What are the long-term cardiovascular outcomes associated with the use of

DPP-4 inhibitors?

Matt Dickinson, PharmD/MBA Candidate

Idaho State UniversityMarch 11, 2016

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Objectives• Investigate the cardiovascular complications

associated with diabetes• Review current treatment guidelines for type II

diabetes and discuss the oral antidiabetic agents• Describe the utility of dipeptidyl peptidase-4 (DPP-4)

inhibitors • Analyze and evaluate clinical trials investigating

cardiovascular outcomes • Discuss the safety concerns and benefits• Provide recommendations on the use of DPP-4

inhibitors in diabetic patients

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Type II Diabetes1-2

• More than 29 million Americans have type II diabeteso 86 million adults have pre-diabetes

• 1 in 3 Americans will develop diabetes in their lifetime• By 2030 there will be ~500 million diabetics

worldwide • Diabetes and its related complications accounted for

$245 billion in total medical costs, lost work, and wages in 2012

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Why Study Cardiovascular Outcomes?3-5,14

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The Slippery Slope4

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Heart Failure in Patients With Type 2 Diabetes4,6-7

• Patients with diabetes are much more likely to develop heart failureo 30.9 vs.12.4 cases per 1,000 person-years

• Other important predictors of HF developmento Poor glycemic controlo Ischemic heart diseaseo Ageo Greater BMI

• However, achievement of A1c < 7% is not necessarily associated with a reduction of HF-related hospitalizations

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Why Study Cardiovascular Outcomes?3-4,8-9

• 1999 - Rosiglitazone (Avandia) approved• 2007 - meta analysis

o Increased the risk of MI by 43%o Increased CV mortality by 64%

• 2008 - “To establish safety of a new antidiabetic drug to treat type II diabetes, sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk” -FDA Advisory Committee

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Management of Type II Diabetes

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Available DPP-4 Inhibitors4-5,11

• Sitagliptin (Januvia) 2006+ metformin (Janumet & Janumet XR)+ simvastatin (Juvisync)

• Saxagliptin (Onglyza) 2009+ metformin (Kombiglyze XR)

• Linagliptin (Tradjenta) 2011+ metformin (Jentadueto)

• Alogliptin (Nesina) 2013+ metformin (Kazano)+ pioglitazone (Oseni)

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DPP-4 Inhibitors2,4,11-12

• Also known aso Dipeptidyl peptidase-IV inhibitorso Gliptinso Incretin enhancers

• MOA:o Inhibits dipeptidyl peptidase IV (DPP-4) enzyme prolonged

active incretin levels. o Incretin hormones regulate glucose homeostasis

• increase insulin synthesis and release• decrease glucagon secretion

• HbA1c reduction: 0.5 – 0.7 %• Cost: ~$350-400/month

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Mechanism of Action4-5,11-13

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Characteristics of DPP-4 Inhibitors2,6,11

Drug Sitagliptin Saxagliptin Linagliptin Alogliptin

Dosage Form 25, 50, & 100 mg tablets

2.5 & 5 mg tablets

5 mg tablets 6.25, 12.5, & 25 mg tablets

Usual Dosage 100 mg once daily 2.5 or 5 mg once daily

5 mg once daily 25 mg once daily

Bioavailability 87% 67% 30% 100%

Protein Binding 38% negligible 70-90% 20%

Time to Peak 1-4 h 2-4 h 1.5 h 1-2 h

Metabolism Hepatic Hepatic Not extensively metabolized

Not extensively metabolized

Half-life 12.4 h 2.5-3.1 h 12 h 21 h

ADR Nasopharyngitis, URI, peripheral edema

UTI, HA, URI Arthralgia, nasopharyngitis, URI

Nasopharyngitis, URI, HA

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Background Summary• The incidence of diabetes continues to increase across

the world• Diabetes increases the likelihood of an MI, stroke, HF or

other cardiovascular event• Oral antidiabetic agents must show that they do not

result in an unacceptable increase in cardiovascular risk• DPP-4 inhibitors have become an important piece of the

standard of care • Long-term cardiovascular outcomes are not fully

understood

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Clinical Question

What are the long-term cardiovascular outcomes

associated with the use of DPP-4 inhibitors?

