Showing papers in "Diabetes Care in 2013"

Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society

Abstract: OBJECTIVE To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice. PARTICIPANTS Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report. EVIDENCE The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions. CONSENSUS PROCESS Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012. CONCLUSIONS The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379

Abstract: Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 …

The Prevalence of Meeting A1C, Blood Pressure, and LDL Goals Among People With Diabetes, 1988–2010

Abstract: OBJECTIVE To determine the prevalence of people with diabetes who meet hemoglobin A1c (A1C), blood pressure (BP), and LDL cholesterol (ABC) recommendations and their current statin use, factors associated with goal achievement, and changes in the proportion achieving goals between 1988 and 2010. RESEARCH DESIGN AND METHODS Data were cross-sectional from the National Health and Nutrition Examination Surveys (NHANES) from 1988–1994, 1999–2002, 2003–2006, and 2007–2010. Participants were 4,926 adults aged ≥20 years who self-reported a previous diagnosis of diabetes and completed the household interview and physical examination ( n = 1,558 for valid LDL levels). Main outcome measures were A1C, BP, and LDL cholesterol, in accordance with the American Diabetes Association recommendations, and current use of statins. RESULTS In 2007–2010, 52.5% of people with diabetes achieved A1C <7.0% (<53 mmol/mol), 51.1% achieved BP <130/80 mmHg, 56.2% achieved LDL <100 mg/dL, and 18.8% achieved all three ABCs. These levels of control were significant improvements from 1988 to 1994 (all P < 0.05). Statin use significantly increased between 1988–1994 (4.2%) and 2007–2010 (51.4%, P < 0.01). Compared with non-Hispanic whites, Mexican Americans were less likely to meet A1C and LDL goals ( P < 0.03), and non-Hispanic blacks were less likely to meet BP and LDL goals ( P < 0.02). Compared with non-Hispanic blacks, Mexican Americans were less likely to meet A1C goals ( P < 0.01). Younger individuals were less likely to meet A1C and LDL goals. CONCLUSIONS Despite significant improvement during the past decade, achieving the ABC goals remains suboptimal among adults with diabetes, particularly in some minority groups. Substantial opportunity exists to further improve diabetes control and, thus, to reduce diabetes-related morbidity and mortality.

Inflammatory markers and risk of type 2 diabetes: a systematic review and meta-analysis.

Abstract: OBJECTIVE There has been growing evidence that inflammatory markers play a role in the development of type 2 diabetes. We aimed to systematically review prospective studies on the associations of elevated levels of interleukin-6 (IL-6) and C-reactive protein (CRP) with increased risk of type 2 diabetes by conducting a meta-analysis. RESEARCH DESIGN AND METHODS A systematic search of the PubMed, EMBASE, ISI Web of Knowledge, and Cochrane Library databases up until 10 February 2012 was conducted to retrieve prospective studies matched to search terms. We used generalized least-squares trend estimation to assess dose-response relationships. The summary risk estimates were pooled using either fixed-effects or random-effects models to incorporate between-study variation. RESULTS The meta-analysis, including 10 prospective studies, with a total of 19,709 participants and 4,480 cases, detected a significant dose-response association of IL-6 levels with type 2 diabetes risk (relative risk [RR] 1.31 [95% CI 1.17–1.46]). For CRP, the meta-analysis involving 22 cohorts, with a total of 40,735 participants and 5,753 cases, showed that elevated CRP levels were significantly associated with increased risk of type 2 diabetes (1.26 [1.16–1.37]), with the absence of publication bias. Sensitivity and subgroup analyses further supported the associations. CONCLUSIONS This meta-analysis provides further evidence that elevated levels of IL-6 and CRP are significantly associated with increased risk of type 2 diabetes.

