- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ACS- Acute coronary syndrome (myocardial infarction or unstable angina)
- ADA- American Diabetes Association
- CI - Confidence interval
- CrCl - Creatinine clearance
- CVD - Cardiovascular disease
- DPP-4 - Dipeptidyl peptidase-4
- GLP-1 - Glucagon-like peptide-1
- RCT - Randomized controlled trial
- T2DM - Type 2 diabetes
- UACR - Urinary albumin:creatinine ratio
- DRUGS IN CLASS
- DPP-4 inhibitors
- Alogliptin (Nesina®)
- Linagliptin (Tradjenta®)
- Saxagliptin (Onglyza®)
- Sitagliptin (Januvia®)
- Combination products with metformin
- Janumet® (sitagliptin + metformin)
- Janumet® XR (sitagliptin + extended-release metformin)
- Jentadueto® (linagliptin + metformin)
- Jentadueto® XR (linagliptin + extended-release metformin)
- Kazano® (alogliptin + metformin)
- Kombiglyze™ XR (saxagliptin + extended-release metformin)
- Combination products with glitazones
- Oseni® (alogliptin + pioglitazone)
- Combination products with SGLT2 inhibitors
- Glyxambi® (linagliptin + empagliflozin)
- Qtern® (saxagliptin + dapagliflozin)
- Steglujan® (sitagliptin + ertugliflozin)
- Combination product with a SGLT2 inhibitor and metformin
- Trijardy® XR (empagliflozin + linagliptin + metformin ER)
- MECHANISM OF ACTION
- DPP-4 is a soluble plasma enzyme for GLP-1 and GIP
- DPP-4 stands for "dipeptidyl peptidase-4 enzyme," GLP-1 stands for "glucagon-like peptide-1," and GIP stands for "glucose-dependent insulinotropic polypeptide." GLP-1 and GIP are hormones secreted by special cells in the small intestine in response to food consumption. In the pancreas, GLP-1 and GIP stimulate insulin release and suppress glucagon secretion during hyperglycemia. GLP-1 and GIP also act in the brain to suppress hunger. The soluble plasma form of DPP-4 rapidly metabolizes GLP-1 and GIP, rendering them inactive. DPP-4 inhibitors block the DPP-4 enzyme, thus prolonging the actions of GLP-1 and GIP.
- DPP-4 is a transmembrane receptor
- In certain cells, DPP-4 is also present as a transmembrane receptor. See infections below for more.
- FDA-APPROVED INDICATIONS
- Alogliptin (Nesina®) - adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- Linagliptin (Tradjenta®) - adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- Saxagliptin (Onglyza®) - adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- Sitagliptin (Januvia®) - adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- TYPE TWO DIABETES
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 |
- Body weight effects
- DPP-4 inhibitors do not appear to have a significant effect on body weight [4,5,6]
- Cholesterol effects
- DPP-4 inhibitors do not appear to have a significant effect on cholesterol (lipid parameters) [1,2,3,4]
- TYPE TWO DIABETES | CVD outcomes
- 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
- 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 |
|
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.
- 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 |
|
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
- 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 |
Severe infection | 7.1% | 7% | p=0.78 |
Opportunistic infection | 0.3% | 0.4% | p=0.06 |
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.
- 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 |
Death from infection | 0.6% | 0.7% | N/A |
|
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
- ADA recommendations
- 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.
