What’s New In The Diabetes Treatment? The TECOS Results · EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus

What’s New In The Diabetes Treatment? The TECOS Results

Dr. F. Javier Ampudia-BlascoUnidad de Referencia de DiabetesS. de Endocrinología y Nutrición

Hospital Clínico Universitario de Valencia

[email protected]

XXXIV LECCIÓN MEMORIALToday Moving Frontiers To Stay Healthy And Living Well Forever

Madrid, 26 de Octubre 2015

Diabetes Is Associated With Increased Risk of CV Disease

• Diabetes confers an increased risk for MI, stroke, and PAD1–3

• It is not clear whether diabetes should be considered a cause or a comorbidity of heart failure4

– Diabetes is associated with an increased risk of developing HF in patients with other causes (eg, acute MI) and is believed to promote diastolic dysfunction

• Diabetes is associated with a 2- to 3-fold increase in the risk of CV and all-cause mortality5

1. Emerging Risk Factors Collaboration. Lancet. 2010;375:2251–2222. 2. American Diabetes Association. Diabetes Care. 2003;26:3333–3341. 3. American Diabetes Association. Diabetes Care. 2014;37:S14–S80. 4. McMurray JJV et al. Lancet

Diabetes Endocrinol. 2014; DOI 10.1016/S2213-8587(14)70031-2. 5. Gregg EW et al. Ann Int Med. 2007;147:149–156.

Am

pu

dia

-Bla

sco

FJ,

MD

CV = cardiovascular; MI = myocardial infarction; PAD = peripheral artery disease; CHD = coronary heart disease; HF

Heart Failure in Patients With Type 2 Diabetes

3,09

1.24

0

0,5

1

1,5

2

2,5

3

3,5

With Diabetes WithoutDiabetes

Incidence of CHF(cases per 100 person-years)

CHF = congestive heart failure; T2DM = type 2 diabetes mellitus; CI = confidence interval.

Retrospective cohort study to update estimates of CHF rate in patients with T2DM

– Follow-up of up to 72 months

1,167 of 8,231 patients with T2DM had incident CHF, vs 526 of 8,845 patients without T2DM

Patients with T2DM experienced CHF at 2.5 times the rate of comparison subjects without T2DM

– (rate ratio: 2.5 [95% CI 2.3–2.7])

P<0.001

Am

pu

dia

-Bla

sco

FJ,

MD

Nichols G et al. Diabetes Care. 2004;27:1879–1884.

Ratio 2.5

Agenda

• Improving glycemic control and CV outcomes

• Lights and shadows on DPP-4 inhibitors? Results from SAVOR-TIMI 53 and EXAMINE.

• TECOS results

• Impact of TECOS in clinical practice

Am

pudia

-Bla

sco F

J,

MD

UKPDS: Micro- and macrovascular complications increase as a function of HbA1c in type 2 diabetes

Estimated 37% decrease in microvascular risk for each 1% reduction in HbA1c

(p<0.0001)

Estimated 14% decrease in myocardial infarction riskfor each 1% reduction in HbA1c

(p<0.0001)

Stratton IM, et al. BMJ. 2000;321:405-12.

Adju

ste

d incid

ence p

er

1000

pers

on y

ears

(%

)

10

30

0

50

60

20

40

10.59.57.5 8.55.5 6.5

Myocardial infarction

Microvascular endpoints

Updated mean HbA1c concentration (%)

Am

pudia

-Bla

sco F

J,

MD

However, in clinical trials, interventions to lower HbA1c

have only reduced microvascular complications

Impact of Intensive vs Conventional Glycemic-Lowering Strategies on Risk of CV Outcomes Is Unclear

StudyDiabetes Duration (mean)

Antihyperglycemic Medicationa

Follow-up(median)