Clinical Inertia in People With Type 2 Diabetes: A retrospective cohort study of more than 80,000 people

Abstract: OBJECTIVE To determine time to treatment intensification in people with type 2 diabetes treated with one, two, or three oral antidiabetes drugs (OADs) and associated levels of glycemic control. RESEARCH DESIGN AND METHODS This was a retrospective cohort study based on 81,573 people with type 2 diabetes in the U.K. Clinical Practice Research Datalink between January 2004 and December 2006, with follow-up until April 2011. RESULTS In people with HbA 1c ≥7.0, ≥7.5, or ≥8.0% (≥53, ≥58, or ≥64 mmol/mol), median time from above HbA 1c cutoff to intensification with an additional OAD was 2.9, 1.9, or 1.6 years, respectively, for those taking one OAD and >7.2, >7.2, and >6.9 years for those taking two OADs. Median time to intensification with insulin was >7.1, >6.1, or 6.0 years for those taking one, two, or three OADs. Mean HbA 1c at intensification with an OAD or insulin for people taking one, two, or three OADs was 8.7, 9.1, and 9.7%. In patients taking one, two, or three OADs, median time from treatment initiation to intensification with an OAD or insulin exceeded the maximum follow-up time of 7.2 years. The probability of patients with poor glycemic control taking one, two, or three OADs, intensifying at end of follow-up with an OAD, was 21.1–43.6% and with insulin 5.1–12.0%. CONCLUSIONS There are delays in treatment intensification in people with type 2 diabetes despite suboptimal glycemic control. A substantial proportion of people remain in poor glycemic control for several years before intensification with OADs and insulin.

Ethnic differences in the relationship between insulin sensitivity and insulin response: A systematic review and meta-analysis

Abstract: OBJECTIVE Human blood glucose levels have likely evolved toward their current point of stability over hundreds of thousands of years. The robust population stability of this trait is called canalization. It has been represented by a hyperbolic function of two variables: insulin sensitivity and insulin response. Environmental changes due to global migration may have pushed some human subpopulations to different points of stability. We hypothesized that there may be ethnic differences in the optimal states in the relationship between insulin sensitivity and insulin response. RESEARCH DESIGN AND METHODS We identified studies that measured the insulin sensitivity index ( S I ) and acute insulin response to glucose (AIR g ) in three major ethnic groups: Africans, Caucasians, and East Asians. We identified 74 study cohorts comprising 3,813 individuals (19 African cohorts, 31 Caucasian, and 24 East Asian). We calculated the hyperbolic relationship using the mean values of S I and AIR g in the healthy cohorts with normal glucose tolerance. RESULTS We found that Caucasian subpopulations were located around the middle point of the hyperbola, while African and East Asian subpopulations are located around unstable extreme points, where a small change in one variable is associated with a large nonlinear change in the other variable. CONCLUSIONS Our findings suggest that the genetic background of Africans and East Asians makes them more and differentially susceptible to diabetes than Caucasians. This ethnic stratification could be implicated in the different natural courses of diabetes onset.

Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea A 52-week randomized trial

Abstract: OBJECTIVE To evaluate the efficacy and safety of canagliflozin, a sodium glucose cotransporter 2 inhibitor, compared with sitagliptin in subjects with type 2 diabetes inadequately controlled with metformin plus sulfonylurea. RESEARCH DESIGN AND METHODS In this 52-week, randomized, double-blind, active-controlled, phase 3 study, subjects using stable metformin plus sulfonylurea ( N = 755) received canagliflozin 300 mg or sitagliptin 100 mg daily. Primary end point was change from baseline in A1C at 52 weeks. Secondary end points included change in fasting plasma glucose (FPG) and systolic blood pressure (BP), and percent change in body weight, triglycerides, and HDL cholesterol. Safety was assessed based on adverse event (AE) reports. RESULTS At 52 weeks, canagliflozin 300 mg demonstrated noninferiority and, in a subsequent assessment, showed superiority to sitagliptin 100 mg in reducing A1C (−1.03% [−11.3 mmol/mol] and −0.66% [−7.2 mmol/mol], respectively; least squares mean difference between groups, −0.37% [95% CI, −0.50 to −0.25] or −4.0 mmol/mol [−5.5 to −2.7]). Greater reductions in FPG, body weight, and systolic BP were observed with canagliflozin versus sitagliptin ( P CONCLUSION Findings suggest that canagliflozin may be a new therapeutic tool providing better improvement in glycemic control and body weight reduction than sitagliptin, but with increased genital infections in subjects with type 2 diabetes using metformin plus sulfonylurea.

Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults

Abstract: OBJECTIVE Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults. RESEARCH DESIGN AND METHODS Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood. RESULTS Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR ( P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38–3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination. CONCLUSIONS Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance.

