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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
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.
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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
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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
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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 (%)
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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.
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Lowering HbA1c may prevent macrovascular disease if started early, but the effects may not be apparent for a very long time
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Rates of Myocardial Infarction and Death from Cardiovascular Causes with Rosiglitazone
Nissen SE, Wolski K. N Engl J Med 2007;356:2457-2471.
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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.
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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
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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
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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.
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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.
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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
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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
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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
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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
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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
20Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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
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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.
23Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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.
24Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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
25Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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.
26Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Glycemic Control Least Squares Mean HbA1c ± 1SD
Overall LS Mean difference
-0.29% (-0.32, -0.27), p<0.0001
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Primary Composite Cardiovascular Outcome* PP Analysis for Non-inferiority
* CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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Hospitalization for Heart Failure*ITT Analysis
* Adjusted for history of heart failure at baseline
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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
32Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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)
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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
34Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
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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
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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.
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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.
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Potential reasons for discrepanciesA
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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.
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