HbA1c: Baseline, Between-arm

DifferenceMicrovascular CVD Mortality

UKPDS1

Newly diagnosed

SU/insulin or metformina vs dietary restriction

10 years7.1% (all patients)b,

–0.9%c ↓ ↔ ↔UKPDS

Long-term follow-up2

10 years post

intervention

No difference in

HbA1c between

treatment armsd↓ ↓ ↓

ADVANCE3 8 yearsIntensive glucose control

including gliclazide vs standard treatment

5 years7.5% (both arms)b,

–0.8%d ↓ ↔ ↔ACCORD4,5 10 years Multiple drugs in both arms 3.4 years

8.1% (both arms)e, –1.1%c ↓ ↔ ↑

VADT6 11.5 years Multiple drugs in both arms 5.6 years9.4% (both arms)b,

–1.5%d ↔ ↔ ↔

aObese patients; bMean baseline HbA1c; cMedian between-arm difference; dMean between-arm difference; eMedian baseline HbA1c.

CV = cardiovascular; UKPDS = United Kingdom Prospective Diabetes Study (UKPDS); ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ACCORD = Action to Control Cardiovascular Risk in Diabetes; VADT = Veterans Affairs Diabetes Trial.

1. UKPDS Group. Lancet. 1998;352:837–853. 2. Holman RR et al. N Engl J Med. 2008;359:1577–1589. 3. ADVANCE Collaborative Group et al. N Engl J Med. 2008;358:2560–2572. 4. Gerstein HC et al. N Engl J Med. 2008;358:2545–2559. 5. Ismail-Beigi F et al. Lancet. 2010;376:419–430. 6. Duckworth W et al. N Engl J Med. 2009;360:129–139.

Am

pu

dia

-Bla

sco

FJ,

MD

Lowering HbA1c may prevent macrovascular disease if started early, but the effects may not be apparent for a very long time

Am

pu

dia

-Bla

sco

FJ,

MD

Rates of Myocardial Infarction and Death from Cardiovascular Causes with Rosiglitazone

Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471.

Am

pu

dia

-Bla

sco

FJ,

MD

FDA Guidance for Industry to Evaluate CV Risk in New Antihyperglycemic Medications- July 2008

• Effects on CV risk to be more thoroughly addressed during antihyperglycemic medication development

• Recommendation to demonstrate that therapy will not result in unacceptable increase in CV risk

• Key areas to be addressed by study sponsors (inclusion of patients with a higher risk of CV events [eg, patients with advanced CV disease, elderly patients, and patients with impaired renal function], study duration ≥2 years)

T2DM = type 2 diabetes mellitus; CV = cardiovascular.

Center for Drug Evaluation and Research. Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. December 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed September 12, 2014.

Am

pu

dia

-Bla

sco

FJ,

MD

FDA Statistical Criteria for Approval1

Five hypothetical examples of possible HRs, and regulatory consequences

FDA = Food and Drug Administration; HR = hazard ratio; CV = cardiovascular.1. Reproduced with permission from Hirshberg B et al. Diabetes Care. 2011:34; (Suppl 2)S101–S106.

BESTSuperiority

Noninferiority

Noninferiority

Inferiority

Underpowered

Approvable;CV safety study post approvalmay not be required

Approvable; need for CV safety study

Not approvable

NoninferiorityBoundary

HR 1.3

NoninferiorityBoundary

HR 1.8

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2

Hazard ratio

Am

pu

dia

-Bla

sco

FJ,

MD

Agenda



• TECOS results


Am

pudia

-Bla

sco F

J,

MD

SAVOR-TIMI 53: Saxagliptin was noninferior for the primary composite end point of CV death, nonfatal

MI, and nonfatal stroke

Composite of death from cardiovascular causes, myocardial infarction, or ischemic stroke

Composite of death from cardiovascular causes, myocardial infarction, ischemic stroke, hospitalization for unstable angina, coronary

revascularization, or heart failure

Scirica BM et al. N Engl J Med. 2013;369:1317–1326.

