DPP-4 INHIBITORS


















  • All values are expressed as average change from baseline. FBS (fasting blood sugar) expressed as mg/dl.
  • Baseline A1C ∼ 8% in all studies
  • Reference [1,2,3,11]
Effects of DPP-4 inhibitors on blood sugars in trials lasting 24 - 26 weeks
Drug A1C
(monotherapy)
FBS
(monotherapy)
A1C
(added to metformin)
FBS
(added to metformin)
Alogliptin 25 mg daily -0.6% -16 -0.6% -17
Linagliptin 5 mg daily -0.4% -9 -0.5% -11
Saxagliptin 2.5 mg daily -0.4% -15 -0.6% -14
Saxagliptin 5 mg daily -0.5% -9 -0.7% -22
Sitagliptin 100 mg daily -0.6% -12 -0.7% -17






EXAMINE Trial - Alogliptin vs Placebo for Prevention of CVD after Acute Coronary Syndrome, NEJM (2013) [PubMed abstract]
  • The EXAMINE Trial enrolled 5380 diabetics with recent acute coronary syndrome
Main inclusion criteria
  • Type 2 diabetes
  • ACS within 15 - 90 days
  • HgA1C 6.5 - 11%
Main exclusion criteria
  • Treatment with DPP-4 inhibitor or GLP-1 analog
  • Uncontrolled hypertension
  • Hemodynamically unstable heart disease
Baseline characteristics
  • Median age 61 years
  • Median duration of diabetes - 7.2 years
  • Average HgA1C - 8%
  • Qualifying event: Myocardial infarction - 77% | Unstable angina - 23%
Randomized treatment groups
  • Group 1 (2679 patients) - Placebo once daily
  • Group 2 (2701 patients) - Alogliptin 6.25 - 25 mg once daily
  • Alogliptin dosing was based on GFR: GFR ≥ 60 ml/min - 25 mg; GFR 30 - 59 ml/min - 12.5 mg; GFR < 30 ml/min - 6.25 mg
  • Patients were managed according to regional standards of care. Non-study DPP-4 inhibitors and GLP-1 analogs were not allowed.
Primary outcome: Composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
Results

Duration: Median of 18 months
Outcome Placebo Alogliptin Comparisons
Primary outcome 11.8% 11.3% p=0.32
Nonfatal myocardial infarction 6.5% 6.9% HR 1.08, 95%CI [0.88 - 1.33], p=0.47
Nonfatal stroke 1.2% 1.1% HR 0.91, 95%CI [0.55 - 1.50], p=0.71
Overall mortality 6.5% 5.7% HR 0.88, 95%CI [0.71 - 1.09], p=0.23
Change in HgA1C at the end of study +0.03% -0.33% p<0.001
Drug discontinuation 22.6% 20.9% N/A
  • The incidences of acute and chronic pancreatitis were similar in the two groups
  • There were no cases of pancreatic cancer during the trial

Findings: Among patients with type 2 diabetes who had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo.
CARMELINA trial - Linagliptin vs Placebo for Prevention of CVD in Type 2 DM, JAMA (2018) [PubMed abstract]
  • The CARMELINA trial enrolled 6979 diabetics with CVD and/or diabetic kidney disease
Main inclusion criteria
  • Type 2 diabetes
  • HgA1C 6.5% - 10%
  • History of CVD and UACR > 30 mcg/mg OR GFR 45 - 75 ml/min with UACR > 200 mcg/mg OR GFR 15 - 45 ml/min
Main exclusion criteria
  • GFR < 15 ml/min
  • Previous treatment with GLP-1 analog, other DPP-4 inhibitor, or SGLT2 inhibitor
  • ACS within 2 months
Baseline characteristics
  • Average age - 66 years
  • History of CAD - 58%
  • Average A1C - 8%
  • Average GFR - 54 ml/min
  • Median UACR - 162 mcg/mg
  • Statin therapy - 71%
Randomized treatment groups
  • Group 1 (3494 patients): Linagliptin 5 mg once daily
  • Group 2 (3485 patients): Placebo
  • Other diabetes meds except nonstudy DPP-4 inhibitors, GLP-1 analogs, and SGLT2 inhibitors were allowed
Primary outcome: Time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke
Results

Duration: Median 2.2 years
Outcome Linagliptin Placebo Comparisons
Primary outcome 12.4% 12.1% HR 1.02, 95%CI [0.89 - 1.17], p=0.74
Composite of ESRD, death from kidney failure, and decrease in GFR ≥ 40% 9.4% 8.8% HR 1.04, 95%CI [0.89 - 1.22], p=0.62
Overall mortality 10.5% 10.7% HR 0.98, 95%CI [0.84 - 1.13], p=0.74
Acute pancreatitis 0.3% 0.1% N/A
Pancreatic cancer 0.3% 0.1% N/A
  • Over the course of the study, average A1C values were 0.36% lower in the linagliptin group

Findings: Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years
SAVOR TIMI 53 Trial - Saxagliptin vs Placebo for Prevention of CVD in Type 2 DM, NEJM (2013) [PubMed abstract]
  • The SAVOR-TIMI 53 trial enrolled 16,492 diabetics with either a history of CVD or risk factors for CVD
Main inclusion criteria
  • Type 2 diabetes
  • HgA1C 6.5% - 12%
  • Established CVD or risk factors for CVD
Main exclusion criteria
  • Treatment with DPP-4 inhibitor or GLP-1 analog within past 6 months
  • End-stage renal disease
  • Serum creatinine > 6 mg/dl
Baseline characteristics
  • Average age 65 years
  • Average BMI - 31
  • Median duration of diabetes - 10.3 years
  • Average HgA1C - 8%
  • Established cardiovascular disease - 78%
  • History of heart failure - 13%
Randomized treatment groups
  • Group 1 (8280 patients) - Saxagliptin 2.5 - 5 mg once daily
  • Group 2 (8212 patients) - Placebo once daily
  • Patients with a GFR ≤ 50 ml/min were given saxagliptin 2.5 mg once daily
  • Diabetes management was at the discretion of the patient's provider. Non-study DPP-4 inhibitors and GLP-1 analogs were not allowed.
Primary outcome: Composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke
Results

Duration: Median of 2.1 years
Outcome Saxagliptin Placebo Comparisons
Primary outcome 7.3% 7.2% HR 1.00, 95%CI [0.89 - 1.12], p=0.99
Myocardial infarction 3.2% 3.4% HR 0.95, 95%CI [0.80 - 1.12], p=0.52
Ischemic stroke 1.9% 1.7% HR 1.11, 95%CI [0.88 - 1.39], p=0.38
Overall mortality 4.9% 4.2% HR 1.11, 95%CI [0.96 - 1.27], p=0.15
Hospitalization for heart failure 3.5% 2.8% HR 1.27, 95%CI [1.07 - 1.51], p=0.007
HgA1C at the end of treatment period 7.7% 7.9% p<0.001
Hypoglycemia 15.3% 13.4% p<0.001
Renal abnormalities 5.8% 5.1% p=0.04
Drug discontinuation 18.4% 20.8% p<0.001
Acute or chronic pancreatitis 24 patients 21 patients p=0.77
Pancreatic cancer 5 cases 12 cases p=0.095

Findings: DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes.
TECOS Study - Sitagliptin vs Placebo for the Secondary Prevention of CVD in Type 2 DM, NEJM (2015) [PubMed abstract]
  • The TECOS study enrolled 14,671 diabetics with established cardiovascular disease
Main inclusion criteria
  • Age ≥ 50 years
  • Type 2 diabetes
  • Established cardiovascular disease
  • HgA1C 6.5% - 8.0%
Main exclusion criteria
  • Treatment with DPP-4 inhibitor, GLP-1 analog, or glitazone other than pioglitazone within past 3 months
  • History of ≥ 2 episodes of severe hypoglycemia within 12 months
  • GFR < 30 ml/min
Baseline characteristics
  • Average age 65.5 years
  • Average BMI - 30
  • Average duration of diabetes - 11.6 years
  • Average HgA1C - 7.2%
  • Coronary artery disease - 74%
  • Cerebrovascular disease - 14.5%
  • PAD - 16.6%
  • History of heart failure - 18%
Randomized treatment groups
  • Group 1 (7332 patients) - Sitagliptin 50 - 100 mg once daily
  • Group 2 (7339 patients) - Placebo once daily
  • Patients with a GFR < 50 ml/min were given sitagliptin 50 mg once daily
  • Diabetes management was at the discretion of the patient's provider. Non-study DPP-4 inhibitors and GLP-1 analogs were not allowed.
Primary outcome: Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina
Results

Duration: Median of 3 years
Outcome Sitagliptin Placebo Comparisons
Primary outcome 11.4% 11.6% HR 0.98, 95%CI [0.89 - 1.08]. p=0.65
Myocardial infarction 4.1% 4.3% HR 0.95, 95%CI [0.81 - 1.11], p=0.49
Stroke 2.4% 2.5% HR 0.97, 95%CI [0.79 - 1.19], p=0.76
Overall mortality 7.5% 7.3% HR 1.01, 95%CI [0.90 - 1.14], p=0.88
Hospitalization for heart failure 3.1% 3.1% HR 1.00, 95%CI [0.83 - 1.20], p=0.98
Acute pancreatitis 0.3% 0.2% p=0.07
Pancreatic cancer 0.1% 0.2% p=0.32
  • Over the course of the study, the average HgA1C value was 0.29% lower in the sitagliptin group than the placebo group (diff 0.29%, 95% CI [-0.32 to -0.27])
  • Decline in GFR over the course of the study was significantly greater in the sitagliptin group (diff 1.34 ml/min, 95%CI [-1.76 to -0.91], p<0.001)

Findings: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events























  • NOTE: Information on metabolic pathways presented here is from the manufacurer's PI, FDA website, and a handful of published reviews. Other metabolic pathways may exist; therefore, the information is not meant to be all-inclusive.
Metabolism and clearance
Drug CYP2C8 CYP3A4 P-glycoprotein OAT
Alogliptin No significant liver metabolism - -
Linagliptin - Substrate and inhibitor Substrate and inhibitor -
Saxagliptin - Substrate Substrate -
Sitagliptin Substrate Substrate Substrate Substrate