Sitagliptin

updated

Sitagliptin is an FDA-approved oral DPP-4 inhibitor for type 2 diabetes, with a 2006 approval, a 24-week efficacy trial in 741 patients and the 14,671-patient TECOS cardiovascular outcome trial. Sellers pair it with injected peptides on the theory that DPP-4 clears them. DPP-4 does make the first cut in growth hormone releasing hormone in plasma, but searches on 9 October 2026 found no study that co-administered sitagliptin with an injected peptide and measured that peptide's exposure or effect.

DPP-4 inhibitor

  • FDA approved JANUVIA under NDA 021995 on 16 October 2006 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
  • In 741 patients with type 2 diabetes over 24 weeks, placebo-subtracted HbA1c fell by 0.79 and 0.94 percent, and body weight changed by -0.2 and -0.1 kg versus -1.1 kg on placebo.
  • TECOS (14,671 patients, median 3.0 years) found the cardiovascular composite at 11.4 versus 11.6 percent (hazard ratio 0.98) and no difference in heart failure hospitalization (hazard ratio 1.00).
  • In human plasma in vitro, the first cleavage of growth hormone releasing hormone is a single DPP-IV cut that a DPP-IV inhibitor blocks.
  • In a 39-adult crossover, sitagliptin raised arginine-stimulated GH and free IGF-1 in women; in 18 chronic DPP-4 inhibitor users IGF-1 did not differ, and in pigs 90% DPP-IV inhibition did not raise IGF-1.
  • A PubMed search on 9 October 2026 returned 2 records for sitagliptin with growth hormone releasing peptides, both in people given sitagliptin alone.

What is sitagliptin approved to do?

FDA approved JANUVIA (sitagliptin) on 16 October 2006 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Use alongside injected peptides is not a labeled use.

The JANUVIA label approves sitagliptin as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Limitations of use: it should not be used in type 1 diabetes, and it has not been studied in patients with a history of pancreatitis. The label version used here took effect on 14 November 2024.

FDA approved JANUVIA under NDA 021995 on 16 October 2006. Approvals outside the United States are not covered here.

Sitagliptin free base is C16H15F6N5O (407.31 g/mol, CAS 486460-32-6, PubChem CID 4369359). The phosphate salt used in JANUVIA appears in the same record's synonyms with CAS 790712-60-6. Label doses are expressed as sitagliptin free base, so salt mass and base mass should not be interchanged.

JANUVIA label, version effective 14 November 2024: indication, mechanism, pharmacodynamics

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01.

The label approves JANUVIA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Limitations of use: it should not be used in type 1 diabetes, and it has not been studied in patients with a history of pancreatitis. Sitagliptin slows inactivation of incretin hormones, raising concentrations of active GLP-1 and GIP. The label states that in patients with type 2 diabetes a dose produced DPP-4 inhibition over a 24-hour period and a 2-fold to 3-fold increase in circulating active GLP-1 and GIP after an oral glucose load or meal, and that in healthy subjects sitagliptin did not lower blood glucose or cause hypoglycemia.

Participants / model
Adults with type 2 diabetes; healthy subjects for the pharmacodynamic statement
Treatment
JANUVIA film-coated oral tablets
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

The label does not address use alongside injected peptides.

Read the original source
Drugs@FDA: JANUVIA approved 16 October 2006

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 021995 (JANUVIA). Date read from the openFDA Drugs@FDA record.

FDA approved JANUVIA under NDA 021995 on 16 October 2006.

Participants / model
Not a clinical population
Treatment
Drug application
Follow-up
Approved 2006
Study design
FDA application record
Funding
not stated in the source

This record gives the approval date. Indications come from the product label.

Read the original source
PubChem: sitagliptin identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 4369359 (sitagliptin).

Sitagliptin free base: PubChem CID 4369359, C16H15F6N5O, 407.31 g/mol, CAS 486460-32-6. The phosphate salt used in JANUVIA appears in the same record's synonyms with CAS 790712-60-6. Doses on the label are expressed as sitagliptin free base, so salt mass and base mass should not be interchanged.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule and salt
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source

What did the diabetes trials find?

In a 24-week trial in 741 patients with type 2 diabetes, sitagliptin lowered HbA1c by 0.79 and 0.94 percent over placebo at two doses. In TECOS, 14,671 patients with cardiovascular disease had cardiovascular outcomes noninferior to placebo and no difference in heart failure hospitalization.