Am

pudia

-Bla

sco F

J,

MD

EXAMINE: Alogliptin was noninferior for the primary composite end point of CV death, nonfatal MI, and

nonfatal stroke

Time to the first occurrence of death from cardiovascular causes, nonfatal myocardial

infarction, or nonfatal stroke

Secondary endpoint: Time to death from cardiovascular causes

White WB, et al. N Engl J Med. 2013;369:1327–1335.

Am

pudia

-Bla

sco F

J,

MD

EXAMINE and SAVOR-TIMI: Hospitalization for Heart Failure

SAVOR-TIMI3

Saxagliptin

n=8,280

Placebo

n=8,212

HR (95% CI)

HHF 3.5% 2.8% 1.27 (1.07–1.51)

EXAMINE1,2

Alogliptin

n=2,701

Placebo

n=2,679

HR (95% CI)

HHFa 3.9% 3.3% 1.19 (0.89–1.58)

SAVOR-TIMI: Hospitalization for HF was significantly increased with saxagliptin compared with placebo3

– Mortality due to HF was not significantly different between saxagliptin and placebo (0.5% for both)3

aPost-hoc analysis.

EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary

Syndrome; SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial

Infarction; HHF = hospitalization for heart failure; HR = hazard ratio; CI = confidence interval; HF = heart failure.

1. Reproduced with permission from White WB et al. N Engl J Med 2013;369:1327–1335. 2. Sanon VP et al. Clin Diabetes. 2014;32:121–126. 3. Reproduced with permission from Scirica

BM et al. N Engl J Med 2013;369:1317–1326.

EXAMINE: In a post-hoc analysis, there was a trend (P=NS) for increased hospitalization for HF with alogliptin compared with placebo2

Am

pu

dia

-Bla

sco

FJ,

MD

CV = cardiovascular; DPP-4 = dipeptidyl peptidase-4; CAD = coronary artery disease; CVD = cardiovascular disease; PAD = peripheral artery disease; ACS = acute coronary syndrome; EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial-Thrombolysis in Myocardial Infarction 53; TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk. 1. White W et al. N Engl J Med. 2013;369:1327–1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317–1326. 3. Bethel MA et al. Diabetes Obes Metab. 2015; 17:395–402. 4. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352. 5. CARMELINA: Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. http://clinicaltrials.gov/ct2/show/ NCT01703298. Accessed September 12, 2014.

Baseline Risk of Patient Populations Enrolled in CV Safety Trials of DPP-4 Inhibitors

Vildagliptin does not have an ongoing CV safety trial

Linagliptin CARMELINA (N=8,300)5

Pre-existing CVD + albuminuria or impaired renal functionEnd Jan 2018

Sitagliptin TECOS (N=14,671)3,4

Pre-existing CVD

Presented

Jun 2015

Alogliptin EXAMINE (N=5,380)1

ACS within 15–90 days

Presented

Sept 2013Saxagliptin SAVOR-TIMI 53 (N=16,492)2

Pre-existing CVD or multiple risk factors for CVD

Presented

Sept 2013

Risk Factors Stable CAD-CVD-PAD Post ACS patients

Am

pudia

-Bla

sco F

J,

MD

Agenda



• TECOS results


Am

pudia

-Bla

sco F

J,

MD

19

Time to first occurrence of:

–Cardiovascular-related death

–Nonfatal myocardial infarction

–Nonfatal stroke

–Hospitalization for unstable angina

A Clinical Endpoints Committee, blinded to therapy allocation,

reviewed all potential CVD endpoints independently.