Blood 25-Hydroxy Vitamin D Levels and Incident Type 2 Diabetes A meta-analysis of prospective studies

Abstract: OBJECTIVE To quantitatively assess the strength and shape of the association between blood 25-hydroxy vitamin D [25(OH)D] levels and incident risk of type 2 diabetes. RESEARCH DESIGN AND METHODS A systematic search of the MEDLINE and Embase databases and a hand search of references from original reports were conducted up to 31 October 2012. Prospective observational studies that assessed the association between blood levels of 25(OH)D and risk of incident type 2 diabetes were included for meta-analysis. DerSimonian and Laird’s random-effects model was used. A quadratic spline regression analysis was used to examine the shape of the association with a generalized least-squares trend test performed for the dose-response relation. RESULTS A total of 21 prospective studies involving 76,220 participants and 4,996 incident type 2 diabetes cases were included for meta-analysis. Comparing the highest to the lowest category of 25(OH)D levels, the summary relative risk for type 2 diabetes was 0.62 (95% CI 0.54–0.70). A spline regression model showed that higher 25(OH)D levels were monotonically associated with a lower diabetes risk. This inverse association did not differ by sex, duration of follow-up, study sample size, diabetes diagnostic criteria, or 25(OH)D assay method. A linear trend analysis showed that each 10 nmol/L increment in 25(OH)D levels was associated with a 4% lower risk of type 2 diabetes (95% CI 3–6; P for linear trend CONCLUSIONS Our meta-analysis showed an inverse and significant association between circulating 25(OH)D levels and risk of type 2 diabetes across a broad range of blood 25(OH)D levels in diverse populations.

Evidence of a Strong Association Between Frequency of Self-Monitoring of Blood Glucose and Hemoglobin A1c Levels in T1D Exchange Clinic Registry Participants

Abstract: OBJECTIVE Despite substantial evidence of the benefit of frequent self-monitoring of blood glucose (SMBG) in type 1 diabetes, certain insurers limit the number of test strips that they will provide. The large database of the T1D Exchange Clinic Registry provided an opportunity to evaluate the relationship between the number of SMBG measurements per day and HbA 1c levels across a wide age range of children and adults. RESEARCH DESIGN AND METHODS The analysis included 20,555 participants in the T1D Exchange clinic registry with type 1 diabetes ≥1 year and not using a continuous glucose monitor (11,641 younger than age 18 years and 8,914 18 years old or older). General linear models were used to assess the association between the number of SMBG measurements and HbA 1c levels after adjusting for potential confounding variables. RESULTS A higher number of SMBG measurements per day were associated with non-Hispanic white race, insurance coverage, higher household income, and use of an insulin pump for insulin delivery ( P 1c level (adjusted P CONCLUSIONS There is a strong association between higher SMBG frequency and lower HbA 1c levels. It is important for insurers to consider that reducing restrictions on the number of test strips provided per month may lead to improved glycemic control for some patients with type 1 diabetes.

Brain atrophy in type 2 diabetes: regional distribution and influence on cognition.

Abstract: OBJECTIVE Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function. RESEARCH DESIGN AND METHODS This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures. RESULTS T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes (all P P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume. CONCLUSIONS Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.

Diabetes and Cardiovascular Disease Outcomes in the Metabolically Healthy Obese Phenotype: A cohort study

Abstract: OBJECTIVE To determine the correlates of the “metabolically healthy obese” (MHO) phenotype and the longitudinal risks of diabetes and cardiovascular disease (CVD)/stroke associated with this phenotype. RESEARCH DESIGN AND METHODS The North West Adelaide Health Study is a prospective cohort study of 4,056 randomly selected adults aged ≥18 years. Participants free of CVD/stroke and not underweight ( n = 3,743) were stratified by BMI categories and metabolic risk, defined as having two or more International Diabetes Federation metabolic syndrome criteria, excluding waist circumference. RESULTS Correlates of the MHO ( n = 454 [12.1%]) included smoking, socioeconomic disadvantage, and physical inactivity. Compared with metabolically healthy normal-weight subjects ( n = 1,172 [31.3%]), the MHO were more likely to develop metabolic risk (15.5 vs. 33.1%, P n = 188 [67%]). Sustained metabolic health in obese participants was associated with age ≤40 years and lower waist circumference. Compared with the metabolically at-risk obese, MHO women demonstrated a significantly higher (mean [SE]) percentage of leg fat (49.9 [0.5] vs. 53.2 [0.7]) and lower waist circumference (104 [0.6] vs. 101 cm [0.8]), despite no significant differences in overall adiposity. CONCLUSIONS “Healthy” obesity was a transient state for one-third of subjects. Persistence of a MHO phenotype, which was associated with favorable outcomes, was related to younger age and a more peripheral fat distribution. The MHO phenotype may be sustained by promoting lower waist circumferences.

