CV Events in SAVOR-TIMI and EXAMINE DPP - … CI...• Improvement in CVD risk factors, except LDL-C; improvement diminished over time ... CV Events in SAVOR-TIMI and EXAMINE DPP -

Data from the DPP-4 inhibitor cardiovascular safety studies, SAVOR-TIMI 531 and EXAMINE2, showed no increase in CV events with saxagliptin or alogliptin compared

with placebo.

Primary endpointsThe primary endpoint in both studies was a composite of CV death, nonfatal MI, or nonfatal stroke.* In SAVOR-TIMI 53, the rate of the primary endpoint was 7.3% in the saxagliptin group and 7.2% in the placebo group (HR, 1.0 [95% CI, 0.89-1.12]; P=0.99 for superiority, P<0.001 for noninferiority). EXAMINE showed a rate of 11.3% in the alogliptin group compared with 11.8% in the placebo group (HR, 0.96 [95% CI, ≤1.16†]; P=0.32 for superiority; P<0.001 for noninferiority).

Secondary endpoints, glycemic controlIn both studies, no increase in CV events was seen for the secondary endpoints, the primary endpoint plus hospitalization for heart failure, coronary revascularization, or UA in SAVOR-TIMI 53 and the primary composite endpoint plus urgent revascularization due to UA within 24 hours of hospital admission in EXAMINE. Signifi cantly better glycemic control was also seen with both DPP-4 inhibitors vs placebo (data not shown).

Adverse eventsIn SAVOR-TIMI 53, a greater number of saxagliptin-treated patients had hypoglycemia vs those who received placebo. Rate of any hypoglycemia with saxagliptin was 15.3% vs 13.4% with placebo (P<0.001). There were similar rates of pancreatitis, thrombocytopenia, lymphocytopenia, infections, hypersensitivity/skin reactions, bone fractures, and liver abnormalities in both groups.

There was no signifi cant between-group difference in the occurrence of serious adverse events in EXAMINE: alogliptin 33.6%, placebo 35.5% (P=0.14). Similar rates of hypoglycemia, acute and chronic pancreatitis (no fatal cases), and changes in eGFR and dialysis initiation were seen in both groups.

Heart failure in SAVOR-TIMI 53Saxagliptin increased hospitalization for heart failure over median follow-up of 2.1 years: 3.5% vs 2.8% in the saxagliptin and placebo groups, respectively (HR, 1.27 [95% CI, 1.07 to 1.51]; P=0.007).

MELANIE VISALLI, MANAGING EDITOR AND WRITERVolume 14, Issue 3 • October 2013

No Increase in CV Events in SAVOR-TIMI 53 and EXAMINE DPP-4 CV Safety StudiesHeart Failure Signal in SAVOR-TIMI 53 Requires Further Exploration

Copyright © 2013 KnowledgePoint360Group, LLC. All rights reserved.

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Continued on pg 3

e and chronic pancreatitis (no fatal cases),

In this issue:

● No CV Benefi ts Seen with Lifestyle Intervention in Look AHEAD............................................2● Spotlight on: Bariatric Surgery Benefi ts in Patients with Type 2 Diabetes................................4● Severe Hypoglycemia Nearly Doubles Cardiovascular Disease Risk......................................5● Studies Explore Statin Use and Diabetes Risk......................................................................6

CLINICAL INSIGHTS® in Diabetes

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No CV Benefi ts Seen with Lifestyle Intervention in Look AHEAD

No reduction in the composite cardiovascular primary outcome of fi rst occurrence of death from CV causes, nonfatal MI, nonfatal stroke, or hospitalization for angina, was seen with intensive lifestyle intervention in the Look AHEAD study.

Primary outcomeThere were 403 events in the intensive lifestyle intervention group (1.83/100 person-years) vs 418 events (1.92/100 person-years) in the diabetes support and education group (control; HR, 0.95; 95% CI, 0.83-1.09; P=0.51). No signifi cant differences were seen when the primary outcome was examined by subgroups, which included baseline CVD, sex, and race/ethnic group.

No reduction was seen in the intensive lifestyle intervention group vs the control group for any of the secondary outcomes that were examined (data not shown).*

Weight reduction Greater weight reduction was seen among subjects assigned to intensive lifestyle intervention vs those assigned to control. • Largest differences seen at Year 1: 8.6% mean weight loss from baseline for intensive lifestyle intervention vs 0.7% for control • Study end: average weight loss from baseline 6.0% for intensive lifestyle intervention group vs 3.5% for control

In the intensive lifestyle intervention group, weight regain was seen through Year 5, followed by a subsequent gradual weight decrease. Gradual but consistent weight loss was seen throughout the trial in the control group.

Improvement in A1C, CVD risk factors When compared with the control group, subjects in the intensive lifestyle intervention group had: • Greater improvement in A1C, which was mostly seen during the fi rst year but benefi t was partly sustained throughout follow-up• Improvement in CVD risk factors, except LDL-C; improvement diminished over time • Greater improvement in fi tness

About Look AHEAD Look AHEAD compared the effects of intensive lifestyle management with diabetes education on weight loss and CV outcomes among overweight/obese patients with type 2 diabetes. Look AHEAD was stopped after median follow-up of 9.6 years due to futility. The study’s primary outcome was a composite of fi rst occurrence of CV death, nonfatal MI, nonfatal stroke, and hospitalization for angina†.

Participant characteristics were similar between the intensive lifestyle intervention (n=2,570) and diabetes support and education (control; n=2,575) groups at baseline, with more subjects in the intensive lifestyle intervention group using statins, insulin, and antihypertensive therapy. The average age of participants was 58.7 years and 60% were female. Mean BMI was 36.0 kg/m2, median diabetes duration was 5 years, and 14% of subjects had CVD history.

*Death from CV causes, nonfatal MI, or nonfatal stroke; death from any cause, nonfatal MI, or nonfatal stroke; and death from any cause, nonfatal MI, nonfatal stroke, hospitalization for angina, CABG, PCI, hospitalization for heart failure, carotid endarterectomy, or peripheral vascular disease †Added to primary outcome after 2 years of study due to lower than expected CV event rate in the control group

Look AHEAD=Action for Health in DiabetesCABG=coronary artery bypass grafting; CI=confi dence interval; CV=cardiovascular; CVD=cardiovascular disease; BMI=body mass index; HR=hazard ratio; MI=myocardial infarction; PCI=percutaneous coronary intervention

The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369(2):145-154.

Volume 14, Issue 3 • October 2013

Learning Objectives

Summarize fi ndings from studies exploring • the cardiovascular safety of the dipeptidyl peptidase-4 (DPP-4) inhibitors saxagliptin and alogliptin

Review data from a study comparing • the effects of intensive lifestyle management with diabetes education on weight loss and cardiovascular outcomes among overweight/obese patients with type 2 diabetes

Discuss fi ndings from studies reviewing the • benefi ts of bariatric surgery in patients with type 2 diabetes

Describe fi ndings from studies examining • the relationship between statin use and diabetes risk

Discuss data from a meta-analysis • exploring the relationship between severe hypoglycemia and cardiovascular disease risk

Target AudienceThis 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.

SponsorClinical Insights® in Diabetes is a component of the National Diabetes Education Initiative® (NDEI®), sponsored by KnowledgePoint360 Group, LLC. All content has been created by KnowledgePoint360 Group, LLC, and is not associated with funding via an educational grant or a promotional/commercial interest.

DisclosuresVice 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 DisclosureClinical Insights® in Diabetes provides important reviews of literature that are balanced, objective, scientifi cally rigorous, and clinically relevant. The pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States. Some reports may discuss uses for products or devices that are not approved by the FDA or appropriate regulating body, or are investigational in nature. Such uses will be noted at the end of the article.

Award-winning diabetes education for

healthcare professionals!


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Cancer incidenceThe rate of cancer was similar between groups in SAVOR-TIMI 53. There was no excess of pancreatic cancer seen with saxagliptin, and numerically more pancreatic cancers were diagnosed in placebo-treated patients (12 cases vs 5 cases in saxagliptin-treated patients; P=0.095). There was no signifi cant between-group difference in cancer incidence and there were no reports of pancreatic cancer in EXAMINE.

*Nonfatal ischemic stroke specifi ed in SAVOR-TIMI 53†Upper boundary of one-sided repeated CI

Alogliptin and saxagliptin are not FDA approved for cardiovascular risk reduction.

EXAMINE=Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care SAVOR-TIMI 53=Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53

ACS=acute coronary syndrome; CI=confi dence interval; CV=cardiovascular; CVD=cardiovascular disease; DPP-4 inhibitor=dipeptidyl peptidase-4 inhibitor; eGFR=estimated glomerular fi ltration rate; GLP-1 receptor agonist=glucagon-like peptide-1 receptor agonist; HR=hazard ratio; MI=myocardial infarction; UA=unstable angina

1. Scirica BM, Bhatt DL, Braunwald E, et al; for the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.2. White WB, Cannon CP, Heller SR, et al; for the EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327-1335

No Increase in CV Events in SAVOR-TIMI 53 and EXAMINE DPP-4 CV Safety StudiesHeart Failure Signal in SAVOR-TIMI 53 Requires Further Exploration continued

About SAVOR-TIMI 53• Double-blind, placebo-controlled trial • Examined CV safety of saxagliptin vs placebo • 16,492 subjects ○ Type 2 diabetes (A1C 6.5%-12%) ○ Established CVD history or multiple CVD risk factors (≥1 of the following: dyslipidemia, hypertension, current smoking)• Randomization 1:1 to saxagliptin (n=8,280) or matched placebo (n=8,212)• Saxagliptin dose: 5 mg daily or 2.5 mg daily for patients with eGFR ≤50 ml/min • Use of other antihyperglycemic and CVD therapies allowed• Primary endpoint: composite of CV death, nonfatal MI, or nonfatal ischemic stroke • Secondary endpoint: primary endpoint plus hospitalization for heart failure, coronary revascularization, or UA• Median follow-up: 2.1 years

About EXAMINE• Randomized, double-blind, noninferiority trial • Investigated CV safety of alogliptin vs placebo • 5,380 subjects with type 2 diabetes and ACS ○ Receiving background antihyperglycemic and CVD therapy ○ ACS 15-90 days prior to randomization ○ A1C 6.5% to 11% (7% to 11% if taking insulin) • Randomization to daily alogliptin (based on eGFR; n=2,701) or placebo (n=2,679) • Alogliptin dose: 25 mg daily for eGFR ≥60 mL/min/1.73 m2; 12.5 mg daily for eGFR 30 to <60 mL/min/1.73 m2; 6.25 mg daily for eGFR <30 mL/min/1.73 m2

• Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke • Secondary endpoint: primary composite endpoint plus urgent revascularization due to UA within 24 hours of hospital admission• Median follow-up: 18 months

Silvio E. Inzucchi MD, on SAVOR-TIMI 53

“Reassurance of the Overall Cardiovascular Safety of Saxagliptin and, One Might Infer, Other DPP-4 Inhibitors—But Heart Failure Signal Needs to Be Explored Further”

Select “Expert Commentary” on the NDEI.org homepage.


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Spotlight on: Bariatric Surgery Benefi ts in Patients with Type 2 Diabetes

Gastric Bypass Improves Control of A1C, Cardiometabolic Risk Factors

Agreater number of subjects who underwent Roux-en-Y gastric bypass surgery achieved the primary composite triple endpoint of A1C <7.0%, LDL-C <100 mg/dL, and systolic BP <130 mm Hg vs those who received lifestyle and medical management at 12 months in the Diabetes Surgery Study.

Primary composite triple endpointIn the lifestyle and medical management group, 19% of subjects achieved the primary endpoint compared with 49% in the gastric bypass group (OR, 4.8; 95% CI, 1.9-11.7). A1C was the only signifi cant treatment effect seen among the components of the triple composite endpoint: 32% achieved A1C <7.0% in the lifestyle group vs 75% in the gastric bypass group (OR, 6.0; 95% CI, 2.6-13.9).

Weight change, medication use, adverse eventsSubjects who underwent Roux-en-Y gastric bypass surgery:• Used fewer medications: 1.7 (mean) for glycemia, BP, and dyslipidemia vs 4.8 in the lifestyle and medical management group (difference, -3.0; 95% CI, -3.6 to -2.3). • Had greater percent mean weight change at 1 year: -26.1% (mean) vs -7.9% in the lifestyle and medical management group (difference, -17.5; 95% CI, -20.7 to -14.2). Most weight loss occurred within the fi rst 6 months, continuing through Month 12. • Experienced greater serious adverse events (22) vs 15 reported from subjects in the lifestyle group

About The Diabetes Surgery Study• Compared Roux-en-Y gastric bypass with lifestyle and intensive medical management for control of comorbid CVD risk factors • Subjects (N=120): ○ Aged 30-67 years ○ Type 2 diabetes for ≥6 months ○ A1C ≥8.0% at entry ○ C-peptide >1.0 ng/mL ○ BMI 30.0-39.9 kg/m2 • All subjects: lifestyle-medical management to achieve weight loss and control glycemia and CVD risk factors. Half of subjects randomized to Roux-en-Y gastric bypass.

BMI=body mass index; BP=blood pressure; CI=confi dence interval; CVD=cardiovascular disease; OR=odds ratio

Ikramuddin S, Korner J, Lee W-J, et al. Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia. JAMA. 2013;309(21):2240-2249.

Metabolic Effects of Bariatric Surgery, Medical Therapy Compared in STAMPEDE

A1C improvement from baseline was seen in all treatment groups at 24 months in a metabolic substudy of the STAMPEDE trial comparing the effects of bariatric surgery and intensive medical therapy.

A1CMean baseline A1C was 9.7%. At 24 months, mean A1C was 8.4% with intensive medical therapy, 6.7% with gastric bypass, and 7.1% with sleeve gastrectomy (P<0.05 for each surgical group vs medical therapy). In the surgical groups vs the medical therapy group: • Greater improvements seen in FPG, HDL-C, triglycerides, and high-sensitivity C-reactive protein • Lower percentage of subjects using insulin

Weight loss, truncal fatGreater weight loss was seen in both the gastric bypass and sleeve gastrectomy groups compared with medical therapy at 12 and 24 months. Reduction in body weight, BMI, and absolute change in total body fat percent was similar between the gastric bypass and sleeve gastrectomy groups at

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h M th 12


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24 months. The absolute reduction in truncal fat from baseline was greater among those who underwent gastric bypass (-15.9%) compared with those who underwent sleeve gastrectomy (-10.1%; P=0.04).

Insulin sensitivity, beta-cell functionGreater increases in insulin sensitivity and beta-cell function at 24 months were seen in the gastric bypass group. Insulin sensitivity (median) at 24 months vs baseline:• Gastric bypass: 3.8 vs 1.4 (P<0.001) – 2.7-fold increase • Sleeve gastrectomy: 5.8 vs 5.3 – 1.2-fold increase • Medical therapy: no change

Beta-cell function (median absolute change) at 24 months vs baseline: • Greater with gastric bypass vs medical therapy:* 0.196 vs 0.027 (P=0.001) • No difference between sleeve gastrectomy and medical therapy:* 0.058 vs 0.027 (P=0.30) • Median 5.8 fold-increase from baseline with gastric bypass; negligible increases in other groups • Inverse correlation seen with percentage of truncal fat and prandial free fatty acid levels

About this study• 2-year extension of a metabolic substudy of the STAMPEDE trial • Evaluated effect on glucose regulation, beta-cell function, and body composition at 12 and 24 months of: intensive medical therapy, intensive medical therapy + Roux-en-Y gastric bypass, and intensive medical therapy + sleeve gastrectomy • Randomization: 1:1:1 • Subjects (N=60) ○ Uncontrolled type 2 diabetes (mean A1C 9.7%) ○ Moderate obesity (average BMI 36 kg/m2)

*Oral disposition indexSTAMPEDE=Surgical Treatment and Medications Potentially Eradicate Diabetes Effi cientlyBMI=body mass index; FPG=fasting plasma glucose

Kashyap SR, Bhatt DL, Wolski, et al. Metabolic effects of bariatric surgery in patients with moderate obesity and type 2 diabetes: analysis of a randomized control trial comparing surgery with intensive medical treatment. Diabetes Care. 2013;36:2175-2182.

Severe hypoglycemia is associated with nearly twice the risk for CVD, data from a meta-analysis show, with a relative risk of 2.05 (95% CI 1.74 to 2.42; P<0.001).

Severe hypoglycemia occurred in 0.6% to 5.8% of subjects during follow-up. When a bias analysis was conducted, fi ndings showed that the association seen between severe hypoglycemia and CVD may not be entirely due to confounding by severe comorbid illness: comorbid severe illness would had to have been extremely strongly associated with both severe hypoglycemia and CVD. Moderate heterogeneity was seen between studies (I2=73.1%; P=0.002 for heterogeneity); however most of the subgroups examined showed similar results in stratifi ed analyses.

The analysis included six cohort studies of patients with type 2 diabetes (N=903,510). Mean diabetes duration was 3.2-11.5 years and mean study follow-up was 1 to 5.6 years.

CI=confi dence interval; CVD=cardiovascular disease; RR=relative risk

Goto A, Onyebuchi AA, Goto M, Terauchi Y, Noda M. Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis. BMJ. 2013;347:f4533 doi: 10.1136/bmj.f4533.

Severe Hypoglycemia Nearly Doubles Cardiovascular Disease Risk

Spotlight on: Bariatric Surgery Benefi ts in Patients with Type 2 Diabetes continued

EASD Wrap-UpSummaries of important clinical data presented at the 2013 EASD meeting in Barcelona.

Select “On-Demand Programs > Conference Coverage” on the NDEI.org homepage.

Create your customized slide presentation! Slides on all of the studies featured in this issue of Clinical Insights® are available for download in our Slide Library.


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Diabetes Risk Highest Among Atorvastatin, Rosuvastatin UsersFindings from a retrospective study showed that individuals using the statins, atorvastatin and rosuvastatin, had the highest risk of new-onset diabetes.1 The study examined the rate of incident diabetes over follow-up of 14 years.

When compared with pravastatin (reference drug), the rate of incident diabetes was highest for atorvastatin and rosuvastatin. Increased risk of new-onset diabetes was seen in patients treated with atorvastatin, rosuvastatin, and simvastatin vs pravastatin. The number of outcomes/1000 person-years (adjusted HR [95% CI]: • Pravastatin (n=38,470): 22.64 (ref) • Atorvastatin (n=268,254): 30.70 (1.22 [1.15 to 1.29]) • Fluvastatin (n=5,636): 21.52 (0.95 [0.81 to 1.11])* • Lovastatin (n=6,287): 21.80 (0.99 [0.86 to 1.14]) • Rosuvastatin (n=76,774): 34.21 (1.18 [1.10 to 1.26])* • Simvastatin (n=75,829): 26.22 (1.10 [1.04 to 1.17])

The rate of incident diabetes was also highest for atorvastatin and rosuvastatin compared with pravastatin for both primary and secondary prevention (data not shown).*

When statins were stratifi ed by potency, the rate of incident diabetes was greater for high- vs moderate- or low-potency statins compared with pravastatin. The number of outcomes/1000 person-years (adjusted HR [95% CI]: • Pravastatin (n=38,470): 22.64 (ref) • High potency (atorvastatin, rosuvastatin; n=345,028): 31.34 (1.22 [1.15 to 1.29) • Moderate potency (simvastatin; n=75,829): 26.22 (1.11 [1.04 to 1.18]) • Low potency (fl uvastatin, lovastatin; n=11,923): 21.68 (0.97 [0.87 to 1.09])

About this studyThis retrospective cohort study examined the relationship between new-onset diabetes and use of different statins. Subjects (N=471,250) were aged ≥66 years, were new statin users, and had no diabetes history. The primary outcome was incident diabetes over 14 years.

Statins Confer Increased Diabetes Risk in Meta-Analysis A meta-analysis of placebo-controlled and active-comparator studies found a class-wide effect of statins on increased risk for development of diabetes.2

The analysis included 246,955 subjects. As a class, statins were associated with a higher risk for developing diabetes (OR, 1.09; 95% CI, 1.02-1.16). Rosuvastatin conferred signifi cantly higher diabetes risk than control in placebo-controlled trials (OR, 1.16; 95% CI,1.02-1.31).

Clinically signifi cant all-cause mortality benefi ts of statins in primary prevention were also noted. The study authors noted that at the population level, mortality and cardiovascular benefi ts of statin therapy greatly outweigh potential harm, even when considering the recent fi nding that statin therapy is associated with a modest increase in diabetes incidence.

Studies Explore Statin Use and Diabetes Risk

Patient Case: Treating Type 2 Diabetes and Renal Impairment

Vivian Fonseca, MD, provides real-world insights.

Select “On-Demand Programs > Case Studies” on the NDEI.org homepage.

rate of incident diabetes was also highest for atorvastatin a

*Fluvastatin is not FDA approved for primary prevention. Rosuvastatin is not FDA approved for secondary prevention.

CI=confi dence interval; HR=hazard ratio; OR=odds ratio

1. Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR, Mamdani MM. Risk of incident diabetes among patients treated with statins: population based study. BMJ. 2013;346:f2610 doi:10.1136/bmj.f2610. 2. Naci H, Brugts J, Ades T. Comparative tolerability and harms of individual statins. A study-level network meta-analysis of 246,955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013;6:390-399.

Documents

CV Events in SAVOR-TIMI and EXAMINE DPP - … CI...• Improvement in CVD risk factors, except LDL-C; improvement diminished over time ... CV Events in SAVOR-TIMI and EXAMINE DPP -