Primary Composite Cardiovascular Outcome

19Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Am

pu

dia

-Bla

sco

FJ, M

D

Time to —

–Secondary composite CV outcome

(nonfatal MI, nonfatal stroke, or CV-related death)

– First confirmed component event in the primary outcome

(Cardiovascular-related death, nonfatal myocardial infarction,

nonfatal stroke, hospitalization for unstable angina)

– First fatal or nonfatal MI

– First fatal or nonfatal stroke

–All-cause mortality

–Hospitalization for heart failure

–Hospitalization for heart failure or CV-related death

Secondary Cardiovascular Outcomes


Am

pu

dia

-Bla

sco

FJ, M

D

Consort Diagram

14,735randomized

64 excluded from all analyses

• 11 did not consent

• 53 at one site excluded

for GCP deviations

14,671included in ITT analysis

7332 sitagliptin ITT

7180 (97.9%) VS known

6972 (95.1%) completed

61 (0.8%) LTFU29 (48%) VS known

299 (4.1%) Withdrawn179 (60%) VS known

7339 placebo ITT

7123 (97.0%) VS known

6905 (94.1%) completed

71 (1.0%) LTFU33 (46%) VS known

363 (4.9%) Withdrawn185 (51%) VS known

ITT = intention-to-treat; LTFU = lost to follow-up;

VS = vital status, GCP = Good Clinical Practice

Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352

Am

pu

dia

-Bla

sco

FJ, M

D

Characteristic

Sitagliptin

n=7332

Placebo

n=7339

Age (years) 65.4 ± 7.9 65.5 ± 8.0

Women 2134 (29.1%) 2163 (29.5%)

Race

White 4955 (67.6%) 5002 (68.2%)

Black 206 (2.8%) 241 (3.3%)

Asian 1654 (22.6%) 1611 (22.0%)

Other 517 (7.1%) 485 (6.6%)

Hispanic or Latino 886 (12.1%) 912 (12.4%)

BMI (kg/m2) 30.2 ± 5.6 30.2 ± 5.7

eGFR (mL/min/1.73 m2)* 74.9 ± 21.3 74.9 ± 20.9

Baseline Characteristics

Values are mean ±SD for continuous variables or n,% for categorical variables.

*MDRD formula used to calculate eGFR. Site-reported values are presented.


Am

pu

dia

-Bla

sco

FJ, M

D

Characteristic

Sitagliptin

n=7332

Placebo

n=7339

Systolic blood pressure (mmHg) 135 ± 16.9 135 ± 17.1

Diastolic blood pressure (mmHg) 77.1 ± 10.3 77.2 ± 10.6

Total cholesterol (mg/dL) 166.1 ± 44.8 165.4 ± 45.9

LDL-C (mg/dL) 91.2 ± 63.8 90.7 ± 51.2

HDL-C (mg/dL) 43.5 ± 12.0 43.4 ± 13.0

Triglycerides (mg/dL) 166.0 ± 101.0 164.8 ± 98.8

Medication

Aspirin use 5764 (78.6%) 5754 (78.4%)

Statin use 5851 (79.8%) 5868 (80.0%)

Baseline Characteristics—CV Risk Management

Values are mean ±SD for continuous variables or n,% for categorical variables.


Am

pu

dia

-Bla

sco

FJ, M

D

Characteristic

Sitagliptin

n=7332

Placebo

n=7339

Prior cardiovascular disease 5397 (73.6%) 5466 (74.5%)

Myocardial infarction 3133 (42.7%) 3122 (42.5%)

PCI 2814 (38.9%) 2900 (40.1%)

CABG 1845 (25.2%) 1819 (24.8%)

≥50% coronary stenosis 3804 (51.9%) 3883 (52.9%)

Prior cerebrovascular disease 1806 (24.6%) 1782 (24.3%)

Stroke 1297 (17.7%) 1258 (17.1%)

TIA 280 (3.8%) 286 (3.9%)

≥50% carotid stenosis 431 (5.9%) 429 (5.8%)

Peripheral arterial disease 1217 (16.6%) 1216 (16.6%)

History of heart failure 1303 (17.8%) 1340 (18.3%)

Baseline Characteristics—CV Disease


Am

pu

dia

-Bla

sco

FJ, M

D

Characteristic

Sitagliptin

n=7332

Placebo

n=7339

Duration of diabetes (years) 11.6 ± 8.1 11.6 ± 8.1

HbA1c (%) 7.2 ± 0.5 7.2 ± 0.5

Medication taken alone or in combination

Metformin 5936 (81.0%) 6030 (82.2%)