- SIDE EFFECTS
- Low blood sugar (hypoglycemia)
- DPP-4 inhibitors by themselves do not increase the risk of hypoglycemia. When they are taken with insulin or insulin secretagogues (e.g. sulfonylureas), the risk of hypoglycemia is increased. [1,2,3]
- Headache
- In some trials, patients taking DPP-4 inhibitors had a slightly higher incidence of headache
- Headache incidence in placebo-controlled trials
- Sitagliptin - 5.1% , placebo - 3.9% [4]
- Alogliptin - 4.2% , placebo - 2.5% [11]
- Saxagliptin - 6.5% , placebo - 5.9% [2]
- Infections
- DPP-4 circulates as a soluble enzyme in plasma, and it is also present in cell membranes where it acts as a transmembrane receptor. DPP-4 receptors are present on T-cells, and they have an identical structure to the leukocyte surface antigen CD26. On T-cells, DPP-4 receptor stimulation by its ligand, caveolin 1, causes T-cell activation. DPP-4 inhibitors have been shown to block DPP-4 receptors and inhibit T-cell function. This effect was illustrated in a study published in 2021 where sitagliptin was found to lower the incidence of graft-versus-host disease in patients receiving stem-cell transplants. [PMID 33406328]
- The immune-modulating effects of DPP-4 inhibitors have raised theoretical concerns that they may raise the risk of infections. In the SAVOR-TIMI 53 trial and TECOS study, there was no significant difference in the incidence of infections between the treatment groups and placebo. A meta-analysis that looked at various outcomes with DPP-4 inhibitors including infections is detailed below. [13,15]
- STUDY
- 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
- DPP-4 inhibitors do have immune-modulating effects, but there is no conclusive evidence to date that they increase the risk of infections
- Pancreatitis
- 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
- 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
- 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
- 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
- In 2015, the FDA issued a drug safety communication warning that reports of severe joint pain in patients taking DPP-4 inhibitors had been reported in their Adverse Event Reporting System
- In reported cases, the pain started from days to years after patients started taking their DPP-4 inhibitors. After stopping the DPP-4 inhibitors, the pain typically resolved in less than a month.
- Bullous pemphigoid
- Cases of bullous pemphigoid, an autoimmune skin disease, have been reported in patients taking DPP-4 inhibitors
- In most cases, symptoms resolved with topical or systemic immunosuppressive therapy and discontinuation of the DPP-4 inhibitor
- Patients should notify their physician if they develop blisters or erosions while taking DPP-4 inhibitors
- Lipase and amylase elevations (linagliptin)
- Lipase and amylase are enzymes involved in digestion that are secreted by the pancreas
- In trials, linagliptin-treated patients had an average increase in lipase levels of 30% at 24 weeks compared to an average decrease of 2% in the placebo groups. Lipase levels > 3 X ULN were seen in 8.2% of linagliptin-treated patients and in 1.7% of placebo-treated patients.
- In a study that compared linagliptin to glimepiride, amylase levels > 3 X ULN were seen in 1% of linagliptin-treated patients and 0.5% of glimepiride-treated patients
- CONTRAINDICATIONS
- All DPP-4 inhibitors
- History of serious hypersensitivity reaction to DPP-4 inhibitors
- PRECAUTIONS
- Kidney disease dosing
- 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 dosing
- Alogliptin (Nesina®)
- Child-Pugh A and B: no dose adjustment is necessary
- Child-Pugh C: has not been studied
- 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®)
- Child-Pugh A and B: no dose adjustment is necessary
- Child-Pugh C: has not been studied extensively
- Heart failure
- 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
- 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
- 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
- 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
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All DPP-4 inhibitors
- Insulin and insulin secretagogues - the risk of hypoglycemia is increased when DPP-4 inhibitors are combined with insulin or insulin secretagogues (e.g. sulfonylureas, meglitinides).
- 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.
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 |
- DOSING
- LONG-TERM SAFETY
- Sitagliptin was the first DPP-4 inhibitor approved in the U.S in 2006
- Long-term safety data for DPP-4 inhibitors is lacking, but they have been studied in a number of large trials and appear to be safe
- BIBLIOGRAPHY
- 1 - Sitagliptin PI
- 2 - Saxagliptin PI
- 3 - Linagliptin PI
- 4 - PMID 17622601
- 5 - PMID 21320267
- 6 - PMID 21205122
- 7 - PMID 18945920
- 8 - PMID 18425967
- 9 - PMID 19278373
- 10 - PMID 20682680
- 11 - Alogliptin PI
- 12 - PMID 24571751
- 13 - PMID 26052984 - TECOS study
- 14 - PMID 23992602 - EXAMINE study
- 15 - PMID 23992601 - SAVOR-TIMI 53
- 16 - PMID 25765696 - Post-hoc analysis of EXAMINE