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Objective: High cereal fiber and low-glycemic index (GI) diets are associated with reduced cardiovascular disease (CVD) risk in cohort studies. Clinical trial evidence on event incidence is lacking. Therefore, to make trial outcomes more directly relevant to CVD, we compared the effect on carotid plaque development in diabetes of a low-GI diet versus a whole-grain wheat-fiber diet.Research Design and Methods: The study randomized 169 men and women with well-controlled type 2 diabetes to counseling on a low GI-diet or whole-grain wheat-fiber diet for 3 years. Change in carotid vessel wall volume (VWV) (prespecified primary end point) was assessed by MRI as an indication of arterial damage.Results: Of 169 randomized participants, 134 completed the study. No treatment differences were seen in VWV. However, on the whole-grain wheat-fiber diet, VWV increased significantly from baseline, 23 mm3 (95% CI 4, 41; P = 0.016), but not on the low-GI diet, 8 mm3 (95% CI -10, 26; P = 0.381). The low-GI diet resulted in preservation of renal function, as estimated glomerular filtration rate, compared with the reduction following the wheat-fiber diet. HbA1c was modestly reduced over the first 9 months in the intention-to-treat analysis and extended with greater compliance to 15 months in the per-protocol analysis.Conclusions: Since the low-GI diet was similar to the whole-grain wheat-fiber diet recommended for cardiovascular risk reduction, the low-GI diet may also be effective for CVD risk reduction. [ABSTRACT FROM AUTHOR]

Objective: Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD.Research Design and Methods: We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial.Results: Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29-3.29]). Similar phenotypes and outcomes were identified in EXSCEL.Conclusions: In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) increases fracture risk despite normal or increased BMD. Abaloparatide reduces fracture risk in patients with postmenopausal osteoporosis (PMO); however, its efficacy in women with T2DM is unknown. This post hoc analysis evaluated the efficacy and safety of abaloparatide in patients with T2DM. The analysis included patients with T2DM from the Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE), a phase 3, double‐blind, randomized, placebo‐ and active‐controlled trial. In ACTIVE, participants were randomized 1:1:1 to daily s.c. injections of placebo, abaloparatide (80 μg), or open‐label teriparatide (20 μg) for 18 months. A total of 198 women with PMO and T2DM from 21 centers in 10 countries were identified from ACTIVE through review of their medical records. The main outcomes measured included effect of abaloparatide versus placebo on BMD and trabecular bone score (TBS), with secondary outcomes of fracture risk and safety, in patients from ACTIVE with T2DM. Significant (p < 0.001) improvements in BMD at total hip (mean change 3.0% versus −0.4%), femoral neck (2.6% versus −0.2%), and lumbar spine (8.9% versus 1.3%) and TBS at lumbar spine (3.72% versus −0.56%) were observed with abaloparatide versus placebo at 18 months. Fracture events were fewer with abaloparatide treatment in patients with T2DM, and differences were not significant between groups except nonvertebral fractures in the abaloparatide versus placebo groups (p = 0.04). Safety was consistent with the ACTIVE population. In conclusion, in women with PMO and T2DM, abaloparatide treatment resulted in significant improvements in BMD and TBS versus placebo, consistent with the overall ACTIVE population © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective: We aimed to explore whether frailty was associated with fracture risk and whether frailty could modify the propensity of type 2 diabetes toward increased risk of fractures.Research Design and Methods: Data were from a prospective cohort study. Our primary outcome was time to the first incident clinical fragility fracture; secondary outcomes included time to hip fracture and to clinical spine fracture. Frailty status was measured by a Frailty Index (FI) of deficit accumulation. The Cox model incorporating an interaction term (frailty × diabetes) was used for analyses.Results: The analysis included 3,149 (70% women) participants; 138 (60% women) had diabetes. Higher bone mineral density and FI were observed in participants with diabetes compared with control subjects. A significant relationship between the FI and the risk of incident fragility fractures was found, with a hazard ratio (HR) of 1.02 (95% CI 1.01-1.03) and 1.19 (95% CI 1.10-1.33) for per-0.01 and per-0.10 FI increase, respectively. The interaction was also statistically significant (P = 0.018). The HR for per-0.1 increase in the FI was 1.33 for participants with diabetes and 1.19 for those without diabetes if combining the estimate for the FI itself with the estimate from the interaction term. No evidence of interaction between frailty and diabetes was found for risk of hip and clinical spine fractures.Conclusions: Participants with type 2 diabetes were significantly frailer than individuals without diabetes. Frailty increases the risk of fragility fracture and enhances the effect of diabetes on fragility fractures. Particular attention should be paid to diabetes as a risk factor for fragility fractures in those who are frail. [ABSTRACT FROM AUTHOR]