Sulfonylurea 3346 (45.6%) 3299 (45.0%)

Thiazolidinedione 196 (2.7%) 200 (2.7%)

Insulin 1724 (23.5%) 1684 (22.9%)

Median daily dose (units) 50 (33, 80) 50 (32, 80)

Monotherapy 3496 (47.7%) 3498 (47.7%)

Dual combination therapy 3766 (51.4%) 3768 (51.3%)

Baseline Characteristics—Diabetes

Values are mean ±SD or median (IQR) for continuous variables

or n,% for categorical variables.


Am

pu

dia

-Bla

sco

FJ, M

D

Glycemic Control Least Squares Mean HbA1c ± 1SD

Overall LS Mean difference

-0.29% (-0.32, -0.27), p<0.0001


Am

pu

dia

-Bla

sco

FJ, M

D

Primary Composite Cardiovascular Outcome* PP Analysis for Non-inferiority

* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina


Am

pu

dia

-Bla

sco

FJ, M

D

Numbers of patients with events Sitagliptin

n=7332

Placebo

n=7339

Primary composite CV Outcome 839 (11.4%) 851 (11.6%)

4.06 per 100 pyrs 4.17 per 100 pyrs

ITT HR=0.98 (0.89, 1.08), p=0.65

Individual components

• CV death 311 (4.2%) 291 (4.0%)

• Nonfatal MI 275 (3.8%) 286 (3.9%)

• Nonfatal stroke 145 (2.0%) 157 (2.1%)

• Hospitalization for unstable angina 108 (1.5%) 117 (1.6%)

Primary Composite Cardiovascular OutcomeITT Population


Am

pu

dia

-Bla

sco

FJ, M

D

Hospitalization for Heart Failure*ITT Analysis

* Adjusted for history of heart failure at baseline


Am

pu

dia

-Bla

sco

FJ, M

D

Am

pu

dia

-Bla

sco

FJ,

MD

Sitagliptin

n=7332

Placebo

n=7339

Initiation of next antidiabetic medication

ITT HR 0.72 (95% CI 0.68, 0.77), p<0.001

# Patients 1591 (21.7%) 2046 (27.9%)

Event rate per 100 pyrs 8.5 11.6

Cumulative incidence (%) of event

1 year, % (95% CI) 6.7 (6.1, 7.3) 9.3 (8.6, 10.0)

2 years, % (95% CI) 14.9 (14.1, 15.7) 20.3 (19.4, 21.3)

3 years, % (95% CI) 23.4 (22.2, 24.5) 31.3 (30.1, 32.6)

4 years, % (95% CI) 33.1 (31.4, 34.9) 41.5 (39.6, 43.3)

Initiation of Additional Antihyperglycemic Agents


Am

pu

dia

-Bla

sco

FJ, M

D

Initiation of Chronic Insulin Therapy

*Patients not on insulin at baseline

Sitagliptin*

n=5608

Placebo*

n=5655

Initiation of insulin

ITT HR 0.70 (95% CI 0.63, 0.79) p<0.001

# Patients 542 (9.7%) 744 (13.2%)

Event rate per 100 pyrs 3.44 4.85

Cumulative incidence (%) of event

1 year, % (95% CI) 3.2 (2.8, 3.7) 4.8 (4.3, 5.4)

2 years, % (95% CI) 6.4 (5.8, 7.1) 9.7 (8.9, 10.5)

3 years, % (95% CI) 9.8 (9.0, 10.7) 14.1 (13.1, 15.1)

4 years, % (95% CI) 13.2 (12.1, 14.5) 17.5 (16.3, 18.9)


Am

pu

dia

-Bla

sco

FJ, M

D

Sitagliptin Placebo

Participants with event

n (%)

Participants with event

n (%)

160 (2.2%) 143 (1.9%)

