1. What are the long-term
cardiovascular outcomes
associated with the use of
DPP-4 inhibitors?
Matt Dickinson, PharmD/MBA Candidate
Idaho State University
March 11, 2016

2. 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
2

3. Type II Diabetes1-2
• More than 29 million Americans have type II diabetes
o 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
3

4. Why Study Cardiovascular
Outcomes?3-5,14
4

5. The Slippery Slope4
5

6. Heart Failure in Patients With
Type 2 Diabetes4,6-7
• Patients with diabetes are much more likely to develop
heart failure
o 30.9 vs.12.4 cases per 1,000 person-years
• Other important predictors of HF development
o Poor glycemic control
o Ischemic heart disease
o Age
o Greater BMI
• However, achievement of A1c < 7% is not necessarily
associated with a reduction of HF-related
hospitalizations
6

7. 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
7

8. Management of
Type II Diabetes
8

9. 9

10. 10

11. 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)
11

12. 12

13. DPP-4 Inhibitors2,4,11-12
• Also known as
o Dipeptidyl peptidase-IV inhibitors
o Gliptins
o 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
13

14. Mechanism of Action4-5,11-13
14

15. 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
15

16. 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
16

17. Clinical Question
What are the long-term
cardiovascular outcomes
associated with the use of DPP-4
inhibitors?
17

18. Literature Search
• PubMed (9/21/15)
o Dipeptidyl peptidase 4 inhibitor AND cardiovascular AND (risk
OR event)
• 112 results
o Filters: clinical trials, humans, within last 10 years
• 16 results
o Excluded: outcomes other than cardiovascular events,
combination treatments with other drugs, drugs not FDA
approved (vildagliptin and voglibose)
• 5 results
18

19. Excluded Studies15-17
19
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%)

20. 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)
20

21. Study 18
SAVOR-TIMI 53
Saxagliptin and cardiovascular outcomes in
patients with type 2 diabetes mellitus.
New England Journal of Medicine, 2013
21

22. SAVOR: Objectives8
• Primary
o Determine if saxagliptin increases the risk of
cardiovascular events when added to standard of
care in high risk patients
• Secondary
o Determine if saxagliptin decreases risk of
cardiovascular events to test the hypothesis that
improved glycemic control will reduce macrovascular
events
22

23. SAVOR: Methods8
• Randomized
• Multicenter
o 788 sites
o 26 countries
• Double-blind
• Placebo-controlled
• Phase-4 clinical trial
23

24. 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
24

25. 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
25

26. SAVOR: Exclusion Criteria8,18
• Receiving long-term treatment (>30 consecutive days) of
oral corticosteroids
• Patients with
o 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
26

27. 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
27

28. SAVOR: Study Design8,18
28

29. SAVOR:
Baseline Characteristics8
29

30. SAVOR:
Baseline Characteristics8
30

31. SAVOR: End Points8
• Primary End Point
o 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
31

32. SAVOR: Safety End Points8
• Severe Infection
• Opportunistic Infection
• Hypersensitivity Reaction
• Bone Fracture
• Skin Reaction
• Cancer
• Any pancreatitis
32
• Any Hypoglycemia
o Major or minor
• Liver abnormalities
o ALT > 10X ULN
o AST > 3X ULN
o AST or ALT > 3X ULN and total
bilirubin > 2X ULN
• Renal abnormality
• Thrombocytopenia
• Lymphocytopenia

33. SAVOR: Statistical Analysis8
• Primary safety and efficacy analysis
o 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
33

34. SAVOR: Statistical Analysis8
• Control for type I error
o 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
34

35. 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
35

36. Concomitant Medications8,18
36

37. Concomitant Medications8,18
37

38. SAVOR: Results8
38

39. SAVOR: Results8
39

40. SAVOR: Results8
40

41. Causes of CV Death8,18
41

42. SAVOR: Hospitalization Due to
HF Event Distribution8,18
42

43. 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 inhibition
o SP acts as a vasodilator but also increases sympathetic outflow
o NP-Y causes vasoconstriction
o 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
43

44. Baseline Characteristics
Revisited18,19
44

45. 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 immensely
o Funded by AstraZeneca and Bristol-Myers Squibb 45

46. 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 failure
o 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
46

47. Study #29
TECOS
Effect of Sitagliptin on Cardiovascular
Outcomes in Type 2 Diabetes.
New England Journal of Medicine, 2015
47

48. 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
48

49. TECOS: Methods9
• Randomized
• Multicenter
o 673 sites
o 38 countries
• Double-blind
• Placebo-controlled
• Phase-4 clinical trial
49

50. 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 SU
o Insulin as monotherapy or in combination with metformin
50

51. TECOS: Exclusion Criteria9
• Planned or anticipated
revascularization
procedure
• Cirrhosis of the liver
• Pregnancy
• Known allergy or
intolerance to sitagliptin
• Type 1 diabetes
51
• ≥ 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

52. TECOS: Study Design9,20
52

53. Comparing SAVOR and
TECOS8-9,18,20
53

54. TECOS: Baseline Characteristics9,20
54

55. TECOS: Concomitant Medications9,20
55

56. 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
56

57. TECOS: Safety End Points9
• Severe infection
• Opportunistic infection
• Hypersensitivity reaction
• Bone fracture
• Diabetic neuropathy
• Diabetic eye disease
• Gangrene
• Cancer
• Any pancreatitis
57
• Any hypoglycemia
o Major or minor
• Liver abnormalities
o ALT > 10X ULN
o AST > 3X ULN
o AST or ALT > 3X ULN and total
bilirubin > 2X ULN
• Renal abnormality
• Thrombocytopenia
• Lymphocytopenia
• PVD
• GI conditions

58. 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 < 1.3
o Cox proportional-hazards model to calculate HR and two-sided
95% CI
o Noninferiority – assuming HR of 1.00
• Upper limit of (95% CI) < 1.3
• 611 patients with primary CV end point would provide 90%
power
o 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
58

59. TECOS: Glucose Results9
59

60. TECOS: Results9
60

61. TECOS: Results9
61

62. TECOS: Results9
62

63. TECOS: Results9
63

64. TECOS: Results9
64

65. TECOS: Results9
65

66. TECOS: Critique9,20
• Strengths
o 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 population
o Physicians were allowed to treat at their discretion reflecting clinical
practice
o Longer follow up than any previous trial
• Weaknesses
o Limited acquisition of data points
o Included only patients with A1c of 6.5-8.0%
o Effects from lifestyle modifications or other medications were not
analyzed
o Practice between prescribers can vary immensely
o Funded by Merck Sharp & Dohme 66

67. 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 inhibitors
o 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
67

68. Clinical Question
What are the long-term
cardiovascular outcomes
associated with the use of DPP-4
inhibitors?
68

69. My Conclusions
• DPP-4 inhibitors as a class do not appear to increase the
risk of cardiovascular events when compared to placebo
o Conflicting data between heart failure results
o Longer trials may be more insightful (5-10 years)
o Await the results of the CAROLINA trial
o 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?
69

70. Questions?
70

71. References
1. 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 71

72. 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.com
12. 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.
72

73. 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. 2012
17. 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.
73

74. 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.
74

75. 75

76. Discussion - Case
Jan 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? 76

77. 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?
77