Objective: Limited data exist regarding safety and efficacy of antihyperglycemic drugs in older patients with type 2 diabetes. The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) was a randomized, double-blind, placebo-controlled trial assessing the impact of sitagliptin on a primary composite outcome of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or unstable angina hospitalizations in patients with type 2 diabetes (HbA1c ≥6.5% [48 mmol/mol] and ≤8.0% [64 mmol/mol]) and cardiovascular disease. We analyzed baseline characteristics and clinical outcomes for TECOS participants aged ≥75 years.Research Design and Methods: Clinical and safety event summaries are presented for older versus younger participants and for the treatment groups within the older cohort.Results: Of 14,351 participants with age recorded, 2,004 (14%) were ≥75 years old (mean age 78.3 years [SD 3.1]), with 68% men and type 2 diabetes duration median 12.0 years (IQR 7, 21). During 2.9 years median follow-up, older participants had higher rates of the primary outcome (6.46 vs. 3.67 events per 100 person-years; hazard ratio 1.72 [95% CI 1.52-1.94]), death (2.52 [2.20-2.89]), severe hypoglycemia (1.53 [1.15-2.03]), and fractures (1.84 [1.44-2.35]). In the older cohort, sitagliptin did not significantly impact the primary composite (1.10 [0.89-1.36]), death (1.05 [0.83-1.32]), heart failure hospitalization (0.99 [0.65-1.49]), severe hypoglycemia (1.03 [0.62-1.71]), rates of acute pancreatitis and pancreatic cancer, or serious adverse events.Conclusions: Among older patients with well-controlled type 2 diabetes and cardiovascular disease, sitagliptin had neutral effects on cardiovascular risk and raised no significant safety concerns. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a complex chronic disease with a prevalence that is increasing at an alarming rate worldwide. Although treatment of diabetes to avoid complications is essential, prevention of this disease would provide even greater benefit for the individual and for society. Intestinal absorption inhibitors, such as α-glucosidase inhibitors and lipase inhibitors, play a relatively minor role in the treatment of type 2 diabetes mellitus. However, recent studies have demonstrated that absorption inhibitors have a role in the prevention of type 2 diabetes in high-risk populations. [Copyright &y& Elsevier]

Summary Background: The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. Methods: In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. Findings: We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea. Interpretation: Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the long-term efficacy of acarbose, an alpha-glucosidase inhibitor, in improving glycemic control in patients with non-insulin-dependent diabetes mellitus.Design: A 1-year, multicenter, randomized, double-blind, placebo-controlled study.Setting: Seven university-affiliated, community-based, tertiary care diabetes clinics.Patients: 354 patients with non-insulin-dependent diabetes mellitus were recruited; 77 were being treated with diet alone, 83 with diet and metformin, 103 with diet and sulfonylurea, and 91 with diet and insulin. Patients in each treatment group were randomly assigned to either acarbose or placebo for 1 year. Eighty-seven percent of patients receiving acarbose and 92% of those receiving placebo were included in the efficacy analysis (n = 316).Measurements: At baseline and at 3-month intervals, levels of hemoglobin A1c (HbA1c), fasting and postprandial plasma glucose, fasting and postprandial serum C-peptide, and fasting serum lipids were measured.Results: Compared with placebo, acarbose treatment caused a significant decrease in the mean postprandial plasma glucose peak (90 minutes) in all four groups (19.0 +/- 0.4 mmol/L to 15.5 +/- 0.4 mmol/L; P < 0.001). Analysis of the postprandial plasma glucose incremental area under the curve showed that the change from baseline to the end of the treatment period differed for placebo and acarbose recipients by 4.73 mmol.h/L in the diet alone group (P < 0.001), 2.06 mmol.h/L in the metformin group (P = 0.01), 2.65 mmol.h/L in the sulfonylurea group (P < 0.001), and 3.13 mmol.h/L in the insulin group (P = 0.001). Corresponding decreases in HbA1c levels occurred; these were 0.9% in the diet alone group (P = 0.005), 0.8% in the metformin group (P = 0.011), 0.9% in the sulfonylurea group (P = 0.002), and 0.4% in the insulin group (P = 0.077). Acarbose did not significantly affect mean serum C-peptide or mean serum lipid levels.Conclusions: Acarbose improved long-term glycemic control in patients with non-insulin-dependent diabetes mellitus regardless of concomitant antidiabetic medication. [ABSTRACT FROM AUTHOR]

The acute effect of increasing meal frequency as a model of slow absorption was studied for 1 d in 11 patients with non-insulin-dependent diabetes. On 1 d they took 13 snacks (the nibbling diet) and on another day the same diet was taken as three meals and one snack (the three-meal diet). The nibbling diet reduced mean blood glucose, serum insulin, and C peptide concentrations over the 9.5 h of observation and 24-h urinary C peptide output by 12.7 ± 3.7% (¯ ± SE) (P = 0.0062), 20.1 ± 5.8% (P = 0.0108), 9.2 ± 2.6% (P = 0.0073), and 20.37 ± 8. 12% (P = 0.039), respectively, compared with the three-meal diet. Serum triglyceride concentrations were lower by 8.5 ± 3.2% (P = 0.037). Despite lower insulin concentrations on the nibbling diet, the concentrations of free fatty acids, 3-hydroxybutyrate, and the insulin-sensitive branched-chain amino acids responded similarly on both treatments. Metabolic benefits seen with increased meal frequency may explain the success of similar agents that prolong absorption, including fiber and enzyme inhibitors. [ABSTRACT FROM AUTHOR]

Recent studies suggest the glycemic response of different mixed meals cannot be predicted from the glycemic index (GI) of individual carbohydrate foods. Postprandial glucose levels following five different mixed meals in six noninsulin-dependent diabetic volunteers were therefore assessed. Each meal comprised 50% carbohydrate, 30% fat, and 20% protein, varying only in type of carbohydrate. The carbohydrate exchanged in each meal (potato, white bread, rice, spaghetti, or lentils and barley) contributed 37% of total meal calories. The correlation between predicted glucose response and postprandial glucose area was highly significant; estimated meal GI was virtually proportional to the actual mean glycemic response. These results demonstrate that the relative glycemic effects of mixed meals can be predicted from the GI of their carbohydrate components, again stressing the importance of type of carbohydrate in regulating postprandial blood-glucose levels. [ABSTRACT FROM AUTHOR]

Objectives: For patients with type 2 diabetes, newer antihyperglycaemic agents (AHA), including the dipeptidyl peptidase IV inhibitors (DPP4i), glucagon‐like peptide‐1 receptor agonists (GLP1RA) and sodium glucose co‐transporter 2 inhibitors (SGLT2i) offer a lower risk of hypoglycaemia relative to sulfonylurea or insulin. However, it is not clear how AHA compare to placebo on risk of any hypoglycaemia. This study evaluates the risk of any and severe hypoglycaemia with AHA and metformin relative to placebo. Design: A systematic review and meta‐analysis was conducted of randomized, placebo‐controlled trials ≥12 weeks in duration. MEDLINE, Embase and the Cochrane Library were searched up to April 16, 2019. Studies allowing use of other diabetes medications were excluded. Mantel‐Haenszel risk ratio with 95% confidence intervals were used to pool estimates based on class of AHA and number of concomitant therapies used. Patients: Eligible studies enrolled patients with type 2 diabetes ≥18 years of age. Results: 144 studies met our inclusion criteria. Any hypoglycaemia was not increased with AHA when used as monotherapy (DPP4i (RR 1.12; 95% CI 0.81‐1.56), GLP1RA (1.77; 0.91‐3.46), SGLT2i (1.34; 0.83‐2.15)), or as add‐on to metformin (DPP4i (0.95; 0.67‐1.35), GLP1RA (1.24; 0.80‐1.91), SGLT2i (1.29; 0.91‐1.83)) or as triple therapy (1.13; 0.67‐1.91). However, metformin monotherapy (1.73; 1.02‐2.94) and dual therapy initiation (3.56; 1.79‐7.10) was associated with an increased risk of any hypoglycaemia. Severe hypoglycaemia was rare not increased for any comparisons. Conclusions: Metformin and the simultaneous initiation of dual therapy, but not AHA used alone or as single add‐on combination therapy, was associated with an increased risk of any hypoglycaemia relative to placebo. [ABSTRACT FROM AUTHOR]

