Scott J. Jacober

Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes: The HEART2D trial

OBJECTIVE—Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) is a multinational, randomized, controlled trial designed to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS—Patients (type 2 diabetes, aged 30–75 years) were randomly assigned within 21 days after AMI to the 1) prandial strategy (PRANDIAL) (three premeal doses of insulin lispro targeting 2-h postprandial blood glucose <7.5 mmol/l) or the 2) basal strategy (BASAL) (NPH twice daily or insulin glargine once daily targeting fasting/premeal blood glucose <6.7 mmol/l). RESULTS—A total of 1,115 patients were randomly assigned (PRANDIAL n = 557; BASAL n = 558), and the mean patient participation after randomization was 963 days (range 1–1,687 days). The trial was stopped for lack of efficacy. Risks of first combined adjudicated primary cardiovascular events in the PRANDIAL (n = 174, 31.2%) and BASAL (n = 181, 32.4%) groups were similar (hazard ratio 0.98 [95% CI 0.8–1.21]). Mean A1C did not differ between the PRANDIAL and BASAL groups (7.7 ± 0.1 vs. 7.8 ± 0.1%; P = 0.4) during the study. The PRANDIAL group showed a lower daily mean postprandial blood glucose (7.8 vs. 8.6 mmol/l; P < 0.01) and 2-h postprandial blood glucose excursion (0.1 vs. 1.3 mmol/l; P < 0.001) versus the BASAL group. The BASAL group showed lower mean fasting blood glucose (7.0 vs. 8.1 mmol/l; P < 0.001) and similar daily fasting/premeal blood glucose (7.7 vs. 7.3 mmol/l; P = 0.233) versus the PRANDIAL group. CONCLUSIONS—Treating diabetic survivors of AMI with prandial versus basal strategies achieved differences in fasting blood glucose, less-than-expected differences in postprandial blood glucose, similar levels of A1C, and no difference in risk for future cardiovascular event rates.

Prevalence and risk factors for vaginal Candida colonization in women with type 1 and type 2 diabetes

BackgroundDiabetes mellitus increases the rate of vaginal colonization and infection with Candida speciesMethodsWe surveyed women with diabetes receiving care at either an urban or suburban diabetes clinic to examine the relationship between vaginal Candida colonization, diabetes type and duration, and HbA1c level. 101 participants completed the self-administered questionnaire and self-collected a vaginal swab for Candida culture. Candida colonization was similar by age and race.ResultsType 1 diabetics were three times as likely as type 2 diabetics to be colonized with any Candida species (OR = 3.4; 95% CI: 1.03, 11.41; p = 0.04); even after adjusting for abnormal HbA1c, which had an independent effect (OR = 1.4; 95% CI: 1.04, 1.76; p = 0.02). Recent antibiotic use (OR = 4.5; 95% CI: 1.18, 16.79; p = 0.03), lifetime history of chlamydia (OR = 5.8; 95% CI: 1.09, 30.54; p = 0.04), and performing oral sex during the past 2 weeks (OR = 4.9; 95% CI:0.84, 28.27; p = 0.08) were also associated with Candida carriage after adjusting for diabetic type and abnormal HbA1c. C. albicans was isolated from the majority of colonized type 1 participants (56%), while C. glabrata was the most common isolate among colonized type 2 participants (54%).ConclusionsImproving glucose control and possibly modifying sexual behavior may reduce risk of Candida colonization, and potentially symptomatic infection, among women with diabetes.

Diabetes and Pregnancy: Factors associated with seeking pre-conception care

OBJECTIVE To define sociodemographic characteristics, medical factors, knowledge, attitudes, and health-related behaviors that distinguish women with established diabetes who seek pre-conception care from those who seek care only after conception. RESEARCH DESIGN AND METHODS A multicenter, case-control study of women with established diabetes making their first pre-conception visit (n = 57) or first prenatal visit without having received pre-conception care (n = 97). RESULTS Pre-conception subjects were significantly more likely to be married (93 vs. 51%), living with their partners (93 vs. 60%), and employed (78 vs. 41%); to have higher levels of education (73% beyond high school vs. 41%) and income (86% >

A Randomized, Controlled Study of Once-Daily LY2605541, a Novel Long-Acting Basal Insulin, Versus Insulin Glargine in Basal Insulin–Treated Patients With Type 2 Diabetes

20,000 vs. 60%); and to have insulin-dependent diabetes mellims (IDDM) (93 vs. 81%). Pre-conception subjects with IDDM were more likely to have discussed preconception care with their health care providers (98 vs. 51%) and to have been encouraged to get it (77 vs. 43%). In the prenatal group, only 24% of pregnancies were planned. Pre-conception patients were more knowledgeable about diabetes, perceived greater benefits of pre-conception care, and received more instrumental support. CONCLUSIONS Only about one-third of women with established diabetes receive pre-conception care. Interventions must address prevention of unintended pregnancy. Providers must regard every visit with a diabetic woman as a pre-conception visit. Contraception must be explicitly discussed, and pregnancies should be planned. In counseling, the benefits of pre-conception care should be stressed and the support of families and friends should be elicited.

Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes: A randomized, crossover study

OBJECTIVE To evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL). RESEARCH DESIGN AND METHODS This 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A1c [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning. RESULTS At 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (−0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: −0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001). CONCLUSIONS In patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.

A decrease in glucose variability does not reduce cardiovascular event rates in type 2 diabetic patients after acute myocardial infarction: a reanalysis of the HEART2D study

OBJECTIVE To compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL. RESULTS LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02). CONCLUSIONS In type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses.

Novel PEGylated Basal Insulin LY2605541 Has a Preferential Hepatic Effect on Glucose Metabolism

OBJECTIVE To assess the effect of intraday glucose variability (GV) on cardiovascular outcomes in a reanalysis of Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) study data. RESEARCH DESIGN AND METHODS Type 2 diabetic patients after acute myocardial infarction were randomized to an insulin treatment strategy targeting postprandial (PRANDIAL; n = 557) or fasting/interprandial (BASAL; n = 558) hyperglycemia. GV was calculated as mean amplitude of glycemic excursions (MAGE), mean absolute glucose (MAG) change, and SD. RESULTS The PRANDIAL strategy resulted in an 18% lower MAG than BASAL (mean [SEM] difference 0.09 [0.04] mmol/L/h, P = 0.02). In addition, MAGE and SD were lower in the PRANDIAL group, however, not significantly. HbA1c levels and cardiovascular event rates were comparable between groups. CONCLUSIONS A PRANDIAL strategy demonstrated lower intraday GV vs. a BASAL strategy with similar overall glycemic control but did not result in a reduction in cardiovascular outcomes. This does not support the hypothesis that targeting GV would be beneficial in reducing subsequent secondary cardiovascular events.

The Reliability of the Diabetes Care Profile for African Americans

The impact of the novel basal insulin LY2605541 (LY) on hepatic and nonhepatic glucose uptake (non-HGU) was evaluated. Conscious dogs underwent euglycemic clamps with tracer and hepatic balance measurements. Clamp period infusions were peripheral venous regular insulin (0.1 nmol ⋅ kg−1 ⋅ h−1 [control], n = 6) or LY (bolus [nmol/kg], continuous [nmol ⋅ kg−1 ⋅ h−1]: 0.5, 0.5 [n = 6]; 0.375, 0.375 [n = 5]; 0.25, 0.25 [n = 4]), somatostatin, and glucose, as well as intraportal glucagon (basal). During the clamp, the dogs switched from net hepatic glucose output to uptake (rates reached 2.1 ± 1.2, 0.9 ± 2.1, 8.6 ± 2.3, and 6.0 ± 1.1 µmol ⋅ kg−1 ⋅ min−1 within 5 h in control, LY0.25, LY0.375, and LY0.5, respectively). Non-HGU in LY increased less than in control; the ratio of change from basal in non-HGU to change in net hepatic glucose balance, calculated when glucose infusion rates (GIRs) were ~20 µmol ⋅ kg-1 ⋅ min−1 in all groups, was higher in control (1.17 ± 0.38) versus LY0.25 (0.39 ± 0.33), LY0.375 (−0.01 ± 0.13), and LY0.5 (−0.09 ± 0.07). Likewise, the change from baseline in glucose Rd-to-Ra ratio was greatest in control (1.4 ± 0.3 vs. 0.6 ± 0.4, 0.5 ± 0.2, and 0.6 ± 0.2 in LY0.25, LY0.375, and LY0.5, respectively). In contrast to exogenously administered human insulin, LY demonstrated preferential hepatic effects, similar to endogenously secreted insulin. Therefore, the analog might reduce complications associated with current insulin therapy.

Rate of Hypoglycemia in Insulin-Treated Patients with Type 2 Diabetes Can Be Predicted from Glycemic Variability Data

The Diabetes Care Profile (DCP) is an instrument used to assess social and psychological factors related to diabetes and its treatment. The reliability of the DCP was established in populations consisting primarily of Caucasians with type 2 diabetes. This study tests whether the DCP is a reliable instrument for African Americans with type 2 diabetes. Both African American (n = 511) and Caucasian (n = 235) patients with type 2 diabetes were recruited at six sites located in the metropolitan Detroit area. Scale reliability was calculated by Cronbachs coefficient alpha. The scale reliabilities ranged from .70 to .97 for African Americans. These reliabilities were similar to those of Caucasians, whose scale reliabilities rangedfrom .68 to .96. The Feldt test was used to determine differences between the reliabilities of the two patient populations. No significant differences were found. The DCP is a reliable survey instrument for African American and Caucasion patients with type 2 diabetes.

Post Hoc Subgroup Analysis of the HEART2D Trial Demonstrates Lower Cardiovascular Risk in Older Patients Targeting Postprandial Versus Fasting/Premeal Glycemia

BACKGROUND We set out to study the relationship between different measures of glycemic variability and the rate of hypoglycemia in patients with type 2 diabetes. SUBJECTS AND METHODS Data were pooled from three 24-week insulin trials including patients on twice-daily (BID) insulin lispro mix 75/25 (75% insulin lispro protamine suspension, 25% insulin lispro) (n=805), daily (QD) insulin glargine (n=1,019), insulin lispro protamine suspension (n=353) (QD or BID), and insulin detemir (n=166) (QD or BID), all with continuation of prestudy oral antihyperglycemic medications. Glycemic variability measures were derived from seven-point self-monitored blood glucose profiles. RESULTS At baseline, mean (±SD) age was 56.9±9.7 years, duration of type 2 diabetes was 9.5±6.1 years, hemoglobin A1c (HbA1c) was 8.9±1.1%, and 51.9% were male. Intra-day glucose coefficient of variation (CV), fasting blood glucose, intra-day minimum glucose and inter-day glucose CV at 24 weeks, and intra-day glucose CV at baseline were significantly correlated with the rate of hypoglycemia events between Weeks 12 to 24 (P<0.05 for all measures). CONCLUSIONS Intra-day and inter-day glycemic variability is significantly associated with the risk of hypoglycemia in insulin-treated patients with type 2 diabetes, even after adjusting for mean glucose and HbA1c. The intra-day glycemic variability before starting insulin is significantly associated with the risk of hypoglycemia during insulin treatment, which points at treatment- and patient-related factors mediating this relationship.