In a 24-week randomized double-blind placebo-controlled monotherapy study in 741 patients with type 2 diabetes (baseline HbA1c 8.0 percent), sitagliptin 100 and 200 mg once daily produced placebo-subtracted HbA1c reductions of -0.79 and -0.94 percent (P<0.001) and 2-hour postprandial glucose reductions of -2.6 and -3.0 mmol/L.

TECOS randomized 14,671 patients with type 2 diabetes and established cardiovascular disease to sitagliptin or placebo added to usual care, with median follow-up of 3.0 years. The HbA1c difference was -0.29 percentage points (95% CI -0.32 to -0.27). The primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina occurred in 11.4 versus 11.6 percent (hazard ratio 0.98, 95% CI 0.88 to 1.09, P<0.001 for noninferiority). The trial is registered as NCT00790205.

Both studies were in people with type 2 diabetes. Neither tested sitagliptin alongside an injected peptide.

741 patients, 24 weeks: HbA1c down 0.79 and 0.94 percent, weight not lower than placebo

Randomized controlled trial

Aschner P et al. Diabetes Care. 2006;29(12):2632-7. PMID 17130196.

Placebo-subtracted HbA1c reductions were -0.79 and -0.94 percent (P<0.001) and 2-hour postprandial glucose reductions -2.6 and -3.0 mmol/L. Body weight changed by -0.2 kg (100 mg) and -0.1 kg (200 mg) versus -1.1 kg on placebo, a difference significant in favor of placebo (P<0.01).

Participants / model
741 patients with type 2 diabetes (baseline HbA1c 8.0 percent)
Treatment
Oral sitagliptin 100 or 200 mg once daily, or placebo
Follow-up
24 weeks
Study design
Randomized double-blind placebo-controlled monotherapy study
Funding
not stated in the source

Sitagliptin is weight-neutral at best in this trial, which matters because supplier pages often place it next to weight-loss compounds.

Read the original source
TECOS: 14,671 patients, cardiovascular outcomes noninferior, no heart failure excess

Randomized controlled trial

Green JB et al. N Engl J Med. 2015;373(3):232-42. PMID 26052984.

The HbA1c difference was -0.29 percentage points (95% CI -0.32 to -0.27). The primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina occurred in 11.4 versus 11.6 percent (hazard ratio 0.98, 95% CI 0.88 to 1.09, P<0.001 for noninferiority). Hospitalization for heart failure did not differ (hazard ratio 1.00, 95% CI 0.83 to 1.20, P=0.98), and there were no significant differences in acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

Participants / model
14,671 adults with type 2 diabetes and established cardiovascular disease
Treatment
Oral sitagliptin or placebo added to usual care
Follow-up
Median follow-up 3.0 years
Study design
Randomized placebo-controlled cardiovascular outcome trial (NCT00790205)
Funding
not stated in the source

Patients with type 2 diabetes and established cardiovascular disease.

Read the original source

Does sitagliptin cause weight loss?

No. In the 24-week monotherapy study, body weight changed by -0.2 kg and -0.1 kg on sitagliptin versus -1.1 kg on placebo, a difference significant in favor of placebo. It is weight-neutral at best in that trial.

In the 24-week study in 741 patients with type 2 diabetes, body weight changed by -0.2 kg (100 mg) and -0.1 kg (200 mg) versus -1.1 kg on placebo, a difference significant in favor of placebo (P<0.01). Sitagliptin is weight-neutral at best in this trial, which matters because supplier pages often place it next to weight-loss compounds.

741 patients, 24 weeks: HbA1c down 0.79 and 0.94 percent, weight not lower than placebo

Randomized controlled trial

Aschner P et al. Diabetes Care. 2006;29(12):2632-7. PMID 17130196.

Placebo-subtracted HbA1c reductions were -0.79 and -0.94 percent (P<0.001) and 2-hour postprandial glucose reductions -2.6 and -3.0 mmol/L. Body weight changed by -0.2 kg (100 mg) and -0.1 kg (200 mg) versus -1.1 kg on placebo, a difference significant in favor of placebo (P<0.01).

Participants / model
741 patients with type 2 diabetes (baseline HbA1c 8.0 percent)
Treatment
Oral sitagliptin 100 or 200 mg once daily, or placebo
Follow-up
24 weeks
Study design
Randomized double-blind placebo-controlled monotherapy study
Funding
not stated in the source

Sitagliptin is weight-neutral at best in this trial, which matters because supplier pages often place it next to weight-loss compounds.

Read the original source

Does sitagliptin make injected peptides last longer?

No study found tests it. A PubMed search on 9 October 2026 returned 2 records for sitagliptin with growth hormone releasing peptides, both in people given sitagliptin alone, and no study in the records reviewed co-administered it with an injected peptide.

Sellers describe sitagliptin, an oral DPP-4 inhibitor for type 2 diabetes, as used off-label alongside injected peptides on the theory that DPP-4 is one of the enzymes clearing them.

A PubMed search on 9 October 2026 for sitagliptin with growth hormone releasing peptide, GHRP, ipamorelin, CJC-1295 or tesamorelin returned 2 records, both measuring circulating ghrelin or gastrin levels in people given sitagliptin alone, neither co-dosing an injected peptide. A search for sitagliptin with the phrase anabolic steroid returned 0 records. On ClinicalTrials.gov the same day, a query for sitagliptin and growth hormone releasing peptide returned 6 studies, the only growth-hormone one being NCT01701973, the arginine-stimulation study described below.

No study in the records reviewed co-administered sitagliptin with an injected growth-hormone secretagogue, GHRH analogue or other research peptide and measured that peptide's exposure, half-life or effect. No interval, dose or combination guidance is supported by these records.

Searches, 9 October 2026: 2 records, 0 records and 6 registry studies, none co-dosing a peptide

PubMed search record

PubMed searches run on 9 October 2026: sitagliptin AND (growth hormone releasing peptide OR GHRP OR ipamorelin OR CJC-1295 OR tesamorelin), 2 records; sitagliptin with the phrase anabolic steroid, 0 records. ClinicalTrials.gov query for sitagliptin and growth hormone releasing peptide on the same date: 6 studies.

The PubMed search returned 2 records, both measuring circulating ghrelin or gastrin levels in people given sitagliptin alone, neither co-dosing an injected peptide. A search for sitagliptin with the phrase anabolic steroid returned 0 records. On ClinicalTrials.gov the same day, a query for sitagliptin and growth hormone releasing peptide returned 6 studies, the only growth-hormone one being NCT01701973, the arginine-stimulation study on this page. No study in the records reviewed co-administered sitagliptin with an injected growth-hormone secretagogue, GHRH analogue or other research peptide and measured that peptide's exposure, half-life or effect.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what PubMed and ClinicalTrials.gov returned on that date. It is not proof that no unindexed study exists.

Read the original source

Is DPP-4 really the enzyme that clears growth hormone releasing hormone?

For that one peptide family, yes in plasma in vitro: the first cleavage of growth hormone releasing hormone is a single DPP-IV cut that a DPP-IV inhibitor blocks. That is enzymology and does not show that inhibiting DPP-4 in a person changes a peptide's clinical effect.

The premise behind the supplier claim is real for one peptide family. In human plasma, the primary proteolytic cleavage of growth hormone releasing hormone at the 2 to 3 amino acid bond is a single-step dipeptidylpeptidase IV cut, blocked by the DPP IV inhibitor diprotin A and prevented by D-amino acid substitution at position 1 or 2. GRH(1-44)-NH2, GRH(1-40)-OH, GRH(1-32)-NH2 and GRH(1-29)-NH2 were all rapidly cleaved; GRH(2-32)-NH2 was not.

The authors concluded that GRH degradation in plasma occurs primarily by DPP IV and to a lesser extent by trypsin-like enzymes. This is in vitro plasma enzymology, not a statement that inhibiting DPP-4 in a person changes a peptide's clinical effect.

In human plasma, DPP-IV makes the first cut in growth hormone releasing hormone

Cell study

Frohman LA et al. J Clin Invest. 1989;83(5):1533-40. PMID 2565342.

In human plasma, the primary proteolytic cleavage of growth hormone releasing hormone at the 2 to 3 amino acid bond is a single-step dipeptidylpeptidase IV cut, blocked by the DPP IV inhibitor diprotin A and prevented by D-amino acid substitution at position 1 or 2. GRH(1-44)-NH2, GRH(1-40)-OH, GRH(1-32)-NH2 and GRH(1-29)-NH2 were all rapidly cleaved; GRH(2-32)-NH2 was not. The authors concluded that GRH degradation in plasma occurs primarily by DPP IV and to a lesser extent by trypsin-like enzymes.

Participants / model
Human plasma in vitro; endogenous immunoreactivity from a human GRH transgenic pig
Treatment
Not a therapeutic route; enzyme incubation
Follow-up
Not applicable
Study design
In vitro mechanistic study
Funding
not stated in the source

This is in vitro plasma enzymology, not a statement that inhibiting DPP-4 in a person changes a peptide's clinical effect.

Read the original source

Does DPP-4 inhibition change growth hormone or IGF-1?

The results point both ways and are narrow. One acute crossover in 39 healthy adults found higher stimulated GH and free IGF-1 on sitagliptin in women. A comparison of 18 chronic DPP-4 inhibitor users and a pig experiment at 90% DPP-IV inhibition found no IGF-1 increase.

The strongest human evidence that DPP-4 inhibition touches the growth hormone axis is narrow. In a two-part double-blind randomized placebo-controlled crossover study, 39 healthy adults (29 women) received sitagliptin or placebo on two separate days, with intravenous arginine 30 g given to stimulate GH. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free IGF-1 (P<0.001 after adjustment for baseline) in women, and enhanced vasodilation (P=0.01) and tissue plasminogen activator (P<0.001) in women only. The effect was reported in women, used a pharmacologic arginine stimulus, and was measured acutely, not over a dosing course. It should not be generalized to men. The trial is registered as NCT01701973.

Chronic DPP-4 inhibition did not move the axis. In 60 patients with type 2 diabetes grouped by the drugs taken over the previous 4 months (17 on exenatide or liraglutide plus metformin, 18 on sitagliptin or vildagliptin plus metformin, 25 on metformin), absolute IGF-1 values and IGF-1 SDS did not differ significantly between the three groups. The authors concluded that DPP-4 inhibition does not significantly influence the GH/IGF-1 system. This is a cross-sectional comparison, not a randomized trial, and it had 18 patients in the DPP-4 inhibitor group.

The same negative result appeared in a controlled animal experiment run by the sponsor of sitagliptin. Growing pigs (78 kg) received saline (n=2), a DPP-IV inhibitor closely related to sitagliptin as a bolus plus 72-hour infusion (n=4), or GHRH by 48-hour infusion (n=4). Plasma inhibitor concentrations held at 1 micromolar, producing 90 percent inhibition of circulating DPP-IV activity. Relative to the predose 24-hour period, IGF-1 AUC tended to be lower with the inhibitor than in controls (P=0.062), while GHRH infusion raised IGF-1 AUC (P=0.049 versus controls, P=0.001 versus inhibitor). The authors concluded that DPP-IV inhibition does not alter circulating IGF-1 in the growing pig. Ninety percent enzyme inhibition did not reproduce what giving the peptide itself did.

39 healthy adults, 29 women: higher stimulated GH and free IGF-1 in women, acute

Randomized controlled trial

Wilson JR et al. J Am Heart Assoc. 2018;7(5). PMID 29478970.

Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free IGF-1 (P<0.001 after adjustment for baseline) in women, and enhanced vasodilation (P=0.01) and tissue plasminogen activator (P<0.001) in women only.

Participants / model
39 healthy adults, 29 of them women
Treatment
Oral sitagliptin or placebo on two separate days, with intravenous arginine 30 g to stimulate GH
Follow-up
Two separate study days
Study design
Two-part double-blind randomized placebo-controlled crossover study (NCT01701973)
Funding
not stated in the source

The effect was reported in women, used a pharmacologic arginine stimulus, and was measured acutely, not over a dosing course. It should not be generalized to men.

Read the original source
60 patients with type 2 diabetes: IGF-1 did not differ, 18 on DPP-4 inhibitors

Human study

Teti C et al. J Endocrinol Invest. 2020;43(3):389-393. PMID 31473983.

Absolute IGF-1 values and IGF-1 SDS did not differ significantly between the three groups. The authors concluded that DPP-4 inhibition does not significantly influence the GH/IGF-1 system.

Participants / model
60 adults with type 2 diabetes grouped by the drugs taken over the previous 4 months: 17 on exenatide or liraglutide plus metformin, 18 on sitagliptin or vildagliptin plus metformin, 25 on metformin
Treatment
Oral DPP-4 inhibitors or injectable GLP-1 agonists plus metformin, as taken in care
Follow-up
Drugs taken over the previous 4 months
Study design
Cross-sectional observational comparison
Funding
not stated in the source

This is a cross-sectional comparison, not a randomized trial, and it had 18 patients in the DPP-4 inhibitor group.

Read the original source
Growing pigs, 10 in total: 90% DPP-IV inhibition did not raise IGF-1, GHRH did

Animal study

Faidley TD et al. Exp Biol Med (Maywood). 2006;231(8):1373-8. PMID 16946406.

Plasma inhibitor concentrations held at 1 micromolar, producing 90 percent inhibition of circulating DPP-IV activity. Relative to the predose 24-hour period, IGF-1 AUC tended to be lower with the inhibitor than in controls (P=0.062), while GHRH infusion raised IGF-1 AUC (P=0.049 versus controls, P=0.001 versus inhibitor). The authors concluded that DPP-IV inhibition does not alter circulating IGF-1 in the growing pig.

Participants / model
Growing pigs (78 kg), 10 in total across three arms: saline (n=2), inhibitor (n=4), GHRH (n=4)
Treatment
Intravenous infusion of a DPP-IV inhibitor closely related to sitagliptin, or of GHRH, versus saline
Follow-up
72-hour inhibitor infusion; 48-hour GHRH infusion
Study design
Controlled animal experiment
Funding
The experiment was run by the sponsor of sitagliptin.

The inhibitor was closely related to sitagliptin, not sitagliptin itself. Ninety percent enzyme inhibition did not reproduce what giving the peptide itself did.

Read the original source

How does sitagliptin work, and what does the body do with it?

Sitagliptin slows inactivation of incretin hormones, raising active GLP-1 and GIP; the label reports 24-hour DPP-4 inhibition and a 2-fold to 3-fold rise after a glucose load or meal. Oral bioavailability is about 87%, and the apparent terminal half-life is about 12.4 hours.

The label states that sitagliptin slows inactivation of incretin hormones, raising concentrations of active GLP-1 and GIP. In patients with type 2 diabetes a dose produced DPP-4 inhibition over a 24-hour period and a 2-fold to 3-fold increase in circulating active GLP-1 and GIP after an oral glucose load or meal. In healthy subjects sitagliptin did not lower blood glucose or cause hypoglycemia.

Absolute oral bioavailability is approximately 87 percent, median Tmax is 1 to 4 hours after a single oral dose in healthy subjects, and a high-fat meal has no food effect. Plasma protein binding is 38 percent. Approximately 79 percent is excreted unchanged in urine, metabolism is a minor pathway through CYP3A4 with contribution from CYP2C8, the apparent terminal half-life is approximately 12.4 hours, and renal clearance is approximately 350 mL/min.

JANUVIA label, version effective 14 November 2024: indication, mechanism, pharmacodynamics

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01.

The label approves JANUVIA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Limitations of use: it should not be used in type 1 diabetes, and it has not been studied in patients with a history of pancreatitis. Sitagliptin slows inactivation of incretin hormones, raising concentrations of active GLP-1 and GIP. The label states that in patients with type 2 diabetes a dose produced DPP-4 inhibition over a 24-hour period and a 2-fold to 3-fold increase in circulating active GLP-1 and GIP after an oral glucose load or meal, and that in healthy subjects sitagliptin did not lower blood glucose or cause hypoglycemia.

Participants / model
Adults with type 2 diabetes; healthy subjects for the pharmacodynamic statement
Treatment
JANUVIA film-coated oral tablets
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

The label does not address use alongside injected peptides.

Read the original source
JANUVIA label PK: 87% bioavailability, 12.4 hour half-life, renal excretion

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01. Pharmacokinetics section.

Absolute oral bioavailability is approximately 87 percent, median Tmax 1 to 4 hours after a single oral dose in healthy subjects, with no food effect from a high-fat meal. Steady-state volume of distribution after a single intravenous dose is approximately 198 litres, and plasma protein binding is 38 percent. Approximately 79 percent is excreted unchanged in urine, metabolism is a minor pathway through CYP3A4 with contribution from CYP2C8, apparent terminal half-life is approximately 12.4 hours, and renal clearance is approximately 350 mL/min.

Participants / model
Healthy subjects in the label PK studies
Treatment
Oral and intravenous sitagliptin
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

Label PK in healthy subjects.

Read the original source

What risks do the label and TECOS report?

The label warns of acute pancreatitis, acute renal failure, hypoglycemia with insulin or an insulin secretagogue, serious hypersensitivity, severe arthralgia and bullous pemphigoid. Its heart-failure warning is a class warning, and TECOS found no heart-failure excess.