Events per 100 patient-years 0.78 0.70

Severe Hypoglycemia*

*Hypoglycemia requiring assistance

ITT HR (95% CI): 1.12 (0.89–1.40), p=0.33


Am

pu

dia

-Bla

sco

FJ, M

D

Patients Events

Sitagliptin

(n=7332)

Placebo

(n=7339)

Sitagliptin Placebo

Acute pancreatitis 23 (0.3%) 12 (0.2%) 25 17

Severe 4 0 4 0

Mild 19 11 21 16

Unknown severity 0 1 0 1

Confirmed Acute Pancreatitis and Pancreatic Cancer

ITT HR 1.93 (0.96, 3.88), p=0.065

35

Sitagliptin

n=7332

Placebo

n=7339

Pancreatic cancer 9 (0.1%) 14 (0.2%)

ITT HR 0.66 (0.28, 1.51), p=0.32


Am

pu

dia

-Bla

sco

FJ, M

D

Agenda



• TECOS results


Am

pudia

-Bla

sco F

J,

MD

TECOS CV Safety Trial: Summary of Results1

Sitagliptin met primary end point (no increased CV risk) when added to usual care in patients with type 2 diabetes and established CV disease

Sitagliptin therapy did not increase all-cause mortality, CV death, or non-CV death

No between-group difference in hospitalization for heart failure

Sitagliptin treatment not associated with a significant increase in severe hypoglycemia

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular.1. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.

Am

pu

dia

-Bla

sco

FJ, M

D

TECOS CV Safety Trial: Summary of Results (continued)1

Fewer patients receiving sitagliptin treatment required additional antihyperglycemic agents or initiation of long-term insulin therapy

Acute pancreatitis uncommon, numerically more frequent in sitagliptin group, whereas pancreatic cancer uncommon, numerically more frequent in placebo group

– Between-group differences not statistically significant

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular.1. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352.

Am

pu

dia

-Bla

sco

FJ, M

D

Am

pu

dia

-Bla

sco

FJ,

MD

Potential reasons for discrepanciesA

mp

ud

ia-B

lasc

o F

J, M

D

Key Takeaways Messages

• Sitagliptin therapy has been shown to be effective in lowering blood glucose when administered as monotherapy or when used in combination with metformin in appropriate patients with type 2 diabetes1–8

• Combination therapy with sitagliptin and metformin improves glycemic control in appropriate patients with type 2 diabetes, with a low risk of hypoglycemia and no weight gain1–8

• TECOS CV Safety Trial showed that treatment with sitagliptin did not increase the risk of major CV events, and did not increase hospitalization for heart failure9

Significance• Most people with type 2 diabetes need antihyperglycemic medicines to help

control their blood sugar10

• Because people with type 2 diabetes are at increased risk for CV events, understanding the CV safety of these medicines is important9

– Objective of TECOS CV Safety Trial was to assess the CV safety of sitagliptin in patients with type 2 diabetes and established CV disease

TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin; CV = cardiovascular.1. Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987. 2. Williams-Herman D et al. Diabetes Obes Metab. 2010;12:442–451. 3. Reasner C et al. Diabetes Obes Metab. 2011;13:644–652. 4. Olansky L et al. Diabetes Obes Metab. 2011;13:841–849. 5. Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205. 6. Seck T et al. Int J Clin Pract. 2010;64:562–576. 7. Seck TL et al. Diabetes Res Clin Pract. 2011;doi:10.1016/j.diabres.2011.03.006.8. Arechavaleta R et al. Diabetes Obes Metab. 2011;13:160–168. 9. Green JB et al. [published online ahead of print June 8, 2015] N Engl J Med. doi: 10.1056/NEJMoa1501352. 10. American Diabetes Association. Diabetes Care. 2015;38(Suppl 1):S1–S93.

Am

pu

dia

-Bla

sco

FJ,

MD

Documents

What’s New In The Diabetes Treatment? The TECOS Results · EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus