Reference: SAVOR-TIMI 53
Clinical Question: Does saxagliptin reduce cardiovascular events in patients with DM and risk for CV events
Background: Previous DM medications (rosiglitazone) may have been associated with increased CV events and the FDA subsequently required
drug manufacturers to prove that their drugs do not increase CV events. So far saxagliptin has been shown to reduce glucose and a meta-analysis
of smaller clinical trials found reduction in CV events
Methods
Multicenter, randomized, double-blind, PLB-controlled, superiority study in 26 countries.
Sponsored by AstraZeneca and Bristol-Myers Squibb. Statistical analysis performed independently of the sponser.
Good randomization/allocation concealment(1:1, blocks of 4, centralized, web based system, stratified by risk factors)
Good blinding: single-dummy
Statistics: ITT, Cox proportional hazards model,1 interim analysis and p-value was adjusted for this, modified ITT (events within 30 days of
last dose) was done for sensitivity
Adjudication: Blinded clinical events committee with experts in CV and pancreatic medicine adjudicated endpoints
PICO
Patient
N=197
Inclusion: DM2, A1C 6.5 to 12%, hx of CVA/CAD/PVD or multiple risk factors (55+ with HTN/Lipids/smoking)
Exclusion: CR >530, renal transplantation, dialysis
Average patient: ~ 65 years old, 33% female, 75% white, Obese (BMI 31), DM for 10 years, CV
disease (80%), HTN, Lipids, 38% past MI, 43% past coronary revasc, A1C 8%, GFR >50 (85%)
ASA 80%, Statin 80%, ace/arb ~80%, MTF 70%
Intervention Saxagliptin 5 mg po daily (dose decreased to 2.5mg po daily if GFR <50)
Comparator Placebo
Treating physician decided on all other interventions except on DPP-inhibitors or GLP-1 agonists
Outcomes
Primary: CV death, nonfatal MI, nonfatal ischemic stroke
Secondary: Primary + HF/coronary revas/UA, severe hypoglycemia (needed 3rd party), mild hypoglycemia (treated on
own), pancreatitis
Endpoint consistent with FDA recommendations for CV endpoints
Results
Primary
Secondary
Death from any
cause
Hospitalization
for HF
Major hypoglyc.
Minor Hypoglyc.
Nonfatal
angioedema
Worsened
Microalbuminuria
Saxagliptin
8280
Placebo
8212
HR
ARD
NNT
p-value
613 (7.3%)
1059 (12.8%)
420 (4.9%)
609 (7.2%)
1034 (12.4%)
378 (4.2%)
NONE
NONE
NONE
Infinite
Infinite
0.99
0.66
0.15
289 (3.5%)
228 (2.8%)
0.7%
NNH 142
0.007
177 (2.1%)
1172 (14.2%)
8
140(1.7%)
1028(12.5%)
1
1.00
1.02
1.11 (0.961.27)
1.27 (1.071.51)
833(13.3%)
969(15.9%)
0.047
0.002
0.001
 No differences in thrombocytopenia, lymphocytopenia, severe infection, bone fracture, pancreatitis, liver abnormality
 A1C levels were lower at 1 year (7.6% vs 7.9%) and at the end of study (7.7% vs 7.9%)
 No delay in the change in creatinine
Limitations


Drug company sponsored so expect some bias
Potentially some differences in the treatments that patient received in the two groups (i.e. non study CV/diabetes medications) though
overall it appeared that the rates were similar between the two groups (see study appendix)
Conclusions
Authors suggest in the discussion that this study is positive because there is no increase in the risk of CV events despite tighter
control of glucose. They suggest (based on previous studies and one secondary endpoint in this study) that saxigliptin
likely reduces microvascular events because of the improved glucose control.
I feel that overall this study is a negative study and should induce ourselves to limit the use of DPP-4 inhibitors for most
patients. The only patients that should be on therapy are those with severely uncontrolled sugars (A1C >10 or so) who
cannot start insulin for whatever reason.