MELANIE VISALLI, MANAGING EDITOR AND WRITER

Transcription

1 CLINICAL INSIGHTS IN Volume 13, Issue 5 December 2012 Learning Objectives Summarize data comparing two long-acting glucagon-like peptide-1 receptor agonists for type 2 diabetes treatment Discuss data exploring the relationship between low HDL-C levels and microvascular risk Review fi ndings from a study exploring statin use and progression of vascular calcifi cation in patients with type 2 diabetes and advanced atherosclerosis Discuss fi ndings from a study exploring cardiovascular disease incidence in obese subjects with type 2 diabetes receiving bariatric surgery Discuss data from studies exploring the treatment and management of type 2 diabetes, and apply to clinical practice as appropriate 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. All content has been created by KnowledgePoint360 Group, LLC, and is not associated with funding via an educational grant or a promotional/commercial interest. Disclosures Faculty reviewer Vivian A. Fonseca, MD, has indicated the following relevant relationships: honoraria for consulting and lectures from Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Inc., Eli Lilly and Company, GlaxoSmithKline, Novo Nordisk, Pamlab, Sanofi - Aventis, Takeda Pharmaceutical Company, and XOMA; research support grants (to Tulane University) from Abbott Laboratories, Eli Lilly and Company, Novo Nordisk, Pamlab, Reata Pharmaceuticals Inc., and Sanofi -Aventis. 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. Copyright All rights reserved. Diabetes MELANIE VISALLI, MANAGING EDITOR AND WRITER DURATION (Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention with Exenatide Once-Weekly) is a series of multinational studies comparing once-weekly exenatide with other antihyperglycemic therapies for treatment of type 2 diabetes. The DURATION-4 study compared once-weekly exenatide with metformin, pioglitazone, and sitagliptin, with results showing once-weekly exenatide to be superior to sitagliptin and noninferior to metformin but not pioglitazone with regard to A1C lowering. 1 DURATION-5, which compared once-weekly exenatide to twice-daily exenatide, showed superior A1C lowering with the once-weekly exenatide formulation. 2 No major hypoglycemia occurred in either study. DURATION-6 is the fi rst head-to-head study comparing two long-acting glucagon-like peptide-1 (GLP-1) receptor agonists onceweekly exenatide and once-daily liraglutide for type 2 diabetes treatment. (See box on pg 2 for considerations when choosing GLP-1 receptor agonist therapy for treatment of type 2 diabetes.) This open-label, parallel-group study randomized participants to once-daily liraglutide (1.8 mg) or once-weekly exenatide (2 mg) over 26 weeks. The intention-to-treat analysis included 911 subjects, of whom 450 received liraglutide and 461 received exenatide. Subjects had type 2 diabetes suboptimally treated with lifestyle modifi cation and oral antihyperglycemic therapy, A1C 7.1%-11.0%, body mass index 45 kg/m 2, and stable weight for 3 months. A1C change from baseline to Week 26 was the primary endpoint. Treatment with both once-weekly exenatide and once-daily liraglutide showed improvements in A1C, with greater mean A1C change seen among liraglutide-treated patients (least-squares mean A1C change: -1.48% [95% confi dence VOLUME 13, ISSUE 5 DECEMBER 2012 DURATION-6: Head-to-Head Comparison of Once-Weekly Exenatide Vs Once-Daily Liraglutide interval {CI}, to -1.38] vs -1.28% [-1.38 to -1.18]; P=0.02). The treatment difference was 0.21% (95% CI, ), which did not meet noninferiority criteria set by the study investigators. (See Figure.) Both liraglutide- and exenatide-treated patients showed decreases in weight* and fasting serum glucose, which were predefi ned secondary endpoints. Liraglutide-treated patients had greater reductions in both of these parameters. Other secondary endpoints, including blood pressure and cardiovascular biomarkers, showed similar improvements in both groups.* Adverse events were primarily gastrointestinal (GI). The most prevalent GI events nausea, diarrhea, and vomiting occurred more frequently among liraglutide-treated patients compared with exenatide-treated patients. Incidence of GI events decreased over time in both treatment groups. A similar number of patients in both treatment groups experienced minor hypoglycemia; no major hypoglycemia occurred. *Once-weekly exenatide and liraglutide are not FDA approved for weight loss, or treatment of blood pressure, lipids, C-reactive protein, or brain natriuretic peptide Clinical Insights is a registered trademark, and KnowledgePoint360 is a trademark, of. pg 1

2 DURATION-6: Head-to-Head Comparison of Once-Weekly Exenatide Vs Once-Daily Liraglutide Continued 1. Russell-Jones D, Cuddihy RM, Hanefeld M, et al; for the DURATION-4 Study Group. Effi cacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naïve patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35(2): Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96(5): Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet Nov 6.pii: S (12) doi: /S (12) [Epub ahead of print] GLP-1 Receptor Agonist Therapy for Type 2 Diabetes: Considerations The 2012 position statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) on management of hyperglycemia in type 2 diabetes stresses that selection of glucose-lowering therapies should be individualized, and side effects should be minimized when possible. 1 GLP-1 receptor agonists are cited in the position statement as add-on therapy if monotherapy with metformin is not effective in reaching A1C targets. Data from DURATION-6 provide the fi rst head-to-head comparison of two long-acting GLP-1 receptor agonists once-weekly exenatide and once-daily liraglutide for type 2 diabetes treatment. 2 GLP-1 receptor agonists as a class offer the general benefi ts of low hypoglycemia risk, weight reduction, and possible potential for improved beta-cell mass/function and cardiovascular protection. 1 Disadvantages of these agents include gastrointestinal side effects and possible acute pancreatitis. 1 Other considerations associated with GLP-1 receptor agonists that should be discussed with patients are cost and the fact that these agents are delivered via injection. 1 Visit NDEI.org for more on the ADA/EASD Position Statement on Management of Hyperglycemia in Type 2 Diabetes: Select Clinical Guidelines from the NDEI.org homepage. 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. 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(6): Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet Nov 6.pii: S (12) doi: /S (12) [Epub ahead of print] Does HDL-C Predict Microvascular Risk? Data from a Post-hoc Analysis of ADVANCE M acro- and microvascular complications remain signifi cant concerns in the treatment of patients with type 2 diabetes. Controlling for factors such as A1C and blood pressure can help to address these concerns; however, identifi cation of additional risk factors could be benefi cial in personalizing treatment strategies for patients, taking into account their individual risk profi les. Low levels of high-density lipoprotein cholesterol (HDL-C) are a risk factor that was shown to be signifi cantly associated with macrovascular complications (specifi cally, coronary artery disease) in the United Kingdom Prospective Diabetes Study (UKPDS). 1 Could low HDL-C have an effect on microvascular complications, as well? The authors of the current analysis investigated the hypothesis that lower HDL-C levels may predispose patients to the development and progression of microvascular complications; it is the largest prospective analysis that specifi cally addresses the relationship between HDL-C and microvascular disease risk among those with type 2 diabetes. Subjects included in this post-hoc analysis were members of The Action in Diabetes and Vascular Disease: preterax and diamicron-mr Controlled Evaluation (ADVANCE) cohort with HDL-C measurements at baseline (N=11,126). ADVANCE examined the effects of standard vs intensive glucose-control interventions on major macro- and microvascular events among subjects who were aged 55 years and had type 2 diabetes and 1 other cardiovascular risk factor. Findings from ADVANCE published in 2008 showed that patients treated with intensive glucose control had greater reduction in the rates of combined major macro- and microvascular Slides featuring the data in this issue of Clinical Insights are available at NDEI.org! Select Slide Library from the NDEI.org homepage. New content is continuously being posted on NDEI.org check back often for updates on all the latest diabetes data. pg 2

3 Does HDL-C Predict Microvascular Risk? Data from a Post-hoc Analysis of ADVANCE Continued events (18.1% intensive therapy vs 20.0% standard therapy; hazard ratio [HR], 0.90; 95% confi dence interval [CI], ; P=0.01) and microvascular events alone (9.4% intensive therapy vs 10.9% standard therapy; HR, 0.86; 95% CI, ; P=0.01) over median followup of 5 years, although the between-group differences were small. 2 The decreased rate of microvascular events was primarily due to a 21% decrease in nephropathy (4.1% in the intensivetherapy group vs 5.2% in the standard-therapy group; HR, 0.79; 95% CI, ; P=0.006), as no signifi cant effect on retinopathy was observed in either treatment group (P=0.50). 2 (See box below for more information on intensive vs standard glycemic control.) The main outcome assessed in the current analysis was microvascular events, defi ned as a composite of total renal and retinal events.* Over a median follow-up of 5 years, 32% (n=3,585) of subjects developed a new or worsening microvascular event. 28% (n=3,161) had a renal event 6% (n=680) had a retinal event Event risk was compared based on three tertiles of baseline HDL-C: tertile 1: <42.5 mg/dl, tertile 2: mg/dl, and tertile 3: >51.8 mg/dl. A 17% higher risk for microvascular events was seen among subjects in the lowest vs the highest HDL-C tertile (See Table at right.). Lower baseline levels of HDL-C signifi cantly and independently predicted the development and progression of nephropathy. Subjects in the lowest tertile of baseline HDL-C had a 19% higher nephropathy risk vs subjects in the highest tertile (See Table at right.). No association was observed between baseline HDL-C and retinopathy risk (See Table at right.). At baseline, evidence of microvascular disease was present among 10% of subjects (n=1,155), and mean HDL-C was 50.3 mg/dl. *Total renal events: development of new microalbuminuria, new macroalbuminuria, doubling of creatinine to 200 μmol/l, need for renal replacement therapy, or death due to renal disease; total retinal events: development of proliferative retinopathy, macular edema, blindness related to diabetes, use of retinal photocoagulation therapy Adjusted for regression dilution and potential confounders 1. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS). BMJ. 1998;316(7134): The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med. 2008;358(24): Morton J, Zoungas S, Li Q, et al; on behalf of the ADVANCE Collaborative Group.Low HDL cholesterol and the risk of diabetic nephropathy and retinopathy. Diabetes Care. 2012;35: Microvascular events (total) Lowest vs highest HDL-C tertile; HR (95% CI) 1.17 ( ) Nephropathy 1.19 ( ) Retinopathy 1.01 ( ) P Intensive vs Standard Glycemic Control: Is Lower Better? Findings from large-scale trials such as ACCORD, ADVANCE, and VADT have shown that therapy targeting more intensive glycemic control may not be benefi cial for all patients. 1 Data have shown that intensive control reduces microvascular disease; however, evidence of a similar benefi t for macrovascular disease is not as clear. Is tighter control better? Based on the approach to glycemic control outlined in the ADA/EASD position statement on management of hyperglycemia, 2 the answer to this question depends on the particular patient that is being treated. Per the position statement, more stringent A1C targets (6.0% to 6.5%) may be considered in patients with short disease duration, long life expectancy, and no signifi cant cardiovascular disease, if these targets can be achieved in the absence of signifi cant hypoglycemia or adverse treatment effects. 2 For patients with history of severe hypoglycemia, limited life expectancy, advanced complications, extensive comorbid conditions, and in whom more stringent targets are diffi cult to achieve despite self-management education, counseling, and use of other antihyperglycemic agents, less stringent A1C targets of 7.5% to 8.0% or higher may be appropriate. 2 An interactive case study by Silvio Inzucchi, MD, explores individualizing treatment targets in a 58-year-old man with uncontrolled type 2 diabetes and history of CVD using concepts from the ADA/ EASD hyperglycemia guideline. Select Case Studies from On-Demand Programs on the NDEI.org homepage. 1. Terry T, Raravikar K, Chokrungvaranon N, Reaven PD. Does aggressive glycemic control benefi t macrovascular and microvascular disease in type 2 diabetes? Insights from ACCORD, ADVANCE, and VADT. Curr Cardiol Rep. 2012;14(1): Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patientcentered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6): pg 3

4 Statin Use and Progression of Vascular Calcification: Post-hoc Data from VADT Cross-sectional data from the Veterans Affairs Diabetes Trial (VADT) showed that participants with coronary artery or abdominal aortic calcifi cation had an increased prevalence of cardiovascular disease, including peripheral artery disease and coronary artery disease. 1 VADT investigated the impact of intensive and standard glucose control on cardiovascular events among military veterans who had a suboptimal response to antihyperglycemic therapy.(see box on pg 3 for more on intensive vs standard glycemic control.) Statin therapy may be prescribed for prevention and risk reduction of cardiovascular events in those with type 2 diabetes. In the VADT study cohort, is statin use associated with progression of vascular calcifi cation? In exploring this query, the authors of the present study found that statin use promotes development of coronary artery calcium (CAC) among those with type 2 diabetes and advanced atherosclerosis, even in the presence of effi cacious lipid-lowering treatment. Subjects included in this analysis (N=197) were from VADT and had type 2 diabetes and presence of extensive atherosclerosis at baseline. The authors assessed progression of both CAC and abdominal aortic artery calcium (AAC) based on the frequency of statin use in these patients. The majority of subjects using statins (82%; n=161) cited frequent statin use (in >50% of study visits). These subjects had increased prevalence of prior cardiovascular disease compared with less frequent statin users (reported statin use in 50% of study visits; n=36; 41% vs 19%; P=0.01). At the end of the study, more frequent statin users had lower levels of total cholesterol, LDL-C, and total cholesterol/ HDL-C ratio compared with less frequent users of statins. Frequency of statin use did not effect cardiovascular disease event incidence. However, more frequent statin use was associated with accelerated progression of coronary artery calcium vs less frequent statin use: 8.2 ± 0.3 mm 3 vs 4.2 ± 1.1 mm 3 (P<0.01; See Figure). No signifi cant association was seen between more frequent statin use and progression of AAC in the overall study population. When subjects were stratifi ed by baseline statin use, those who were not receiving statins at baseline and subsequently reported frequent statin use had increased progression of both AAC and CAC after adjustment for age and baseline calcium compared with less frequent statin users. Mean age of study participants was 61 years, and mean duration of type 2 diabetes was 12 years. Baseline statin use in the study cohort was 61% (n=121). 1. Reaven PD, Sacks J. Coronary artery and abdominal aortic calcifi cation are associated with cardiovascular disease in type 2 diabetes. Diabetologia. 2005;48(2): Saremi A, Bahn G, Reaven PD; for the VADT Investigators. Progression of vascular calcifi cation is increased with statin use in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2012;35: Visit NDEI.org for patient education handouts that you can use in your practice. Our latest handout provides patients with information on A1C goals, lifestyle changes, and medications that may be part of their individualized diabetes management plan. Select Patient Education on the NDEI.org homepage. Bariatric Surgery and Cardiovascular Events in Obese Individuals with Type 2 Diabetes: Post-hoc Data from SOS The Swedish Obese Subjects (SOS) study is a nonrandomized, controlled, prospective interventional trial that compares the effects of bariatric surgery and usual care on morbidity and mortality outcomes. Previously published fi ndings from SOS showed that bariatric surgery conferred a reduction in both cardiovascular deaths and incidence of cardiovascular events among the overall SOS population. 1 (See box on page 5 for information on long-term evidence regarding bariatric surgery benefi ts.) This post-hoc analysis by Romeo and colleagues focuses on cardiovascular events in SOS participants who had type 2 diabetes at baseline (N=607). It is the fi rst prospective report to demonstrate that bariatric surgery reduces the incidence of myocardial infarction among obese individuals with type 2 diabetes. Participants in the current analysis were aged years and had body mass index 34 kg/m 2 (men) or 38 kg/m 2 (women). The bariatric surgery pg 4

5 Bariatric Surgery and Cardiovascular Events in Obese Individuals with Type 2 Diabetes: Post-hoc Data from SOS Continued group included 345 subjects, who received vertical-banded gastroplasty, gastric banding, or gastric bypass. Those in the usual care (control) group (n=262) received standard care for obesity and type 2 diabetes. Fatal and nonfatal cardiovascular events (myocardial infarction or stroke, whichever occurred fi rst) were the end points analyzed over mean follow-up of 13.3 years. Patients in the bariatric surgery group experienced fewer fatal and nonfatal cardiovascular events compared with the usual care group. 63 events/345 subjects in the surgery group (18.3%) vs 65 events/262 subjects in the usual care group (24.8%) Adjusted hazard ratio, 0.53 (95% confi dence interval, ); P=0.002 The incidence of myocardial infarction alone was lower among patients in the surgical group compared with usual care. (See Figure at right.) 38 events/345 subjects in the surgery group (11.0%) vs 43 events/262 subjects in the usual care group (16.4%) Adjusted hazard ratio, 0.56 (95% confi dence interval, ); P=0.025 Bariatric surgery did not exert any effect on stroke incidence when compared with subjects in the usual-care group. 34 events/345 subjects in the surgery group (9.9%) vs 24 events/262 subjects in the usual care group (9.2%) Adjusted hazard ratio, 0.73 (95% confi dence interval, ); P=0.29 Type 2 diabetes was defi ned as fasting blood glucose mg/dl and/or self-reported use of antihyperglycemic medications at baseline. 1. Sjöström L, Peltonen M, Jacobson P, et al. Bariatric surgery and long-term cardiovascular events. JAMA. 2012;307(1): Romeo S, Maglio C, Burza CA, et al. Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes. Diabetes Care. 2012;35: Check the Metabolic Surgery & Diabetes category in the NDEI.org Slide Library for slides featuring data from the SOS study. Evidence for Long-Term Clinical Benefits of Bariatric Surgery An editorial in JAMA by Courcoulas states that gaps in the bariatric surgery evidence base contribute to the small fraction of obese patients who undergo surgery. 1 The author cites several gaps, including insuffi cient randomized controlled trials, limits to the generalizability of the reports of bariatric surgical interventions, and uncertainty regarding long-term outcomes. With respect to long-term outcomes, results from the SOS post-hoc analysis by Romeo and colleagues presented in this issue of Clinical Insights provide the fi rst dataset showing a reduction in myocardial infarction among obese individuals with type 2 diabetes who received bariatric surgery over 13.3 years of follow-up. 2 Findings from two other recent studies regarding bariatric surgery outcomes, which both looked at data over 6 years: Adams and colleagues showed that obese subjects who had Roux-en-Y gastric bypass (RYGB) had greater remission and lower incidence of diabetes, as well as greater improvement in incidence and remission of hypertension and dyslipidemia values, when compared with nonsurgical, noninterventional control groups 3 When outcomes were examined among subjects with type 2 diabetes and mild obesity (BMI kg/m 2 ), Cohen and colleagues found that subjects who received RYGB had decreases in A1C, FPG, and insulin resistance; resolution in hypertension, hypercholesterolemia, and hypertriglyceridemia; and improvements in blood pressure, total cholesterol, LDL-C, triglycerides, and HDL-C 4 Coming soon: Webcast featuring expert clinical commentary from NDEI Education Council Member Vivian A. Fonseca, MD, exploring data from the post-hoc analyses of ADVANCE, SOS, and VADT presented in this issue of Clinical Insights in Diabetes. 1. Courcoulas AP. Progress in fi lling the gaps in bariatric surgery. JAMA. 2012;308(11): Romeo S, Maglio C, Burza CA, et al. Cardiovascular events after bariatric surgery in obese subjects with type 2 diabetes. Diabetes Care. 2012;35: Adams TD, Davidson LE, Litwin SE, et al. Health benefi ts of gastric bypass surgery after 6 years. JAMA. 2012;308(11): Cohen RV, Pinheiro JC, Schiavon CA, Salles JE, Wajchenberg BL, Cummings DE. Effects of gastric bypass surgery in patients with type 2 diabetes and only mild obesity. Diabetes Care. 2012;35: pg 5