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





Overview
  • The effect of each DPP-4 inhibitor on CVD outcomes has been evaluated in a large randomized controlled trial
  • The trials for each drug are presented below
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 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 Group 1 than Group 2 (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
Summary
  • DPP-4 inhibitors had no significant effect on CVD outcomes when compared to placebo in the four large trials above. DPP-4 inhibitor-treated patients achieved lower A1C values, but the difference was small (0.20% - 0.36%) and less than what has been seen with other classes of DM meds in similar trials (e.g. SGLT2 inhibitors, GLP-1 inhibitors).
  • DPP-4 inhibitors are less effective than other classes of DM meds for lowering blood sugars. They have no obvious beneficial or detrimental class-specific effect on clinical outcomes, although in the SAVOR-TIMI 53 trial, saxagliptin was associated with a slightly higher risk of hospitalization for heart failure when compared to placebo (3.5% vs 2.8%). See heart failure for more.



Low blood sugar (hypoglycemia)

Headache

Infections
Overview
  • The DPP-4 enzyme is present on cell membranes throughout the body including lymphocytes. Because DPP-4 is present on lymphocytes, there is theoretical concern that DPP-4 inhibitors could affect immunity.
  • In the SAVOR-TIMI 53 trial and the TECOS study there was no significant difference in the incidence of infections between the treatment groups and placebo. [13,15]
  • The meta-analysis detailed below looked at various outcomes with DPP-4 inhibitors including infections. The only DPP-4 inhibitor available in the U.S. that was included in the study was sitagliptin.
STUDY
Efficacy and Safety of Incretin Therapy in Type 2 Diabetes, JAMA (2007) [PubMed abstract]
  • A JAMA meta-analysis looked at infection rates in trials involving DPP-4 inhibitors. Sitagliptin was the only DPP-4 inhibitor available in the U.S that was included in the analysis.
  • The following results were seen when sitagliptin was compared to placebo or other diabetes meds:
    • Nasopharyngitis (n=3488): Risk ratio 1.38, 95%CI [1.06 - 1.81]
    • Upper respiratory infection (n=3488): Risk ratio 1.09, 95%CI [0.84 - 1.43]
    • Sinusitis (n=1262): Risk ratio 0.81, 95%CI [0.41 - 1.58]
    • Urinary tract infection (n=3135): Risk ratio 1.42, 95%CI [0.95 - 2.11] [4]
Summary
  • There is no conclusive evidence that DPP-4 inhibitors increase the risk of infections

Pancreatitis
Overview
  • Pancreatitis is a condition where the pancreas becomes inflamed. Pancreatitis is painful and can be life-threatening.
  • After DPP-4 inhibitors were released, a number of case reports linking DPP-4 inhibitors to pancreatitis began to surface
  • After reviewing a large amount of data from clinical trials, observational studies, and animal studies, the FDA published a paper in 2014 that stated there was no definitive link between DPP-4 inhibitors and an increased risk of pancreatitis
  • The paper went on to state that the FDA will continue to monitor studies for a possible link [12]
  • A number of large trials with DPP-4 inhibitors have now been published where pancreatitis was a reported outcome
Clinical trials
  • In the CVD outcome trials detailed above, the incidence of pancreatitis was similar between DPP-4 inhibitor-treated patients and placebo-treated patients
STUDY
Combined analysis of SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), and TECOS (sitagliptin) trials, Diabetes Care (2017) [Pubmed abstract]
  • A meta-analysis published in Diabetes Care combined the results of the SAVOR-TIMI 53, EXAMINE, and TECOS trials
  • The analysis found that the incidence of acute pancreatitis was significantly increased in the DPP-4 inhibitor-treated patients when compared with the control groups (odds ratio 1.79 [95% CI 1.13-2.82], P = 0.013). The difference in the absolute risk was small (0.13%).
FDA recommendations
  • Patients taking sitagliptin or saxagliptin should be aware of the signs and symptoms of pancreatitis (e.g. abdominal pain that may or may not radiate to the back, nausea, and vomiting). If symptoms of pancreatitis develop, seek medical attention immediately
Summary
  • DPP-4 inhibitors may increase the risk of pancreatitis, but the risk is very small

Pancreatic cancer
Overview
  • Because DPP-4 inhibitors increase pancreatic stimulation, there are theoretical concerns that they may increase the risk of pancreatic cancer
FDA review
  • In March 2013, the FDA released a warning about the possible association of GLP-1 analogs and DPP-4 inhibitors with pancreatic duct metaplasia and pancreatitis
  • In 2014, the FDA published a paper stating that after having reviewed a large amount of data from clinical trials, observational studies, and animal studies, they found no definitive link between pancreatic cancer and GLP-1 analogs
  • The paper went on to say that the FDA will continue to monitor studies for a possible link [13]
Clinical trials
  • In the CVD outcome trials detailed above, the incidence of pancreatic cancer was similar between DPP-4 inhibitor-treated patients and placebo-treated patients
STUDY
Incretin based drugs and the risk of pancreatic cancer, nested case-control study, BMJ (2016) [PubMed abstract]
  • A nested case-control study compared the risk of pancreatic cancer among patients exposed to incretin mimetics (GLP-1 analogs and DPP-4 inhibitors) and those exposed to sulfonylureas. The study included 639 cases of pancreatic cancer who were matched with 8651 controls.
  • The study found no increased risk of pancreatic cancer among patients exposed to incretin mimetics (GLP-1 analogs and DPP-4 inhibitors) when compared to those exposed to sulfonylureas (adjusted HR 1.02, 95%CI [0.84 - 1.23])
  • For DPP-4 inhibitors alone, no increased risk was found (adjusted HR 1.02, 95%CI [0.84 - 1.24])
  • For GLP-1 analogs alone, no increased risk was found (adjusted HR 1.13, 95%CI [0.38 - 3.38])
  • No association of risk with length of use was observed
Summary
  • There is no good evidence that DPP-4 inhibitors increase the risk of pancreatic cancer

Severe joint pain

Bullous pemphigoid

Lipase elevations (linagliptin)






Kidney disease
Alogliptin (Nesina®)
  • CrCl ≥ 60 ml/min - no dosage adjustment necessary
  • CrCl 30 - 59 ml/min - dose of 12.5 mg once daily should be used
  • CrCl < 30 ml/min - dose of 6.25 mg once daily should be used [11]
Linagliptin (Tradjenta®)
  • No dose adjustment is recommended in kidney disease [3]
Saxagliptin (Onglyza®)
  • CrCl > 50 ml/min - no dosage adjustment necessary
  • CrCl ≤ 50 ml/min - dose of 2.5 mg once a day should be used [2]
Sitagliptin (Januvia®)
  • CrCl ≥ 45 ml/min - no dosage adjustment necessary
  • CrCl 30 - 44 ml/min - dose is 50 mg once daily
  • CrCl < 30 ml/min - dose is 25 mg once daily
  • Postmarketing reports of kidney failure have been reported in patients taking sitagliptin. No causal link has been established. In clinical trials, sitagliptin did not adversely affect kidney function. [1]

Liver disease
Alogliptin (Nesina®)
  • For mild-to-moderate liver disease (Child-Pugh A and B), no dose adjustment is necessary
  • Alogliptin has not been studied in patients with severe liver disease (Child-Pugh C)
  • There have been postmarketing reports of liver failure in patients taking alogliptin. No causal link between alogliptin and liver toxicity has been established. In clinical trials, the incidence of significantly elevated liver function tests with alogliptin was no different than comparator treatments.
  • The manufacturer recommends checking liver function tests before initiating alogliptin therapy and if symptoms of liver toxicity occur (ex. fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice)
Linagliptin (Tradjenta®)
  • No dose adjustment is recommended in liver disease [3]
Saxagliptin (Onglyza®)
  • No dose adjustment is recommended in liver disease [2]
Sitagliptin (Januvia®)
  • For mild to moderate liver disease (Child-Pugh A and B), no dose adjustment is necessary
  • Sitagliptin has not been studied extensively in patients with severe liver disease (Child-Pugh C) [1]

