empagliflozin given in addition to standard of care reduced the risk of CV death by 38% versus placebo (hazard ratio [HR] 0.62 [95% CI 0.49, 0.77]). This exploratory mediation analysis assesses the extent to which treatment group differences in covariates during the trial contributed to CV death risk reduction with empagliflozin., Research Design and Methods: Effects of potential mediators, identified post hoc, on the HR for CV death with empagliflozin versus placebo were analyzed by Cox regression models, with treatment group adjusted for the baseline value of the variable and its change from baseline or updated mean (i.e., considering all prior values), each as a time-dependent covariate. HRs were compared with a model without adjustment for covariates. Multivariable analyses also were performed., Results: Changes in hematocrit and hemoglobin mediated 51.8% and 48.9%, respectively, of the effect of empagliflozin versus placebo on the risk of CV death on the basis of changes from baseline, with similar results in analyses on the basis of updated means. Smaller mediation effects (maximum 29.3%) were observed for uric acid, fasting plasma glucose, and HbA 1c . In multivariable models, which incorporated effects of empagliflozin on hematocrit, fasting glucose, uric acid, and urine albumin:creatinine ratio, the combined changes from baseline provided 85.2% mediation, whereas updated mean analyses provided 94.6% mediation of the effect of empagliflozin on CV death., Conclusions: In this exploratory analysis from the EMPA-REG OUTCOME trial, changes in markers of plasma volume were the most important mediators of the reduction in risk of CV death with empagliflozin versus placebo., (© 2017 by the American Diabetes Association.)

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date., (© 2017 by the American Diabetes Association.)

Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin's affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative that precedes the counterpoint narrative below, Drs. Abdul-Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative below, Dr. Inzucchi argues that based on the medical community's extensive experience and the drug's demonstrated efficacy, safety, low cost, and cardiovascular benefits, metformin should remain the "foundation therapy" for all patients with type 2 diabetes, barring contraindications.-William T. CefaluChief Scientific, Medical & Mission Officer, American Diabetes Association., (© 2017 by the American Diabetes Association.)

Objective: To examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM)., Research Design and Methods: Using claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1 ) age- and sex-standardized proportion of patients who filled each class of agents; 2 ) age-, sex-, race-, and region-standardized proportion with hemoglobin A 1c (HbA 1c ) <6%, 6 to <7%, 7 to <8%, 8 to <9%, ≥9%; and 3 ) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18-44, 45-64, 65-74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more)., Results: From 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P < 0.001). The proportion of patients with HbA 1c <7% declined (from 56.4 to 54.2%; P < 0.001) and with HbA 1c ≥9% increased (9.9 to 12.2%; P < 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P < 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36)., Conclusions: During the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged., (© 2017 by the American Diabetes Association.)

Objective: The Insulin Resistance Intervention after Stroke (IRIS) trial recently found that pioglitazone reduced risk for stroke and myocardial infarction in patients with insulin resistance but without diabetes who had had a recent ischemic stroke or transient ischemic attack (TIA). This report provides detailed results on the metabolic effects of pioglitazone and the trial's prespecified secondary aim of diabetes prevention., Research Design and Methods: A total of 3,876 patients with recent ischemic stroke or TIA, no history of diabetes, fasting plasma glucose (FPG) <126 mg/dL, and insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR) score >3.0 were randomly assigned to pioglitazone or placebo. Surveillance for diabetes onset during the trial was accomplished by periodic interviews and annual FPG testing., Results: At baseline, the mean FPG, HbA1c, insulin, and HOMA-IR were 98.2 mg/dL (5.46 mmol/L), 5.8% (40 mmol/mol), 22.4 μIU/mL, and 5.4, respectively. After 1 year, mean HOMA-IR and FPG decreased to 4.1 and 95.1 mg/dL (5.28 mmol/L) in the pioglitazone group and rose to 5.7 and 99.7 mg/dL (5.54 mmol/L), in the placebo group (all P < 0.0001). Over a median follow-up of 4.8 years, diabetes developed in 73 (3.8%) participants assigned to pioglitazone compared with 149 (7.7%) assigned to placebo (hazard ratio [HR] 0.48 [95% CI 0.33-0.69]; P < 0.0001). This effect was predominately driven by those with initial impaired fasting glucose (FPG >100 mg/dL [5.6 mmol/L]; HR 0.41 [95% CI 0.30-0.57]) or elevated HbA1c (>5.7% [39 mmol/mol]; HR 0.46 [0.34-0.62])., Conclusions: Among patients with insulin resistance but without diabetes who had had a recent ischemic stroke or TIA, pioglitazone decreased the risk of diabetes while also reducing the risk of subsequent ischemic events. Pioglitazone is the first medication shown to prevent both progression to diabetes and major cardiovascular events as prespecified outcomes in a single trial., (© 2016 by the American Diabetes Association.)