Obesity Paradox Does Exist

Abstract: Adipose tissue has been shown to be a pivotal organ in the aging process and in the determination of life span. Owing to the rising prevalence of obesity, especially at younger ages, a potential decline in life expectancy is expected in the U.S. in the 21st century. Obesity, and mainly its abdominal form, is considered a major risk factor not only for type 2 diabetes, lipid disorders, and hypertension but also for coronary heart disease and certain cancers. In epidemiological studies, BMI, an indicator of relative weight for height (weight in kilograms divided by the square of height in meters) is frequently used as a surrogate for assessment of excess body fat. For characterization of the relative risks (RRs) of mortality and morbidity, the rates in underweight (BMI 40 kg/m2) are compared with those in normal-weight subjects (18.5 to <25 kg/m2). A plot of the RR of mortality against BMI follows a U-shaped, or J-shaped, curve with the minimum mortality close to a BMI of 25 kg/m2. Mortality increases as BMI increases above 25 kg/m2 and as BMI decreases below 25 kg/m2 (1). During the past decade, there is increasing evidence that patients, especially elderly, with several chronic diseases and elevated BMI may demonstrate lower all-cause and cardiovascular mortality compared with patients of normal weight. This article summarizes some of these paradoxical findings known as the “obesity paradox” and discusses potential causes of its manifestation. ### Obesity paradox in overweight and obese patients with coronary heart disease Ten years ago, Gruberg and coworkers observed better outcomes in overweight and obese patients with coronary heart disease undergoing percutaneous coronary intervention compared with their normal-weight counterparts. This unexpected …

Most Youth With Type 1 Diabetes in the T1D Exchange Clinic Registry Do Not Meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes Clinical Guidelines

Abstract: OBJECTIVE To assess the proportion of youth with type 1 diabetes under the care of pediatric endocrinologists in the United States meeting targets for HbA 1c , blood pressure (BP), BMI, and lipids. RESEARCH DESIGN AND METHODS Data were evaluated for 13,316 participants in the T1D Exchange Clinic Registry younger than 20 years old with type 1 diabetes for ≥1 year. RESULTS American Diabetes Association HbA 1c targets of CONCLUSIONS Most children with type 1 diabetes have HbA 1c values above target levels. Achieving American Diabetes Association goals remains a significant challenge for the majority of youth in the T1D Exchange registry.

Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type 2 diabetes.

Abstract: OBJECTIVE To assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs. RESEARCH DESIGN AND METHODS This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Co–primary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA 1c 1c , waist circumference, fasting blood glucose, and lipids. RESULTS In the modified intent-to-treat population (54% female, 80% Caucasian, and mean 54 years old, weight 106 kg, BMI 37 kg/m 2 , and HbA 1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (−5.0 vs. −1.8%; P P 1c reduction (−0.6 vs. −0.1% [6.6 vs. 1.1 mmol/mol]; P 1c P CONCLUSIONS NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.

β-Cell Mass and Turnover in Humans: Effects of obesity and aging

Abstract: OBJECTIVE We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age. RESEARCH DESIGN AND METHODS We examined human autopsy pancreas from 167 nondiabetic individuals 20–102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects. RESULTS β-Cell mass is increased by ∼50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age. CONCLUSIONS β-Cell mass in human obesity increases by ∼50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.

Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial.

Abstract: OBJECTIVE To investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients inadequately controlled on metformin and sulfonylurea (HbA1c ≥7 to ≤10%) were randomized and treated with once-daily empagliflozin 10 mg ( n = 225), empagliflozin 25 mg ( n = 216), or placebo ( n = 225) for 24 weeks. The primary end point was change from baseline in HbA1c at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24. RESULTS At week 24, adjusted mean (SE) changes from baseline in HbA1c were −0.17% (0.05) for placebo vs. −0.82% (0.05) and −0.77% (0.05) for empagliflozin 10 and 25 mg, respectively (both P < 0.001). Empagliflozin significantly reduced MDG, weight, and systolic (but not diastolic) blood pressure versus placebo. Adverse events were reported in 62.7, 67.9, and 64.1% of patients on placebo and empagliflozin 10 and 25 mg, respectively. Events consistent with urinary tract infection were reported in 8.0, 10.3, and 8.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 13.3, 18.0, and 17.5%, respectively; males: 2.7, 2.7, and 0%, respectively). Events consistent with genital infection were reported in 0.9, 2.7, and 2.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 0.9, 4.5, and 3.9%, respectively; males: 0.9% in each group). CONCLUSIONS Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin plus sulfonylurea improved glycemic control, weight, and systolic blood pressure and were well tolerated.

Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease.

Abstract: OBJECTIVE The two major classes of antidiabetic drugs, sulfonylureas and metformin, may differentially affect macrovascular complications and mortality in diabetic patients. We compared the long-term effects of glipizide and metformin on the major cardiovascular events in type 2 diabetic patients who had a history of coronary artery disease (CAD). RESEARCH DESIGN AND METHODS This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age = 63.3 years (range, 36–80 years), were enrolled. Participants were randomly assigned to receive either glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the composite of recurrent cardiovascular events, including death from a cardiovascular cause, death from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization. RESULTS At the end of study drug administration, both groups achieved a significant decrease in the level of glycated hemoglobin (7.1% in the glipizide group and 7.0% in the metformin group). At a median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat analysis showed an adjusted hazard ratio (HR) of 0.54 (95% CI 0.30–0.90; P = 0.026) for the composites of cardiovascular events among the patients that received metformin, compared with glipizide. The secondary end points and adverse events were not significantly different between the two groups. CONCLUSIONS Treatment with metformin for 3 years substantially reduced major cardiovascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a potential benefit of metformin therapy on cardiovascular outcomes in high-risk patients.

Long-Term Complications and Mortality in Young-Onset Diabetes: Type 2 diabetes is more hazardous and lethal than type 1 diabetes

Abstract: OBJECTIVE To evaluate long-term clinical outcomes and survival in young-onset type 2 diabetes (T2DM) compared with type 1 diabetes (T1DM) with a similar age of onset. RESEARCH DESIGN AND METHODS Records from the Royal Prince Alfred Hospital Diabetes Clinical Database, established in 1986, were matched with the Australian National Death Index to establish mortality outcomes for all subjects until June 2011. Clinical and mortality outcomes in 354 patients with T2DM, age of onset between 15 and 30 years (T2DM 15–30 ), were compared with T1DM in several ways but primarily with 470 patients with T1DM with a similar age of onset (T1DM 15–30 ) to minimize the confounding effect of age on outcome. RESULTS For a median observation period of 21.4 (interquartile range 14–30.7) and 23.4 (15.7–32.4) years for the T2DM and T1DM cohorts, respectively, 71 of 824 patients (8.6%) died. A significant mortality excess was noted in T2DM 15–30 (11 vs. 6.8%, P = 0.03), with an increased hazard for death (hazard ratio 2.0 [95% CI 1.2–3.2], P = 0.003). Death for T2DM 15–30 occurred after a significantly shorter disease duration (26.9 [18.1–36.0] vs. 36.5 [24.4–45.4] years, P = 0.01) and at a relatively young age. There were more cardiovascular deaths in T2DM 15–30 (50 vs. 30%, P 15–30 cohort, even soon after diabetes onset. Neuropathy scores and macrovascular complications were also increased in T2DM 15–30 ( P CONCLUSIONS Young-onset T2DM is the more lethal phenotype of diabetes and associated with a greater mortality, more diabetes complications and unfavorable cardiovascular disease risk factors than T1DM.

High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control: The Rotterdam Study

Abstract: OBJECTIVEdIndividuals with type 2 diabetes have increased fracture risk despite higher bonemineraldensity(BMD).Ouraimwastoexaminetheinfluenceofglucosecontrolonskeletal complications. RESEARCH DESIGN AND METHODSdData of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA1c ,7.5%), inadequately controlled diabetes (ICD; n = 217; HbA1c $7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]).