Heart failure
Overview
  • In the SAVOR-TIMI 53 trial, patients randomized to saxagliptin had a higher risk of hospitalization for heart failure compared to patients randomized to placebo (3.5% vs 2.8%; HR 1.27, 95%CI [1.07 to 1.51] p=0.007)
  • In the TECOS study, there was no significant increase in risk for hospitalization for heart failure in patients taking sitagliptin. A post-hoc analysis of the EXAMINE trial also found no increased risk with alogliptin. [13,16]
  • Three observational studies that examined the association between DPP-4 inhibitors and heart failure are detailed below
STUDY
Incretin-based drugs and heart failure, NEJM (2016) [PubMed abstract]
  • Study design: nested case-control
  • Patient population: patient cohorts were formed from databases in the U.S., Canada, and the U.K. Patients who received a prescription for a new diabetic drug during the year in which incretin-based drugs entered the market at each site or at any time thereafter were included. The study population included 1,499,650 patients with 3,242,291 person-years of follow-up.
  • Exposure group: Prescription for incretin-based drugs (DPP-4 inhibitors and GLP-1 analogs)
  • Control group: Combination of ≥ 2 antidiabetic drugs. A combination was chosen since incretin mimetics are considered second- or third-line drugs and thus management points would be similar.
  • Primary outcome: Hospitalization due to heart failure
  • Results:
    • Patients without a history of heart failure
      • Primary outcome (DPP-4 inhibitors): Exposure vs Control - HR 0.84, 95%CI [0.69 - 1.02], nonsignificant
      • GLP-1 analogs also showed no significant association
      • Overall crude incidence of primary outcome was 7.5 events/1000 person-years
    • Patients with a history of heart failure
      • Primary outcome (DPP-4 inhibitors): Exposure vs Control - HR 0.87, 95%CI [0.63 - 1.21], nonsignificant
      • GLP-1 analogs also showed no significant association
      • Overall crude incidence of primary outcome was 43.5 events/1000 person-years
  • Findings: In this analysis of data from large cohorts of patients with diabetes, incretin-based drugs were not associated with an increased risk of hospitalization for heart failure, as compared with commonly used combinations of oral antidiabetic drugs
STUDY
DPP-4 inhibitors and risk of heart failure in type 2 diabetes, BMJ (2016) [PubMed abstract]
  • A meta-analysis published in the BMJ in 2016 pooled results from 38 randomized controlled trials (28,292 patients) that compared DPP-4 inhibitors to control. The analysis found no increased risk of heart failure events (OR 0.97, 95% CI [0.61 - 1.6]). Five trials (TECOS, EXAMINE, SAVOR-TIMI 53, and 2 smaller trials) reported hospital admissions for heart failure. Pooled analysis of these 5 trials found a borderline increased risk of hospital admission for heart failure (OR 1.13, 95%CI [1.0 - 1.26]). There was insufficient data to draw conclusions about individual DPP-4 inhibitors.
STUDY
Risk for Hospitalization for Heart Failure with DPP-4 inhibitors, Annals of Internal Medicine (2016) [PubMed abstract]
  • A cohort study published in the Annals of Internal Medicine in 2016 compared the risk of hospitalization for heart failure between patients initiating saxagliptin, sitagliptin, pioglitazone, sulfonylureas, or insulin. The cohort included 78,553 saxagliptin-users and 298,124 sitagliptin-users. The study did not find an elevated risk of heart failure hospitalizations among users of saxagliptin or sitagliptin.
FDA warning
  • In April 2016, the FDA issued a warning stating that saxagliptin and alogliptin may increase the risk of heart failure, particularly in patients who already have heart or kidney disease - FDA drug safety communication
Summary
  • In the SAVOR-TIMI 53 trial, patients on saxagliptin had a slightly higher risk of hospitalization for heart failure (0.7% absolute risk increase). In the EXAMINE and TECOS trials, sitagliptin and alogliptin did not increase the risk.
  • Several large observational studies have found no increased risk of heart failure with DPP-4 inhibitors as a class. The Annals of Internal Medicine cohort study looked specifically at sitagliptin and saxagliptin and found no increased risk.
  • It's unclear if DPP-4 inhibitors increase the risk of heart failure. If a risk exists, it is likely very small.
  • Until more information is available, patients with significant heart failure may want to avoid saxagliptin and alogliptin



Linagliptin (Tradjenta®)

  • Strong CYP3A4 inducers - Strong CYP3A inducers may lower linagliptin blood levels to subtherapeutic levels. The manufacturer recommends alternative therapy.
  • P-glycoprotein inducers - P-glycoprotein inducers may lower linagliptin blood levels to subtherapeutic levels. The manufacturer recommends alternative therapy.

Saxagliptin (Onglyza®)

  • Strong CYP3A4 inducers and inhibitors - The dose of saxagliptin should not exceed 2.5 mg when taken with strong CYP3A inhibitors. Strong CYP3A inducers may lower saxagliptin blood levels to subtherapeutic levels

Sitagliptin (Januvia®)

  • Digoxin - Sitagliptin may increase digoxin levels. Monitor levels closely. No dose adjustment is recommended.

  • 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