Cardiovascular disease risk factor control as primary prevention in patients with type 2 diabetes mellitus has changed substantially in the past few years. The purpose of this scientific statement is to review the current literature and key clinical trials pertaining to blood pressure and blood glucose control, cholesterol management, aspirin therapy, and lifestyle modification. We present a synthesis of the recent literature, new guidelines, and clinical targets, including screening for kidney and subclinical cardiovascular disease for the contemporary management of patients with type 2 diabetes mellitus., (© 2015 by the American Diabetes Association and the American Heart Association, Inc.)

Objective: This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy., Research Design and Methods: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12 weeks in 170 patients with type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m(2)) that was inadequately controlled with sitagliptin alone (A1C ≥7.5%) during a 12-week run-in period. The primary efficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, stratification by baseline A1C, and percentage of A1C responders., Results: Imeglimin reduced A1C levels (least-squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (between-group difference 0.72%, P < 0.001). The corresponding changes in FPG were -0.93 mmol/L with imeglimin vs. -0.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ≥0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8% of subjects receiving imeglimin achieved a decrease in A1C level of ≤7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well tolerated, with a safety profile comparable to placebo and no related treatment-emergent adverse events., Conclusions: Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies., (© 2014 by the American Diabetes Association.)

Objective: To determine which measures-impaired fasting glucose (IFG), elevated HbA1c, or both-best predict incident diabetes in older adults., Research Design and Methods: From the Health, Aging, and Body Composition study, we selected individuals without diabetes, and we defined IFG (100-125 mg/dL) and elevated HbA1c (5.7-6.4%) per American Diabetes Association guidelines. Incident diabetes was based on self-report, use of antihyperglycemic medicines, or HbA1c ≥6.5% during 7 years of follow-up. Logistic regression analyses were adjusted for age, sex, race, site, BMI, smoking, blood pressure, and physical activity. Discrimination and calibration were assessed for models with IFG and with both IFG and elevated HbA1c., Results: Among 1,690 adults (mean age 76.5, 46% men, 32% black), 183 (10.8%) developed diabetes over 7 years. Adjusted odds ratios of diabetes were 6.2 (95% CI 4.4-8.8) in those with IFG (versus those with fasting plasma glucose [FPG] <100 mg/dL) and 11.3 (7.8-16.4) in those with elevated HbA1c (versus those with HbA1c <5.7%). When FPG and HbA1c were considered together, odds ratios were 3.5 (1.9-6.3) in those with IFG only, 8.0 (4.8-13.2) in those with elevated HbA1c only, and 26.2 (16.3-42.1) in those with both IFG and elevated HbA1c (versus those with normal FPG and HbA1c). Addition of elevated HbA1c to the model with IFG resulted in improved discrimination and calibration., Conclusions: Older adults with both IFG and elevated HbA1c have a substantially increased odds of developing diabetes over 7 years. Combined screening with FPG and HbA1c may identify older adults at very high risk for diabetes.

Objective: We examined the association between HbA1c level and self-reported severe hypoglycemia in patients with type 2 diabetes., Research Design and Methods: Type 2 diabetic patients in a large, integrated healthcare system, who were 30-77 years of age and treated with glucose-lowering therapy, were asked about severe hypoglycemia requiring assistance in the year prior to the Diabetes Study of Northern California survey conducted in 2005-2006 (62% response rate). The main exposure of interest was the last HbA1c level collected in the year preceding the observation period. Poisson regression models adjusted for selected demographic and clinical variables were specified to evaluate the relative risk (RR) of severe hypoglycemia across HbA1c levels. We also tested whether the HbA1c-hypoglycemia association differed across potential effect modifiers (age, diabetes duration, and category of diabetes medication)., Results: Among 9,094 eligible survey respondents (mean age 59.5 ± 9.8 years, mean HbA1c 7.5 ± 1.5%), 985 (10.8%) reported experiencing severe hypoglycemia. Across HbA1c levels, rates of hypoglycemia were 9.3-13.8%. Compared with those with HbA1c of 7-7.9%, the RR of hypoglycemia was 1.25 (95% CI 0.99-1.57), 1.01 (0.87-1.18), 0.99 (0.82-1.20), and 1.16 (0.97-1.38) among those with HbA1c <6, 6-6.9, 8-8.9, and ≥9%, respectively, in a fully adjusted model. Age, diabetes duration, and category of diabetes medication did not significantly modify the HbA1c-hypoglycemia relationship., Conclusions: Severe hypoglycemia was common among patients with type 2 diabetes across all levels of glycemic control. Risk tended to be higher in patients with either near-normal glycemia or very poor glycemic control.

Currently patients with diabetes comprise up to 25-30% of the census of adult wards and critical care units in our hospitals. Although evidence suggests that avoidance of hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) is beneficial for positive outcomes in the hospitalized patient, much of this evidence remains controversial and at times somewhat contradictory. We have recently formed a consortium for Planning Research in Inpatient Diabetes (PRIDE) with the goal of promoting clinical research in the area of management of hyperglycemia and diabetes in the hospital. In this article, we outline eight aspects of inpatient glucose management in which randomized clinical trials are needed. We refer to four as system-based issues and four as patient-based issues. We urge further progress in the science of inpatient diabetes management. We hope this call to action is supported by the American Diabetes Association, The Endocrine Society, the American Association of Clinical Endocrinologists, the American Heart Association, the European Association for the Study of Diabetes, the International Diabetes Federation, and the Society of Hospital Medicine. Appropriate federal research funding in this area will help ensure high-quality investigations, the results of which will advance the field. Future clinical trials will allow practitioners to develop optimal approaches for the management of hyperglycemia in the hospitalized patient and lessen the economic and human burden of poor glycemic control and its associated complications and comorbidities in the inpatient setting.

In June 2012, 13 thought leaders convened in a Diabetes Care Editors' Expert Forum to discuss the concept of personalized medicine in the wake of a recently published American Diabetes Association/European Association for the Study of Diabetes position statement calling for a patient-centered approach to hyperglycemia management in type 2 diabetes. This article, an outgrowth of that forum, offers a clinical translation of the underlying issues that need to be considered for effectively personalizing diabetes care. The medical management of type 2 diabetes has become increasingly complex, and its complications remain a great burden to individual patients and the larger society. The burgeoning armamentarium of pharmacological agents for hyperglycemia management should aid clinicians in providing early treatment to delay or prevent these complications. However, trial evidence is limited for the optimal use of these agents, especially in dual or triple combinations. In the distant future, genotyping and testing for metabolomic markers may help us to better phenotype patients and predict their responses to antihyperglycemic drugs. For now, a personalized ("n of 1") approach in which drugs are tested in a trial-and-error manner in each patient may be the most practical strategy for achieving therapeutic targets. Patient-centered care and standardized algorithmic management are conflicting approaches, but they can be made more compatible by recognizing instances in which personalized A1C targets are warranted and clinical circumstances that may call for comanagement by primary care and specialty clinicians.