Increased risk of cognitive impairment in patients with diabetes is associated with metformin

Abstract: OBJECTIVE To investigate the associations of metformin, serum vitamin B 12 , calcium supplements, and cognitive impairment in patients with diabetes. RESEARCH DESIGN AND METHODS Participants were recruited from the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, and the Barwon region of southeastern Australia. Patients with Alzheimer disease (AD) ( n = 480) or mild cognitive impairment ( n = 187) and those who were cognitively intact ( n = 687) were included; patients with stroke or with neurodegenerative diseases other than AD were excluded. Subgroup analyses were performed for participants who had either type 2 diabetes ( n = 104) or impaired glucose tolerance ( n = 22). RESULTS Participants with diabetes ( n = 126) had worse cognitive performance than participants who did not have diabetes ( n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B 12 , and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]). CONCLUSIONS Metformin use was associated with impaired cognitive performance. Vitamin B 12 and calcium supplements may alleviate metformin-induced vitamin B 12 deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B 12 and calcium use on cognition in older people with diabetes who are taking metformin.

The Effects of Free-Living Interval-Walking Training on Glycemic Control, Body Composition, and Physical Fitness in Type 2 Diabetic Patients A randomized, controlled trial

Abstract: OBJECTIVE To evaluate the feasibility of free-living walking training in type 2 diabetic patients and to investigate the effects of interval-walking training versus continuous-walking training upon physical fitness, body composition, and glycemic control. RESEARCH DESIGN AND METHODS Subjects with type 2 diabetes were randomized to a control ( n = 8), continuous-walking ( n = 12), or interval-walking group ( n = 12). Training groups were prescribed five sessions per week (60 min/session) and were controlled with an accelerometer and a heart-rate monitor. Continuous walkers performed all training at moderate intensity, whereas interval walkers alternated 3-min repetitions at low and high intensity. Before and after the 4-month intervention, the following variables were measured: VO 2 max, body composition, and glycemic control (fasting glucose, HbA 1c , oral glucose tolerance test, and continuous glucose monitoring [CGM]). RESULTS Training adherence was high (89 ± 4%), and training energy expenditure and mean intensity were comparable. VO 2 max increased 16.1 ± 3.7% in the interval-walking group ( P P P P = 0.05) and maximum ( P CONCLUSIONS Free-living walking training is feasible in type 2 diabetic patients. Continuous walking offsets the deterioration in glycemia seen in the control group, and interval walking is superior to energy expenditure–matched continuous walking for improving physical fitness, body composition, and glycemic control.

Limitations in the Use of Indices Using Glucose and Insulin Levels to Predict Insulin Sensitivity: Impact of Race and Gender and Superiority of the Indices Derived From Oral Glucose Tolerance Test in African Americans

Abstract: OBJECTIVE To examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs). RESEARCH DESIGN AND METHODS Two-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SI is OGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression. RESULTS GDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SI is OGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/ r / = 0.381–0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SI is OGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall. CONCLUSIONS Insulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SI is OGTT are reliable in studies that include AA males.

Type 2 Diabetes: Etiology and reversibility

Abstract: Reversal of type 2 diabetes to normal metabolic control by either bariatric surgery or hypocaloric diet allows for the time sequence of underlying pathophysiologic mechanisms to be observed. In reverse order, the same mechanisms are likely to determine the events leading to the onset of hyperglycemia and permit insight into the etiology of type 2 diabetes. Within 7 days of instituting a substantial negative calorie balance by either dietary intervention or bariatric surgery, fasting plasma glucose levels can normalize. This rapid change relates to a substantial fall in liver fat content and return of normal hepatic insulin sensitivity. Over 8 weeks, first phase and maximal rates of insulin secretion steadily return to normal, and this change is in step with steadily decreasing pancreatic fat content. The difference in time course of these two processes is striking. Recent information on the intracellular effects of excess lipid intermediaries explains the likely biochemical basis, which simplifies both the basic understanding of the condition and the concepts used to determine appropriate management. Recent large, long-duration population studies on time course of plasma glucose and insulin secretion before the diagnosis of diabetes are consistent with this new understanding. Type 2 diabetes has long been regarded as inevitably progressive, requiring increasing numbers of oral hypoglycemic agents and eventually insulin, but it is now certain that the disease process can be halted with restoration of normal carbohydrate and fat metabolism. Type 2 diabetes can be understood as a potentially reversible metabolic state precipitated by the single cause of chronic excess intraorgan fat. Type 2 diabetes has long been known to progress despite glucose-lowering treatment, with 50% of individuals requiring insulin therapy within 10 years (1). This seemingly inexorable deterioration in control has been interpreted to mean that the condition is treatable but not curable. Clinical guidelines recognize …

A Systematic Review and Meta-analysis of the Association Between Depression and Insulin Resistance

Abstract: Objective Depression is associated with the onset of type 2 diabetes. A systematic review and meta-analysis of observational studies, controlled trials, and unpublished data was conducted to examine the association between depression and insulin resistance (IR). Research design and methods Medline, EMBASE, and PsycINFO were searched for studies published up to September 2011. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria (study design and measure of depression and IR, excluding prevalent cases of diabetes). Individual effect sizes were standardized, and a meta-analysis was performed to calculate a pooled effect size using random effects. Subgroup analyses and meta-regression were conducted to explore any potential source of heterogeneity between studies. Results Of 967 abstracts reviewed, 21 studies met the inclusion criteria of which 18 studies had appropriate data for the meta-analysis (n = 25,847). The pooled effect size (95% CI) was 0.19 (0.11-0.27) with marked heterogeneity (I(2) = 82.2%) using the random-effects model. Heterogeneity between studies was not explained by age or sex, but could be partly explained by the methods of depression and IR assessments. Conclusions A small but significant cross-sectional association was observed between depression and IR, despite heterogeneity between studies. The pathophysiology mechanisms and direction of this association need further study using a purposively designed prospective or intervention study in samples at high risk for diabetes.

Diabetes Is an Independent Predictor for Severe Osteoarthritis: Results from a longitudinal cohort study

Abstract: OBJECTIVE To evaluate if type 2 diabetes is an independent risk predictor for severe osteoarthritis (OA). RESEARCH DESIGN AND METHODS Population-based cohort study with an age- and sex-stratified random sample of 927 men and women aged 40–80 years and followed over 20 years (1990–2010). RESULTS Rates of arthroplasty (95% CI) were 17.7 (9.4–30.2) per 1,000 person-years in patients with type 2 diabetes and 5.3 (4.1–6.6) per 1,000 person-years in those without ( P P P = 0.023) after adjustment for age, BMI, and other risk factors for OA. The probability of arthroplasty increased with disease duration of type 2 diabetes and applied to men and women, as well as subgroups according to age and BMI. Our findings were corroborated in cross-sectional evaluation by more severe clinical symptoms of OA and structural joint changes in subjects with type 2 diabetes compared with those without type 2 diabetes. CONCLUSIONS Type 2 diabetes predicts the development of severe OA independent of age and BMI. Our findings strengthen the concept of a strong metabolic component in the pathogenesis of OA.

Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype: Action LADA 7

Abstract: OBJECTIVE Specific autoantibodies characterize type 1 diabetes in childhood but are also found in adult-onset diabetes, even when initially non–insulin requiring, e.g., with latent autoimmune diabetes (LADA). We aimed to characterize adult-onset autoimmune diabetes. RESEARCH DESIGN AND METHODS We consecutively studied 6,156 European diabetic patients attending clinics within 5 years of diagnosis (age range, 30–70 years) examined cross-sectionally clinically and for GAD antibodies (GADA) and antibodies to insulinoma-associated antigen-2 (IA-2A) and zinc-transporter 8 (ZnT8A). RESULTS Of 6,156 patients, 541 (8.8%) had GADA and only 57 (0.9%) IA-2A or ZnT8A alone. More autoantibody-positive than autoantibody-negative patients were younger, leaner, on insulin (49.5 vs. 13.2%), and female ( P 200 World Health Organization IU) ( n = 403) compared with low ( n = 138) titer were female, lean, and insulin treated (54.6 vs. 39.7%) ( P CONCLUSIONS Adult-onset autoimmune diabetes emerges as a prevalent form of autoimmune diabetes. Our results indicate that adult-onset autoimmune diabetes in Europe encompasses type 1 diabetes and LADA in the same broad clinical and autoantibody-positive spectrum. At diagnosis, patients with adult-onset autoimmune diabetes are usually non–insulin requiring and clinically indistinguishable from patients with type 2 diabetes, though they tend to be younger and leaner. Only with screening for autoantibodies, especially GADA, can they be identified with certainty.

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin A 24-week, randomized, placebo-controlled comparison (GetGoal-l)

Abstract: OBJECTIVE To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA 1c ). RESEARCH DESIGN AND METHODS A double-blind, parallel-group, placebo-controlled trial. Patients ( n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA 1c reduction from baseline was the primary end point. RESULTS Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA 1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA 1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA 1c at end point was 7.8%. HbA 1c P P P P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo. CONCLUSIONS By improving HbA 1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.

The Relative Contribution of Prepregnancy Overweight and Obesity, Gestational Weight Gain, and IADPSG-Defined Gestational Diabetes Mellitus to Fetal Overgrowth

Abstract: OBJECTIVE The International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for diagnosis of gestational diabetes mellitus (GDM) identifies women and infants at risk for adverse outcomes, which are also strongly associated with maternal overweight, obesity, and excess gestational weight gain. RESEARCH DESIGN AND METHODS We conducted a retrospective study of 9,835 women who delivered at ≥20 weeks’ gestation; had a prenatal, 2-h, 75-g oral glucose tolerance test; and were not treated with diet, exercise, or antidiabetic medications during pregnancy. Women were classified as having GDM based on IADPSG criteria and were categorized into six mutually exclusive prepregnancy BMI/GDM groups: normal weight ± GDM, overweight ± GDM, and obese ± GDM. RESULTS Overall, 5,851 (59.5%) women were overweight or obese and 1,892 (19.2%) had GDM. Of those with GDM, 1,443 (76.3%) were overweight or obese. The prevalence of large-for-gestational-age (LGA) infants was significantly higher for overweight and obese women without GDM compared with their normal-weight counterparts. Among women without GDM, 21.6% of LGA infants were attributable to maternal overweight and obesity, and the combination of being overweight or obese and having GDM accounted for 23.3% of LGA infants. Increasing gestational weight gain was associated with a higher prevalence of LGA in all groups. CONCLUSIONS Prepregnancy overweight and obesity account for a high proportion of LGA, even in the absence of GDM. Interventions that focus on maternal overweight/obesity and gestational weight gain, regardless of GDM status, have the potential to reach far more women at risk for having an LGA infant.

Relationships Between Gastric Emptying, Postprandial Glycemia, and Incretin Hormones

Abstract: The importance of achieving tight glycemic control, usually assessed by glycated hemoglobin (HbA1c), for both the prevention and delay in the progression of diabetes-related microvascular complications, is established, and the American Diabetes Association/European Association for the Study of Diabetes joint committee has recommended an HbA1c <7% as the goal in patients with type 2 diabetes (1). The relative contributions of pre- and postprandial glycemia to HbA1c have been clarified during the last decade following the seminal report by Monnier et al. (2) indicating that in type 2 diabetes, postprandial glycemic excursions account for about 70% of variability when HbA1c is <7.3%, while the contribution of “fasting” glycemia is greater in less well-controlled patients. Subsequent studies have confirmed the predominance of postprandial glycemia in determining overall glycemic control in “well-controlled” type 2 diabetic patients managed by oral hypoglycemic agents or basal insulin (3). The importance of postprandial glycemia to overall glycemic control is not surprising considering that 1 ) humans in modern societies spend only about 3 or 4 h before breakfast in a truly fasting state because in health, gastric emptying of meals occurs at an overall rate of 1–4 kcal/min (4), and 2 ) postprandial hyperglycemia occurs frequently in diabetes (1). The relevance of postprandial glycemia is further increased by the recognition that it may represent an independent risk factor for adverse cardiovascular outcomes in both diabetic and nondiabetic populations (5). The determinants of postprandial glycemia include preprandial glycemic levels, meal composition, gastric emptying, insulin secretion, small intestinal glucose absorption, and hepatic and peripheral glucose metabolism. Furthermore, the relative contribution of each of these factors may vary over time during the postprandial state. Nevertheless, both the rate of gastric emptying and the secretion and action of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide …