Results from the Risk and Prevention Study showed no effect of omega-3. Findings from ORIGIN-GRACE showed no statistically

Transcription

1 VOLUME 14, ISSUE 2 JULY 2013 MELANIE VISALLI, MANAGING EDITOR AND WRITER No Difference in Annualized CIMT Change in ORIGIN-GRACE Findings from ORIGIN-GRACE showed no statistically signifi cant difference in annualized change in maximum carotid intima-media thickness (CIMT) for 12 carotid artery segments, the study s primary outcome, with insulin glargine or omega-3 fatty acid treatment. ORIGIN-GRACE examined the effects of insulin glargine and omega-3 fatty acids on CIMT in patients with dysglycemia and additional risk factors for atherosclerosis progression. Primary outcome There was a statistically nonsignifi cant 11% reduction in the slope of CIMT progression in the glargine arm: Insulin glargine: ± mm/year vs standard care, ± mm/year (P=0.145) Omega-3 fatty acid: ± mm/year vs placebo, ± mm/year (P=0.650) Maximum CIMT for four common coronary artery segments: Statistically signifi cant 20% reduction in slope of CIMT progression in the glargine arm Insulin glargine: ± mm/year vs standard care, ± mm/year (P=0.049) Omega-3 fatty acid: ± mm/year vs placebo, ± mm/year (P=0.812) Maximum CIMT for eight common carotid and bifurcation segments: Statistically signifi cant 18% reduction in slope of CIMT progression in the glargine arm Insulin glargine: ± mm/year vs standard care, ± mm/year (P=0.032) Omega-3 fatty acid: ± mm/year vs placebo, ± mm/year (P=0.288) No statistically signifi cant differences in annualized change in maximum far-wall CIMT were seen in either treatment arm, although a 15% reduction in the slope of CIMT progression was seen in the glargine arm. No differences were seen in major cardiovascular (CV) events between groups. About ORIGIN-GRACE ORIGIN-GRACE was a substudy of ORIGIN. ORIGIN was a randomized, double-blind trial of 12,537 patients at high risk for CV events and who had impaired fasting glucose, impaired glucose tolerance, or newly diagnosed diabetes. Subjects in ORIGIN-GRACE were randomized in a 2x2 factorial design to open-label insulin glargine (targeting fasting glucose 95 mg/dl) or standard glycemic care or double-blind omega-3 fatty acid (1-g capsule) or placebo. Secondary outcomes Statistically signifi cant changes in maximum CIMT were seen for the glargine arm only. ORIGIN=Outcome Reduction with an Initial Glargine Intervention GRACE=Glucose Reduction and Atherosclerosis Continuing Evaluation Lonn EM, Bosch J, Diaz R, et al; for the GRACE and ORIGIN Investigators. Effect of insulin glargine and n-3fa on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the Glucose Reduction and Atherosclerosis Continuing Evaluation Study (ORIGIN- GRACE). Diabetes Care Epub ahead of print. No Effect of Omega-3 Fatty Acids on CV Events in Risk and Prevention Study Results from the Risk and Prevention Study showed no effect of omega-3 fatty acids on cardiovascular (CV) events and mortality among subjects at high CV risk. Primary endpoint A null result was seen for the primary endpoint, a composite of time to death from CV causes or hospital admission for CV causes, over 5 years of follow-up (median): the primary endpoint occurred among 11.7% of subjects in the omega-3 fatty acid group vs 11.9% in the placebo group (adjusted hazard ratio [HR], 0.97; 95% confidence interval [CI], ; P=0.58). Continued on pg 4 Copyright 2013 KnowledgePoint360 Group, LLC. All rights reserved. Clinical Insights is a registered trademark, and KnowledgePoint360 is a trademark, of. 1

2 Volume 14, Issue 2 July 2013 Learning Objectives Review fi ndings from a study examining the effects of insulin glargine and omega-3 fatty acids on carotid intima-media thickness Review data from a study examining the effect of omega-3 fatty acids on cardiovascular events Summarize data from studies exploring the safety and effi cacy of canaglifl ozin Discuss fi ndings from a post-hoc analysis exploring the relationship between intensive glycemic therapy and weight gain Describe fi ndings from a study comparing glycemic control with a single dose of daily basal insulin plus corrective glulisine and a basal bolus regimen Discuss fi ndings from a study exploring the diurnal pattern to insulin action in type 1 diabetes Target Audience This newsletter is designed for primary care physicians, internal medicine specialists, endocrinologists, diabetologists, cardiologists, and other healthcare professionals involved in the care and management of patients with diabetes and its complications and comorbidities. Sponsor Clinical Insights in Diabetes is a component of the National Diabetes Education Initiative (NDEI ), sponsored by KnowledgePoint360 Group, LLC. All content has been created by, and is not associated with funding via an educational grant or a promotional/commercial interest. Disclosures Vice President, Independent Educational Initiatives, Danielle Gabriel, has no relevant fi nancial relationships to disclose. Managing Editor and Writer, Melanie Visalli, discloses that her spouse is a salaried employee of Eisai. Off-Label Disclosure Clinical Insights in Diabetes provides important reviews of literature that are balanced, objective, scientifi cally rigorous, and clinically relevant. Some reports may discuss uses for products or devices that are not approved by the US Food and Drug Administration or appropriate regulating body, or are investigational in nature. Such uses will be noted at the end of the article. How would you treat this patient with cardiometabolic disease? Frank Lavernia, MD, offers insights on personalized therapy for an overweight patient with poorly controlled type 2 diabetes and dyslipidemia. Select On-Demand Programs > Case Studies on the NDEI.org homepage. Spotlight on: Canagliflozin Canagliflozin Noninferior to Sitagliptin for A1C Lowering in CANTATA-D2 Canaglifl ozin was shown to be noninferior to sitagliptin for A1C lowering in the CANTATA-D2 trial, which compared these antihyperglycemic agents as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin plus sulfonylurea. Primary endpoint Mean change in A1C from baseline to Week 52 was -1.03% in the canaglifl ozin group and -0.66% in the sitagliptin group. Additional outcomes A signifi cantly greater reduction in fasting plasma glucose (FPG) was seen with canaglifl ozin versus sitagliptin: mean change of mg/dl vs -2.2 mg/dl (P<0.001). Statistically signifi cant reductions in weight and systolic blood pressure were also seen with canaglifl ozin treatment versus sitagliptin at 52 weeks. With regard to lipid values, larger increases in LDL-C and HDL-C were observed with canaglifl ozin treatment versus sitagliptin. Adverse events The overall incidence of adverse events, including the incidence of urinary tract infections and hypoglycemia, was similar in the canaglifl ozin and sitagliptin groups. A higher rate of genital mycotic infections and osmotic diuresis (polyuria) was seen among canaglifl ozin-treated patients. About CANTATA-D2 CANTATA-D2 was a randomized, double-blind, active-controlled, Phase III trial examining the effi cacy and safety of canaglifl ozin versus sitagliptin over 52 weeks. Subjects had A1C 7.0% to 10.5% and were randomized 1:1 to 300 mg canagliflozin once daily (n=378) or 100 mg sitagliptin once daily (n=378). Mean baseline A1C in the trial was 8.1%, and participants mean type 2 diabetes duration was 9.6 years. Baseline FPG was mg/dl in the canaglifl ozin group and mg/dl in the sitagliptin group. Canaglifl ozin and sitagliptin are not indicated for weight loss or antihypertensive or lipid-lowering treatment. One formulation of canaglifl ozin (INVOKANA ) has been FDA approved as of July CANTATA-D2=Canaglifl ozin Treatment and Trial Analysis dipeptidyl-peptidase-4 inhibitor Schernthaner G, Gross JL, Rosenstock J, et al. Canaglifl ozin 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. Diabetes Care Epub ahead of print. See pg 3 for results from a canagliflozin monotherapy study. Get your patients moving! Our patient education handout on Physical Activity features: Tips for incorporating physical activity into a weekly routine A weekly activity planner And more! Select Patient Education on the NDEI.org homepage. 2

3 Spotlight on: Canagliflozin Significant A1C, FPG Reductions with Canagliflozin Monotherapy Vs Placebo in CANTATA-M Canagliflozin monotherapy showed significant A1C and FPG reductions compared with placebo among subjects with type 2 diabetes inadequately controlled with diet and exercise in the CANTATA-M trial. Figure 1 Primary endpoint Mean change in A1C from baseline to Week 26 was -0.77% among subjects who received canagliflozin 100 mg, -1.03% among subjects who received canagliflozin 300 mg, and 0.14% among subjects who received placebo. Comparisons for both dosages versus placebo were statistically significant (P<0.001). (See Figure 1.) Additional outcomes A greater proportion of canagliflozin-treated subjects achieved A1C <7.0% at 26 weeks: 44.5%, 62.4%, and 20.6% in the canagliflozin 100-mg, canagliflozin 300-mg, and placebo groups, respectively; P<0.001 for both canagliflozin doses. (See Figure 2.) Reductions in FPG were significantly greater among canagliflozin-treated subjects: mg/dl (-1.5 mmol/l), mg/dl (-1.9 mmol/l), and 9.01 mg/dl (0.5 mmol/l) in the canagliflozin 100-mg, canagliflozin 300-mg, and placebo groups, respectively; P<0.001 for both canagliflozin doses versus placebo at 26 Weeks. Figure 2 Statistically significant reductions in weight and systolic blood pressure were also seen with canagliflozin treatment. With regard to lipid values, significant increases in HDL-C were seen in both canagliflozin groups; nonsignificant reductions in triglycerides were also observed. Adverse events The overall incidence of adverse events was modestly higher among canagliflozin-treated patients versus placebo; there were no reports of severe hypoglycemia. Genital mycotic infections, osmotic diuresis (polyuria), and urinary tract infections were increased with canagliflozin treatment. About CANTATA-M CANTATA-M was a 26-week, randomized, double-blind, placebo-controlled Phase III study. Subjects had A1C 7.0% 0%to 10% and were randomized 1:1:1 to once-daily canagliflozin 100 mg (n=195), canagliflozin 300 mg (n=197), or placebo (n=192). Mean baseline A1C in the trial was 8.0%, FPG, mg/dl, and mean type 2 diabetes duration, 4.3 years. Canagliflozin is not indicated for weight loss or antihypertensive or lipid-lowering treatment. One formulation of canagliflozin (INVOKANA ) has been FDA approved as of July CANTATA-M=Canagliflozin Treatment and Trial Analysis Monotherapy Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4): NDEI.org has been honored by the Web Health Awards and the Interactive Media Awards! Make NDEI.org your go-to resource for diabetes and metabolic guidelines: AACE glycemic control guidelines: Interactive summary recommendations. Bonus for registered members: download summary recommendations in a convenient PDF. Hypoglycemia recommendations from the American Diabetes Association and Endocrine Society And more! Select Clinical Guidelines on the NDEI.org homepage. 3

4 No Effect of Omega-3 Fatty Acids on CV Events in Risk and Prevention Study (cont d) Secondary endpoints Null results were also seen for all secondary endpoints. Selected endpoints in the omega-3 fatty acid and placebo groups, respectively: Death from CV cause: 2.3% vs 2.2%, HR, 1.03 (95% CI, ); P=0.80 Hospitalization for CV cause: 9.9% vs 10.1%; HR, 0.98 (95% CI, ); P=0.68 Death or nonfatal myocardial infarction (MI) or stroke: 7.8% vs 7.5%, HR, 1.03 (95% CI, ); P=0.64 Death from CV cause or nonfatal MI or stroke: 4.6% vs 4.4%, HR, 1.05 (95% CI, ); P=0.59 Death from coronary cause: 1.3% vs 1.2%, HR, 1.07 (95% CI, ); P=0.66 Sudden death from cardiac cause: 0.8% vs 0.6%, HR, 1.22 (95% CI, ); P=0.36 About the Risk and Prevention Study Subjects were randomized to 1 g omega-3 fatty acids/day (n=6,239) or placebo (olive oil; n=6,266) in this double-blind, placebo-controlled study. High CV risk was considered 1 of the following: multiple CV risk factors, evidence of atherosclerotic vascular disease, or any other condition putting the patient at high CV risk. Individuals with prior MI were excluded from the study. The study s initial primary endpoint was cumulative rate of death, nonfatal MI, and nonfatal stroke. At 1 year, the event rate was lower than expected, and the primary endpoint was revised to a composite of death from CV causes or hospital admission for CV causes. The Risk and Prevention Study Collaborative Group. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368(19): Determinants of Weight Gain Associated with Intensive Therapy in ACCORD A post-hoc analysis of ACCORD found greater weight gain over at least 2 years among patients assigned intensive therapy compared with patients who received standard therapy to control glycemia. These data were used to identify determinants of weight gain associated with intensive therapy. Characteristics associated with weight gain Significantly more weight gain was noted in the intensive glycemia arm of ACCORD than in the standard glycemia arm. At the end of year 2, the average weight gain was 3.0 (±7.0) kg in the intensive arm. Weight gain and A1C, medication use In the intensive and standard glycemia arms, participants with the highest baseline A1C gained weight as A1C levels improved. Among participants whose baseline A1C was <7.8%, weight loss occurred as A1C improved in both treatment groups. In the intensive group: Statistically significant relationship between change in A1C and change in weight (P<0.001) with a decrease in A1C associated with weight gain Decreased A1C and weight gain occurred among 59% of participants; decreased A1C and weight loss occurred in 28.8% of participants Overall change in weight due to medication use accounted for <15% of the variability in weight gain. Insulin, thiazolidinediones (TZDs), and metformin conferred the most influence on weight gain which was more pronounced in the intensive group. Baseline characteristics associated with increased weight at 2 years in the intensive and standard glycemic control arms in ACCORD included: Younger age Male gender Asian race No smoking history Baseline A1C >8.5% Baseline body mass index (BMI) kg/m 2 High waist circumference Baseline insulin use Baseline metformin use About ACCORD ACCORD 1 was a randomized, multicenter, double 2X2 factorial trial in 10,251 patients with type 2 diabetes designed to test the effects on major cardiovascular disease events of intensive glycemia control, of fibrate treatment to increase HDL-C and lower triglycerides, and of intensive blood pressure control, each compared to an appropriate control. All 10,251 participants were in an overarching glycemia trial. This post-hoc analysis included 8,929 ACCORD participants. ACCORD=Action to Control Cardiovascular Risk in Diabetes 1. Gerstein HC, Miller ME, Byington RP, et al; for the ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358: Fonseca V McDuffie R, Calles J, et al; for the ACCORD Study Group. Determinants of weight gain in the Action to Control Cardiovascular Risk in Diabetes trial. Diabetes Care Epub ahead of print. 4

5 Glycemic Control Similar with Single Daily Basal Insulin Plus Corrective Glulisine and Basal Bolus Regimen The Basal Plus Trial showed that a basal plus regimen basal insulin once daily plus corrective doses of glulisine as needed with a meal yielded glycemic control similar to that seen with a standard basal bolus regimen among hospitalized patients with type 2 diabetes. Improvements in blood glucose The Basal Plus Trial compared basal bolus, basal plus, and regular sliding-scale insulin (SSI) treatment regimens. The primary outcome was between-group difference in glycemic control measured by mean daily blood glucose (BG), and all regimens yielded prompt, sustained improvement in mean daily BG during hospital stay. The basal bolus and basal plus regimens showed similar improvements in daily BG after day 1 of treatment (P=0.16) and better glycemic control vs SSI (P=0.04). No between-group differences in the rate of severe hypoglycemia (<40 mg/dl) were seen (P=0.76). The percentage of glucose readings within the mg/dl target range was highest with the basal plus regimen (42%) compared with the basal bolus (37%) and SSI (32%) regimens (P=0.04). The percentage of glucose readings >180 mg/dl was lower in the basal bolus group (27%) compared with the basal plus (32%) and SSI (38%) regimens (P=0.11). About the Basal Plus Trial A total of 375 subjects in general medical and surgical wards (aged 18 to 80 years) with type 2 diabetes treated with diet, oral antidiabetic agents (OADs), or low-dose insulin ( 4 units/kg/day) were enrolled. Prior to randomization, BG was between 140 and 400 mg/dl; subjects were recruited when BG was >140 mg/dl. OADs were stopped at admission. Randomization was in a 2:2:1 ratio: Basal bolus: glargine once daily, glulisine before meals, corrective doses of glulisine by sliding scale for BG >140 mg/dl Basal plus: glargine once daily, corrective glulisine given by sliding scale before meals for BG >140 mg/dl Regular SSI (no basal insulin): for BG >140 mg/dl The goal of insulin therapy was maintenance of fasting and premeal glucose levels between 100 and 140 mg/dl. Mean glucose level at admission was 204 ± 84 mg/dl for all groups. Treatment failure, hypoglycemia In the SSI group, 19% of subjects had treatment failure,* vs 0% in the basal bolus group and 2% in the basal plus group (P<0.0001). There were no differences in the frequency of hypoglycemic events between the basal bolus and basal plus regimens: 16% of subjects in the basal bolus group had BG <70 mg/dl, vs 13% in the basal plus group and 3% in the SSI group (P=0.009). *Defi ned as mean daily blood glucose >240 mg/dl or 2 consecutive values >240 mg/dl Umpierrez GE, Smiley D, Hermayer K, et al. Randomized study comparing a basal bolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes: Basal Plus Trial. Diabetes Care Epub ahead of print. Vivian Fonseca, MD, on the Basal Plus Trial Insights from Dr Fonseca on Basal Plus and another important study exploring personalized insulin therapy. Select Expert Commentary on the NDEI.org homepage. 5

6 Diurnal Pattern to Insulin Action in Type 1 Diabetes is Individual Specific, Data Suggests Data from a recent study by Hinshaw and colleagues showed no uniformly identifiable diurnal pattern of postprandial insulin sensitivity that can be generalized to individuals with type 1 diabetes as a whole. Large inter-subject variability was seen, which could be due to greater variability of insulin action in type 1 diabetes. These findings are contrary to recent data from a cohort of healthy subjects. 1 Results for glucose, hormones Glucose Preprandial: no difference between meals ( P=0.083) Peak postprandial: differed by meal ( P=0.010); lower at dinner than at breakfast (P<0.01) subjects with type 1 diabetes: 5.1 to 7.5 to dl/kg/min per μu/ml for breakfast to lunch to dinner (P=0.34). The opposite occurred among healthy subjects: 11.2 to 7.9 to dl/kg/min per μu/ml for breakfast to lunch to dinner (P<0.05). This suggests that a diurnal pattern to insulin action in type 1 diabetes is individual specific. Insulin Preprandial: differed by meal ( P=0.002); lunch higher than breakfast or dinner Peak postprandial: no difference between meals ( P=0.13) Glucagon Preprandial: lower at breakfast than lunch ( P=0.023) or dinner (P=0.013) Peak postprandial: no difference between meals ( P=0.22) There was no difference between meals for meal glucose appearance and disappearance. Endogenous glucose production was lower at breakfast and lunch at baseline. Indices of insulin action When data were compared for healthy subjects 1 and individuals with type 1 diabetes, estimated mean profiles for insulin response were shown to be increased from breakfast through dinner in About this study This study examined whether a diurnal pattern to insulin secretion exists in type 1 diabetes. Subjects (N=19) had C-peptide negative type 1 diabetes and were on an insulin pump. Additional subject characteristics: aged years, body mass index <40 kg/m 2, A1C 8.5%, creatinine 1.5 mg/dl, normal gastric emptying to solids and liquids. Subjects received mixed meals for breakfast, lunch, and dinner on three consecutive days in randomized Latin Square order. Daily physical activity was equal for all subjects. Pre-meal insulin bolus with pump was based on the usual insulin:carbohydrate ratio and sensitivity factor was administered. Subjects were continued on basal insulin infusion patterns. Primedcontinuous glucose infusion was started 3 hours prior to the first bite of the mixed meal to estimate postprandial glucose kinetics (triple tracer mixed meal). 1. Saad A, Dalla Man C, Nandy DK, et al. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes. 2012;61(11): Hinshaw L, Dalla Man C, Nandy DK, et al. Diurnal pattern of insulin action in type 1 diabetes: implications for a closed loop system. Diabetes. 2013;62(7): Do your patients know the basics of low blood glucose? NDEI s latest patient education handout covers the basics of hypoglycemia: What it is How it happens What to do if does happen Plus, a space for patients to record questions about blood glucose Select Patient Education on the NDEI.org homepage. 6