Objective: A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone., Research Design and Methods: A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500-2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio., Results: After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was -0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (-0.91 mg/dL and -7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo., Conclusions: Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.

Objective: To evaluate the relationship between A1C and glucose therapy intensification (GTI) in patients with diabetes mellitus (DM) hospitalized for acute myocardial infarction (AMI)., Research Design and Methods: A1C was measured as part of routine care (clinical A1C) or in the core laboratory (laboratory A1C, results unavailable to clinicians). GTI predictors were identified using hierarchical Poisson regression., Results: Of 1,274 patients, 886 (70%) had clinical A1C and an additional 263 had laboratory A1C measured. Overall, A1C was <7% in 419 (37%), 7-9% in 415 (36%), and >9% in 315 patients (27%). GTI occurred in 31% of patients and was more frequent in those with clinical A1C both before (34 vs. 24%, P < 0.001) and after multivariable adjustment (relative risk 1.34 [95% CI 1.12-1.62] vs. no clinical A1C)., Conclusions: Long-term glucose control is poor in most AMI patients with DM, but only a minority of patients undergo GTI at discharge. Inpatient A1C assessment is strongly associated with intensification of glucose-lowering therapy.

Objective: The purpose of this study was to assess whether the prevalence of inducible myocardial ischemia increases over time in patients with type 2 diabetes., Research Design and Methods: Participants enrolled in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study underwent repeat adenosine-stress myocardial perfusion imaging 3 years after initial evaluation. Patients with intervening cardiac events or revascularization and those who were unable or unwilling to repeat stress imaging were excluded., Results: Of the initial 522 DIAD patients, 358 had repeat stress imaging (DIAD-2), of whom 71 (20%) had ischemia at enrollment (DIAD-1). Of 287 patients with normal DIAD-1 studies, 259 (90%) remained normal in DIAD-2, whereas 28 (10%) developed new ischemia in DIAD-2. Of the 71 patients with abnormal DIAD-1 studies, 56 (79%) demonstrated resolution of ischemia, whereas 15 (21%) remained abnormal. During this 3-year interval, medical treatment was intensified, with more patients using statins, aspirin, and ACE inhibitors than at baseline. Patients with resolution of ischemia had significantly greater increases in these medications than patients who developed new ischemia (P = 0.04)., Conclusions: Thus, the majority of asymptomatic patients with type 2 diabetes demonstrated resolution of ischemia upon repeat stress imaging after 3 years. This resolution was associated with more intensive treatment of cardiovascular risk factors.

Objective: In a recent randomized controlled trial, lowering blood glucose levels to 80-110 mg/dl improved clinical outcomes in critically ill patients. In that study, the insulin infusion protocol (IIP) used to normalize blood glucose levels provided valuable guidelines for adjusting insulin therapy. In our hands, however, ongoing expert supervision was required to effectively manage the insulin infusions. This work describes our early experience with a safe, effective, nurse-implemented IIP that provides detailed insulin dosing instructions and requires minimal physician input., Research Design and Methods: We collected data from 52 medical intensive care unit (MICU) patients who were placed on the IIP. Blood glucose levels were the primary outcome measurement. Relevant clinical variables and insulin requirements were also recorded. MICU nurses were surveyed regarding their experience with the IIP., Results: To date, our IIP has been employed 69 times in 52 patients admitted to an MICU. Using the IIP, the median time to reach target blood glucose levels (100-139 mg/dl) was 9 h. Once blood glucose levels fell below 140 mg/dl, 52% of 5,808 subsequent hourly blood glucose values fell within our narrow target range; 66% within a "clinically desirable" range of 80-139 mg/dl; and 93% within a "clinically acceptable" range of 80-199 mg/dl. Only 20 (0.3%) blood glucose values were <60 mg/dl, none of which resulted in clinically significant adverse events. In general, the IIP was readily accepted by our MICU nursing staff, most of whom rated the protocol as both clinically effective and easy to use., Conclusions: Our nurse-implemented IIP is safe and effective in improving glycemic control in critically ill patients.