Summary: Aims: TECOS was a randomized, double‐blind, placebo‐controlled trial assessing the impact of sitagliptin vs. placebo on cardiovascular outcomes when added to usual care in patients with type 2 diabetes. We report the use of concomitant diabetes medications and the risk for progression to insulin during follow‐up. Materials and Methods: TECOS enrolled 14 671 participants with HbA1c 6.5%‐8.0% on monotherapy with metformin, pioglitazone, sulfonylurea (SU), or dual therapy with two oral agents or insulin with or without metformin. Subsequent diabetes management was by the participant's usual care physician. Time to initiation of insulin and risk of hypoglycaemia were estimated using Cox proportional hazards models. Results: The most common glucose‐lowering regimens at baseline were metformin monotherapy (30.2%), SU monotherapy (8.5%), metformin/SU therapy (35.1%), and insulin with or without metformin (13.9% and 8.6%, respectively). Over a median 3.0 years' follow‐up, diabetes therapy was intensified in 25.2% of participants (sitagliptin 22.0%, placebo 28.3%). Medications most commonly added were SU (8.3%) or insulin (8.8%). Insulin initiation in the usual care setting occurred at mean (standard deviation) HbA1c of 8.5 (1.5)%. Sitagliptin did not impact rates of severe hypoglycaemia, but delayed progression to insulin when added to metformin or metformin/SU regimens. Conclusion: Consistent with the trial's pragmatic design, TECOS participants underwent typical progression of diabetes medications. Sitagliptin was associated with lower HbA1c, without increased risk for severe hypoglycaemia and was associated with delayed progression to insulin when added to metformin with or without SU. The TECOS study assessed the impact of sitagliptin compared to placebo on cardiovascular outcomes in 14 671 participants with type 2 diabetes over a median duration of 3 years. During the study, diabetes therapy was intensified in 25.2% of participants, most commonly by the addition of a sulfonylurea or insulin. A delay in the progression to insulin was observed in sitagliptin‐treated participants who entered the study on metformin or metformin/sulfonylurea treatment [ABSTRACT FROM AUTHOR]

Background: Intensive risk factor modification significantly improves outcomes for patients with diabetes mellitus and cardiovascular disease. However, the degree to which secondary prevention treatment goals are achieved in international clinical practice is unknown.Methods: Attainment of 5 secondary prevention parameters-aspirin use, lipid control (low-density lipoprotein cholesterol <70 mg/dL or statin therapy), blood pressure control (<140 mm Hg systolic, <90 mm Hg diastolic), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and nonsmoking status-was evaluated among 13 616 patients from 38 countries with diabetes mellitus and known cardiovascular disease at entry into TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin). Logistic regression was used to evaluate the association between individual and regional factors and secondary prevention achievement at baseline. Cox proportional hazards regression analysis was used to determine the association between baseline secondary prevention achievement and cardiovascular death, myocardial infarction, or stroke.Results: Overall, 29.9% of patients with diabetes mellitus and cardiovascular disease achieved all 5 secondary prevention parameters at baseline, although 71.8% achieved at least 4 parameters. North America had the highest proportion (41.2%), whereas Western Europe, Eastern Europe, and Latin America had proportions of ≈25%. Individually, blood pressure control (57.9%) had the lowest overall attainment, whereas nonsmoking status had the highest (89%). Over a median 3.0 years of follow-up, a higher baseline secondary prevention score was associated with improved outcomes in a step-wise graded relationship (adjusted hazard ratio, 0.60; 95% confidence interval, 0.47-0.77 for those patients achieving all 5 measures versus those achieving ≤2).Conclusions: In an international trial population, significant opportunities exist to improve the quality of cardiovascular secondary prevention care among patients with diabetes mellitus and cardiovascular disease, which in turn could lead to reduced risk of downstream cardiovascular events.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00790205. [ABSTRACT FROM AUTHOR]

We hypothesized that diet would have direct effects on glucose metabolism with direct and indirect effects on bone metabolism in a cohort of Canadian adults. We assessed dietary patterns (Prudent [fruit, vegetables, whole grains, fish, and legumes] and Western [soft drinks, potato chips, French fries, meats, and desserts]) from a semiquantitative food frequency questionnaire. We used fasting blood samples to measure glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), 25-hydroxyvitamin D (25OHD), parathyroid hormone, bone-specific alkaline phosphatase (a bone formation marker), and serum C-terminal telopeptide (CTX; a bone resorption marker). We used multivariate regression models adjusted for confounders and including/excluding body mass index. In a secondary analysis, we examined relationships through structural equations models. The Prudent diet was associated with favorable effects on glucose metabolism (lower insulin and HOMA-IR) and bone metabolism (lower CTX in women; higher 25OHD and lower parathyroid hormone in men). The Western diet was associated with deleterious effects on glucose metabolism (higher glucose, insulin, and HOMA-IR) and bone metabolism (higher bone-specific alkaline phosphatase and lower 25OHD in women; higher CTX in men). Body mass index adjustment moved point estimates toward the null, indicating partial mediation. The structural equation model confirmed the hypothesized linkage with strong effects of Prudent and Western diet on metabolic risk, and both direct and indirect effects of a Prudent diet on bone turnover. In summary, a Prudent diet was associated with lower metabolic risk with both primary and mediated effects on bone turnover, suggesting that it is a potential target for reducing fracture risk. [ABSTRACT FROM AUTHOR]