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Literature Search• PubMed (9/21/15)

o Dipeptidyl peptidase 4 inhibitor AND cardiovascular AND (risk OR event)

• 112 resultso Filters: clinical trials, humans, within last 10 years

• 16 resultso Excluded: outcomes other than cardiovascular events,

combination treatments with other drugs, drugs not FDA approved (vildagliptin and voglibose)

• 5 results

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Excluded Studies15-17

Author/ Trial Name

Study Design Patients Treatment Primary End Point

Results

White, WB, Cannon CP, Heller SR, et. Al.   EXAMINE

Randomized, multicentered, placebo-controlled, double-blind trial

5380 patients who had an acute coronary syndrome within the last 15-90 days

Alogliptin vs. placebo over a mean of 1.5 years

CV death, Nonfatal MI, or Nonfatal stroke

Alogliptin was noninferior to placebo 11.3% vs. placebo 11.8%; HR = 0.96*

Marx N, Rosenstock J, Kahn SE, et. Al.  

CAROLINA

Randomized, multicentered, double-blind trial

6041 patients with mean diabetes duration of 6.2 years

Linagliptin vs. glimepiride

CV death, Nonfatal MI, Nonfatal stroke, or hospitalization for unstable angina

To be concluded in 2018

Gallwitz B, Rosenstock J, Rauch T, et. Al.

Randomized, double-blind, non-inferiority trial

1552 patients with HbA1c 6.5-10% who were inadequately controlled on metformin

Linagliptin vs. glimepiride over 2 years

change in HbA1c from baseline to week 104. Secondary end point included CV outcomes

Linagliptin had significantly fewer CV events (RR 46%)

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Selected Studies8,9

Study 1 Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI 53)

Study 2 Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes (TECOS)

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Study 18

SAVOR-TIMI 53Saxagliptin and cardiovascular outcomes in

patients with type 2 diabetes mellitus.

New England Journal of Medicine, 2013

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SAVOR: Objectives8

• Primaryo Determine if saxagliptin increases the risk of

cardiovascular events when added to standard of care in high risk patients

• Secondaryo Determine if saxagliptin decreases risk of

cardiovascular events to test the hypothesis that improved glycemic control will reduce macrovascular events

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SAVOR: Methods8

• Randomized• Multicenter

o 788 siteso 26 countries

• Double-blind • Placebo-controlled • Phase-4 clinical trial

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SAVOR: Inclusion Criteria8,18

• Documented history of type II diabetes o A1c level of 6.5% to 12.0%

• History of established cardiovascular disease o Men or women 40+ years of age with a history of a clinical event

associated with atherosclerosis• ischemic heart disease and/or• peripheral vascular disease and/or • ischemic stroke

• Or multiple risk factors for vascular disease o Men 55+ years of age or women 60+ with hypertension,

dyslipidemia, and/or currently smoking

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SAVOR: Exclusion Criteria8,18

• Current or previous (within 6 months) treatment with an incretin-based therapy

• Acute vascular (cardiac or stroke) event less than 2 months before randomization

• Initiation of chronic dialysis and/or renal transplant and/or serum creatinine higher than 6.0 mg/dL

• Pregnant or breast-feeding • History of human immunodeficiency virus • Treated for severe autoimmune disease

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SAVOR: Exclusion Criteria8,18

• Receiving long-term treatment (>30 consecutive days) of oral corticosteroids

• Patients witho BMI > 50 kg/m2 o Last measured A1c 12% or greater o Sustained BP > 180/100 mmHg o LDL > 250 mg/dL, TG > 1,000 mg/dL, or HDL < 25 mg/dL in the

previous 6 months regardless of lipid-lowering therapy o Known LFTs > 3 times ULN within the previous 6 months

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SAVOR: Exclusion Criteria8,18

• Any condition that renders the patient unable to complete the study, (e.g., active malignancy, cardiomyopathy) with a likely fatal outcome within 5 years

• Involvement in the planning and/or conduct of study• Participation in another clinical study within 30 days

before first visit • Individuals at risk for poor protocol or medication

compliance

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SAVOR: Study Design8,18

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SAVOR: Baseline Characteristics8

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SAVOR: Baseline Characteristics8

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SAVOR: End Points8

• Primary End Pointo Composite of cardiovascular death, nonfatal myocardial

infarction, or nonfatal ischemic stroke • Secondary End Point

o Primary composite plus hospitalization for heart failure, coronary revascularization or unstable angina

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SAVOR: Safety End Points8

• Severe Infection• Opportunistic Infection• Hypersensitivity Reaction• Bone Fracture • Skin Reaction• Cancer • Any pancreatitis

• Any Hypoglycemiao Major or minor

• Liver abnormalitieso ALT > 10X ULNo AST > 3X ULNo AST or ALT > 3X ULN and total

bilirubin > 2X ULN

• Renal abnormality• Thrombocytopenia• Lymphocytopenia

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SAVOR: Statistical Analysis8

• Primary safety and efficacy analysiso Intent‐to‐treat (ITT) ‐ all randomized subjects

• Sensitivity analysis o Modified intent‐to‐treat as a sensitivity analysis

• Subjects who received at least 1 dose of study medication• Only events that occurred within 30 days of the last dose

• Cox proportional hazards model o Stratified by baseline renal function and CV risk group with

treatment as a model term• P-value < 0.049 was considered statistically significant • 2-year Kaplan-Meier rates

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SAVOR: Statistical Analysis8

• Control for type I erroro Alpha = 2.45%, 1-sided level HR < 1.30 (chosen by the FDA)

• If null hypothesis is rejected, saxagliptin is considered non-inferior to placebo

o Approximately 1,040 primary end points required• Providing 85% power to test for superiority• Providing 98% power to test for noninferiority

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SAVOR: Glucose Results8

• A1c was significantly lower than placebo group at o 1 year (7.6% vs. 7.9%)o 2 years (7.5% vs. 7.8%) o End of treatment period (7.7% vs. 7.9%) o P < 0.001 for all comparisons

• Significantly more patients in the saxagliptin group achieved an A1c < 7%o 36.2% vs. 27.9%, p < 0.001

• Significantly more patients in the saxagliptin group experienced hypoglycemic events o 15.3% vs. 13.4%, p < 0.001

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Concomitant Medications8,18

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Concomitant Medications8,18

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SAVOR: Results8

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SAVOR: Results8

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SAVOR: Results8

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Causes of CV Death8,18

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SAVOR: Hospitalization Due to HF Event Distribution8,18

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HF and DPP-4 Inhibitors19

• Increased hospitalization due to HF may be related to several neurohormonal axes, namely substance P (SP) and neuropeptide Y (NP-Y)

• SP and NP-Y are byproducts of DPP-4 inhibitiono SP acts as a vasodilator but also increases sympathetic outflowo NP-Y causes vasoconstrictiono May increase sympathetic activity worsening of HF in diabetes

patients • Low dose ACE-I + sitagliptin = lower blood pressure• High dose ACE-I + sitagliptin = higher blood pressure

o ACE degrades SP

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Baseline Characteristics Revisited18,19

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SAVOR: Critique8,18

• Strengths o Randomized, placebo-controlled, double-blind, multicentered o Large population o Physicians were allowed to treat at their discretion o Adjudication of events by an independent, blinded committee of

cardiologists o Independent data analysis performed by TIMI study group

• Limitations o Effects from lifestyle modifications or other medications were not

analyzed o A median of 2 years may not be long enough to see the

beneficial/harmful effects o Practice between prescribers can vary immenselyo Funded by AstraZeneca and Bristol-Myers Squibb

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SAVOR: Author’s Conclusions8

• When added to standard of care in diabetic patients at high risk for CV events, saxagliptin was noninferior to placebo in terms of increasing or decreasing the risk of cardiovascular death, MI, or ischemic stroke.

• More patients in the saxagliptin group than in the placebo group were hospitalized due to heart failureo New data that was not observed in phase 2 & 3 trials

• Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes

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Study #29

TECOSEffect of Sitagliptin on Cardiovascular

Outcomes in Type 2 Diabetes.

New England Journal of Medicine, 2015

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TECOS: Objective9

• Assess the long-term CV safety of adding sitagliptin to usual care, as compared with usual care alone, in patients with type 2 diabetes and established CV disease and inadequate glycemic control

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TECOS: Methods9

• Randomized• Multicenter

o 673 siteso 38 countries

• Double-blind• Placebo-controlled• Phase-4 clinical trial

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TECOS: Inclusion Criteria9

• Aged ≥ 50 years with type 2 diabetes • Documented vascular disease in the coronary, cerebral,

or peripheral arteries • Patients with inadequate control (HbA1c of 6.5%–8.0%)

for at least 3 months despite: o Monotherapy or dual combination therapy with metformin,

pioglitazone, and/or SUo Insulin as monotherapy or in combination with metformin

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TECOS: Exclusion Criteria9

• Planned or anticipated revascularization procedure

• Cirrhosis of the liver• Pregnancy • Known allergy or

intolerance to sitagliptin• Type 1 diabetes

• ≥ 2 episodes of severe hypoglycemia requiring assistance ≤12 months prior to enrollment

• Use of DPP-4 inhibitor, GLP-1 analogue, or TZD other than pioglitazone ≤ 3 months prior to enrollment

• eGFR < 30 mL/min/1.73 m2

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TECOS: Study Design9,20

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Comparing SAVOR and TECOS8-9,18,20

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TECOS: Baseline Characteristics9,20

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TECOS: Concomitant Medications9,20

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TECOS: End Points9

• Primary o Composite of the first confirmed event of CV death, nonfatal MI,

nonfatal stroke, or hospitalization for unstable angina.• Secondary

o Time to the occurrence of the individual components of the primary end point

o Time to all-cause mortality o Time to hospital admission for heart failure

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TECOS: Safety End Points9

• Severe infection• Opportunistic infection• Hypersensitivity reaction• Bone fracture • Diabetic neuropathy• Diabetic eye disease• Gangrene• Cancer • Any pancreatitis

• Any hypoglycemiao Major or minor

• Liver abnormalitieso ALT > 10X ULNo AST > 3X ULNo AST or ALT > 3X ULN and total

bilirubin > 2X ULN

• Renal abnormality• Thrombocytopenia• Lymphocytopenia• PVD• GI conditions

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TECOS: Statistical Analysis9

• Goal: the upper boundary of the two-sided 95% CI of the HR for the risk of the primary composite CV outcome < 1.3o Cox proportional-hazards model to calculate HR and two-sided

95% CIo Noninferiority – assuming HR of 1.00

• Upper limit of (95% CI) < 1.3 • 611 patients with primary CV end point would provide 90%

powero Superiority – assuming HR of 0.85

• Upper limit of (95% CI) < 1.0• 1,300 patients with primary CV end point would provide 81%

power• 2-year Kaplan-Meier rates

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TECOS: Glucose Results9

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TECOS: Results9

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TECOS: Results9

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TECOS: Results9

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TECOS: Results9

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TECOS: Results9

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TECOS: Results9

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TECOS: Critique9,20

• Strengthso Randomized, placebo-controlled, double-blind, multicentered o Designed and run independently by the Duke Clinical Research

Institute (DCRI) and the University of Oxford Diabetes Trials Unit (DTU)o Large patient populationo Physicians were allowed to treat at their discretion reflecting clinical

practiceo Longer follow up than any previous trial

• Weaknesseso Limited acquisition of data pointso Included only patients with A1c of 6.5-8.0%o Effects from lifestyle modifications or other medications were not

analyzedo Practice between prescribers can vary immenselyo Funded by Merck Sharp & Dohme

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TECOS: Author’s Conclusions9,20

• Addition of sitagliptin to usual care did not affect rates of major cardiovascular events.

• Sitagliptin therapy did not change rates of death from any cause, cardiovascular death, or noncardiovascular death.

• Sitagliptin therapy was not associated with changes in rates of hospitalization for heart failure (HR = 1.00), as has been suggested in trials of other DPP-4 inhibitorso No between-group differences in the rate of the composite

outcome of hospitalization for heart failure or cardiovascular death • No significant increase in the rate of severe hypoglycemia

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Clinical Question

What are the long-term cardiovascular outcomes

associated with the use of DPP-4 inhibitors?

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My Conclusions• DPP-4 inhibitors as a class do not appear to increase the

risk of cardiovascular events when compared to placeboo Conflicting data between heart failure resultso Longer trials may be more insightful (5-10 years)o Await the results of the CAROLINA trialo Are GLP-1 agonists safer?

• Do not recommend saxagliptin for patients with heart failure or those at high risk

• Are these medications worth the risk or $350+ per month for the low-moderate HbA1c benefit?

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Questions?

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References1. Centers for Disease Control and Prevention. National diabetes statistics report: estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2014. 2. Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011 May;34 Suppl 2:S276-8. 3. Sarwar N, Gao P, Seshasai SR, et al. The Emerging Risk Factors Collaboration. Diabetes Mellitus, Fasting Blood Glucose Concentration, and Risk of Vascular Disease: A Collaborative Meta-Analysis of 102 Prospective Studies. Lancet 375.9733 (2010): 2215–2222. 4. Paneni F. DPP-4 inhibitors, heart failure and type 2 diabetes: all eyes on safety. Cardiovasc Diagn Ther. 2015 Dec;5(6):471-8.5. Clifton P. Do dipeptidyl peptidase IV (DPP-IV) inhibitors cause heart failure? ClinTher. 2014 Dec 1;36(12):2072-9.6. Takahashi A, Ihara M, Yamazaki S, et. Al. Impact of Either GLP-1 Agonists or DPP-4 Inhibitors on Pathophysiology of Heart Failure. Int Heart J. 2015;56(4):372-6. 7. Nichols G et al. The Incidence of Congestive Heart Failure in Type 2 Diabetes. Diabetes Care. 2004;27:1879–1884

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References Cont.8. Scirica BM, Bhatt DL, Braunwald E, Steg PG, et. Al. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013 Oct 3;369(14):1317-26.9. Green JB, Bethel MA, Armstrong PW, Buse JB, et. Al. TECOS Study Group. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 16;373(3):232-42.10. Garber AJ, Abrahamson MJ, Barzilay JI, et. Al Consensus Statement by The American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2016 Executive Summary . Endocr Pract. 2016 Jan;22(1):84-113.11. Saxagliptin, Sitagliptin, Alogliptin, Linogliptin. Drug Facts and Comparisons. Facts and Comparisons. Clinical Drug Information, LLC.; From http://online.factsandcomparisons.com12. Read PA, Khan FZ, Heck PM, Hoole SP, Dutka DP. DPP-4 inhibition by sitagliptin improves the myocardial response to dobutamine stress and mitigates stunning in a pilot study of patients with coronary artery disease. Circ Cardiovasc Imaging. 2010 Mar;3(2):195-201.

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References Cont.13. Deacon CF, Nauck MA, Toft-Nielsen M et. Al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995 Sep;44(9):1126-31.14. Lehrke M, Marx N. Cardiovascular Effects of Incretin-Based Therapies. The Review of Diabetic Studies : RDS. 2011;8(3):382-391. doi:10.1900/RDS.2011.8.382.15. White WB, Cannon CP, Heller SR, Nissen SE, et. Al. EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013 Oct 3;369(14):1327-35.16. Gallwitz B, Rosenstock J, Rauch T, Bhattacharya S. et. Al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 201217. Marx N, Rosenstock J, Kahn SE, Zinman B. et. Al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res. 2015 May;12(3):164-74.

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References Cont.18. Scirica BM, Bhatt DL, Braunwald E, Steg PG et. al. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 53 study. Am Heart J. 2011 Nov;162(5):818-825.19. Marney A, Kunchakarra S, Byrne L, Brown NJ. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension. 2010 Oct;56(4):728-33.20. Green JB, Bethel MA, Paul SK et.al. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J. 2013 Dec;166(6):983-989.e7. 21. Sportiello L, Rafaniello C, Scavone C, Vitale C, Rossi F, Capuano A. The importance of Pharmacovigilance for the drug safety: Focus on cardiovascular profile of incretin-based therapy. Int J Cardiol. 2016 Jan 1;202:731-5. 22. Ravassa S, Barba J, Coma-Canella I. et. al. The activity of circulating dipeptidyl peptidase-4 is associated with subclinical left ventricular dysfunction in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2013 Oct 7;12:143.23.23. Petrie JR. The cardiovascular safety of incretin-based therapies: a review of the evidence. Cardiovasc Diabetol. 2013 Sep 6;12:130.

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Discussion - CaseJan Uvia is a 60 y/o female diagnosed with type II diabetes 10 years ago, NYHA Stage II HF 3 years ago, as well as an MI 2 years ago. She currently has a BMI of 31 and a recent HbA1c of 8.8%. She is hesitant to do any injections and hopes to use only oral medications. Meds: metformin 1000 mg BID, ramipril 10 mg daily, ASA 81 mg daily, metoprolol XL 100 mg daily, atorvastatin 80 mg daily, lasix 40 mg daily, glipizide XL 10 mg daily. • Do you feel comfortable adding a DPP-4 inhibitor? If so,

which one?• Alternatively, let’s say she’s been taking saxagliptin for 2

years and her heart failure is now stage III. Would you substitute it for something else?

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Discussion• From the data presented, do you think that the increase

in hospitalization due to heart failure can be considered a class effect or drug-specific only?

• These medications can cost up to $400 per month. Who should pay for them? Do you think that they’re cost effective?

• What future research do you think would be the most valuable to assess the utility of DPP-4 inhibitors?