The label's warnings for adults with type 2 diabetes include postmarketing acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing cases; acute renal failure sometimes requiring dialysis; increased hypoglycemia risk with insulin or an insulin secretagogue; serious hypersensitivity including anaphylaxis, angioedema and exfoliative skin conditions; severe and disabling arthralgia, with onset from one day to years and recurrence on rechallenge; and bullous pemphigoid requiring hospitalization. It is contraindicated after a serious hypersensitivity reaction to sitagliptin.

The label also mentions heart failure, observed with two other members of the DPP-4 inhibitor class, and tells prescribers to weigh risks and benefits in patients with heart-failure risk factors. That is a class warning, not a sitagliptin finding. In TECOS, hospitalization for heart failure did not differ from placebo (hazard ratio 1.00, 95% CI 0.83 to 1.20, P=0.98), and there were no significant differences in acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

All of these data are from sitagliptin used for type 2 diabetes. No study in the records reviewed measured safety when sitagliptin was combined with an injected peptide.

JANUVIA label warnings: pancreatitis, heart failure, renal failure, arthralgia, bullous pemphigoid

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01. Warnings and precautions, contraindications.

Postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis; heart failure, observed with two other members of the DPP-4 inhibitor class, with instruction to weigh risks and benefits in patients with heart-failure risk factors; acute renal failure sometimes requiring dialysis; increased hypoglycemia risk with insulin or an insulin secretagogue; serious hypersensitivity including anaphylaxis, angioedema and exfoliative skin conditions; severe and disabling arthralgia reported with DPP-4 inhibitors, with onset from one day to years and recurrence on rechallenge; and bullous pemphigoid requiring hospitalization. Contraindicated after a serious hypersensitivity reaction to sitagliptin.

Participants / model
Adults with type 2 diabetes in trials and postmarketing reports
Treatment
Oral sitagliptin
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

The heart-failure warning is a class warning carried from two other DPP-4 inhibitors, not a sitagliptin finding. TECOS found no heart-failure excess.

Read the original source
TECOS: 14,671 patients, cardiovascular outcomes noninferior, no heart failure excess

Randomized controlled trial

Green JB et al. N Engl J Med. 2015;373(3):232-42. PMID 26052984.

The HbA1c difference was -0.29 percentage points (95% CI -0.32 to -0.27). The primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina occurred in 11.4 versus 11.6 percent (hazard ratio 0.98, 95% CI 0.88 to 1.09, P<0.001 for noninferiority). Hospitalization for heart failure did not differ (hazard ratio 1.00, 95% CI 0.83 to 1.20, P=0.98), and there were no significant differences in acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

Participants / model
14,671 adults with type 2 diabetes and established cardiovascular disease
Treatment
Oral sitagliptin or placebo added to usual care
Follow-up
Median follow-up 3.0 years
Study design
Randomized placebo-controlled cardiovascular outcome trial (NCT00790205)
Funding
not stated in the source

Patients with type 2 diabetes and established cardiovascular disease.

Read the original source
Searches, 9 October 2026: 2 records, 0 records and 6 registry studies, none co-dosing a peptide

PubMed search record

PubMed searches run on 9 October 2026: sitagliptin AND (growth hormone releasing peptide OR GHRP OR ipamorelin OR CJC-1295 OR tesamorelin), 2 records; sitagliptin with the phrase anabolic steroid, 0 records. ClinicalTrials.gov query for sitagliptin and growth hormone releasing peptide on the same date: 6 studies.

The PubMed search returned 2 records, both measuring circulating ghrelin or gastrin levels in people given sitagliptin alone, neither co-dosing an injected peptide. A search for sitagliptin with the phrase anabolic steroid returned 0 records. On ClinicalTrials.gov the same day, a query for sitagliptin and growth hormone releasing peptide returned 6 studies, the only growth-hormone one being NCT01701973, the arginine-stimulation study on this page. No study in the records reviewed co-administered sitagliptin with an injected growth-hormone secretagogue, GHRH analogue or other research peptide and measured that peptide's exposure, half-life or effect.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what PubMed and ClinicalTrials.gov returned on that date. It is not proof that no unindexed study exists.

Read the original source

Why does sitagliptin sit in A tier?

The A rests on an FDA approval since 2006, randomized efficacy trials and a 14,671-patient cardiovascular outcome trial with a neutral result. The supplier's peptide co-dosing use has a real enzyme premise but no study that co-administered it with an injected peptide.

The A applies to the labeled use in type 2 diabetes. The supplier claim has a real premise but is unproven where it counts: DPP-4 does make the position 2 cut in growth hormone releasing hormone in plasma, and one acute randomized crossover in 39 healthy adults found higher arginine-stimulated GH and free IGF-1 on sitagliptin in women.

Against that, a cross-sectional comparison of 18 chronic DPP-4 inhibitor users found no IGF-1 difference, a controlled pig experiment at 90 percent enzyme inhibition found no IGF-1 increase while GHRH infusion did raise it, and no study in the records reviewed on 9 October 2026 co-administered sitagliptin with any injected research peptide and measured that peptide's exposure or effect.

JANUVIA label, version effective 14 November 2024: indication, mechanism, pharmacodynamics

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01.

The label approves JANUVIA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Limitations of use: it should not be used in type 1 diabetes, and it has not been studied in patients with a history of pancreatitis. Sitagliptin slows inactivation of incretin hormones, raising concentrations of active GLP-1 and GIP. The label states that in patients with type 2 diabetes a dose produced DPP-4 inhibition over a 24-hour period and a 2-fold to 3-fold increase in circulating active GLP-1 and GIP after an oral glucose load or meal, and that in healthy subjects sitagliptin did not lower blood glucose or cause hypoglycemia.

Participants / model
Adults with type 2 diabetes; healthy subjects for the pharmacodynamic statement
Treatment
JANUVIA film-coated oral tablets
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

The label does not address use alongside injected peptides.

Read the original source
TECOS: 14,671 patients, cardiovascular outcomes noninferior, no heart failure excess

Randomized controlled trial

Green JB et al. N Engl J Med. 2015;373(3):232-42. PMID 26052984.

The HbA1c difference was -0.29 percentage points (95% CI -0.32 to -0.27). The primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina occurred in 11.4 versus 11.6 percent (hazard ratio 0.98, 95% CI 0.88 to 1.09, P<0.001 for noninferiority). Hospitalization for heart failure did not differ (hazard ratio 1.00, 95% CI 0.83 to 1.20, P=0.98), and there were no significant differences in acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

Participants / model
14,671 adults with type 2 diabetes and established cardiovascular disease
Treatment
Oral sitagliptin or placebo added to usual care
Follow-up
Median follow-up 3.0 years
Study design
Randomized placebo-controlled cardiovascular outcome trial (NCT00790205)
Funding
not stated in the source

Patients with type 2 diabetes and established cardiovascular disease.

Read the original source
In human plasma, DPP-IV makes the first cut in growth hormone releasing hormone

Cell study

Frohman LA et al. J Clin Invest. 1989;83(5):1533-40. PMID 2565342.

In human plasma, the primary proteolytic cleavage of growth hormone releasing hormone at the 2 to 3 amino acid bond is a single-step dipeptidylpeptidase IV cut, blocked by the DPP IV inhibitor diprotin A and prevented by D-amino acid substitution at position 1 or 2. GRH(1-44)-NH2, GRH(1-40)-OH, GRH(1-32)-NH2 and GRH(1-29)-NH2 were all rapidly cleaved; GRH(2-32)-NH2 was not. The authors concluded that GRH degradation in plasma occurs primarily by DPP IV and to a lesser extent by trypsin-like enzymes.

Participants / model
Human plasma in vitro; endogenous immunoreactivity from a human GRH transgenic pig
Treatment
Not a therapeutic route; enzyme incubation
Follow-up
Not applicable
Study design
In vitro mechanistic study
Funding
not stated in the source

This is in vitro plasma enzymology, not a statement that inhibiting DPP-4 in a person changes a peptide's clinical effect.

Read the original source
39 healthy adults, 29 women: higher stimulated GH and free IGF-1 in women, acute

Randomized controlled trial

Wilson JR et al. J Am Heart Assoc. 2018;7(5). PMID 29478970.

Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free IGF-1 (P<0.001 after adjustment for baseline) in women, and enhanced vasodilation (P=0.01) and tissue plasminogen activator (P<0.001) in women only.

Participants / model
39 healthy adults, 29 of them women
Treatment
Oral sitagliptin or placebo on two separate days, with intravenous arginine 30 g to stimulate GH
Follow-up
Two separate study days
Study design
Two-part double-blind randomized placebo-controlled crossover study (NCT01701973)
Funding
not stated in the source

The effect was reported in women, used a pharmacologic arginine stimulus, and was measured acutely, not over a dosing course. It should not be generalized to men.

Read the original source
60 patients with type 2 diabetes: IGF-1 did not differ, 18 on DPP-4 inhibitors

Human study

Teti C et al. J Endocrinol Invest. 2020;43(3):389-393. PMID 31473983.

Absolute IGF-1 values and IGF-1 SDS did not differ significantly between the three groups. The authors concluded that DPP-4 inhibition does not significantly influence the GH/IGF-1 system.

Participants / model
60 adults with type 2 diabetes grouped by the drugs taken over the previous 4 months: 17 on exenatide or liraglutide plus metformin, 18 on sitagliptin or vildagliptin plus metformin, 25 on metformin
Treatment
Oral DPP-4 inhibitors or injectable GLP-1 agonists plus metformin, as taken in care
Follow-up
Drugs taken over the previous 4 months
Study design
Cross-sectional observational comparison
Funding
not stated in the source

This is a cross-sectional comparison, not a randomized trial, and it had 18 patients in the DPP-4 inhibitor group.

Read the original source
Growing pigs, 10 in total: 90% DPP-IV inhibition did not raise IGF-1, GHRH did

Animal study

Faidley TD et al. Exp Biol Med (Maywood). 2006;231(8):1373-8. PMID 16946406.

Plasma inhibitor concentrations held at 1 micromolar, producing 90 percent inhibition of circulating DPP-IV activity. Relative to the predose 24-hour period, IGF-1 AUC tended to be lower with the inhibitor than in controls (P=0.062), while GHRH infusion raised IGF-1 AUC (P=0.049 versus controls, P=0.001 versus inhibitor). The authors concluded that DPP-IV inhibition does not alter circulating IGF-1 in the growing pig.

Participants / model
Growing pigs (78 kg), 10 in total across three arms: saline (n=2), inhibitor (n=4), GHRH (n=4)
Treatment
Intravenous infusion of a DPP-IV inhibitor closely related to sitagliptin, or of GHRH, versus saline
Follow-up
72-hour inhibitor infusion; 48-hour GHRH infusion
Study design
Controlled animal experiment
Funding
The experiment was run by the sponsor of sitagliptin.

The inhibitor was closely related to sitagliptin, not sitagliptin itself. Ninety percent enzyme inhibition did not reproduce what giving the peptide itself did.

Read the original source
Searches, 9 October 2026: 2 records, 0 records and 6 registry studies, none co-dosing a peptide

PubMed search record

PubMed searches run on 9 October 2026: sitagliptin AND (growth hormone releasing peptide OR GHRP OR ipamorelin OR CJC-1295 OR tesamorelin), 2 records; sitagliptin with the phrase anabolic steroid, 0 records. ClinicalTrials.gov query for sitagliptin and growth hormone releasing peptide on the same date: 6 studies.

The PubMed search returned 2 records, both measuring circulating ghrelin or gastrin levels in people given sitagliptin alone, neither co-dosing an injected peptide. A search for sitagliptin with the phrase anabolic steroid returned 0 records. On ClinicalTrials.gov the same day, a query for sitagliptin and growth hormone releasing peptide returned 6 studies, the only growth-hormone one being NCT01701973, the arginine-stimulation study on this page. No study in the records reviewed co-administered sitagliptin with an injected growth-hormone secretagogue, GHRH analogue or other research peptide and measured that peptide's exposure, half-life or effect.

Participants / model
Records reviewed, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry search
Funding
not stated in the source

A search result shows what PubMed and ClinicalTrials.gov returned on that date. It is not proof that no unindexed study exists.

Read the original source

Studies and sources

PubChem: sitagliptin identity

Chemical identity record

National Library of Medicine. PubChem compound record CID 4369359 (sitagliptin).

Sitagliptin free base: PubChem CID 4369359, C16H15F6N5O, 407.31 g/mol, CAS 486460-32-6. The phosphate salt used in JANUVIA appears in the same record's synonyms with CAS 790712-60-6. Doses on the label are expressed as sitagliptin free base, so salt mass and base mass should not be interchanged.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule and salt
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
JANUVIA label, version effective 14 November 2024: indication, mechanism, pharmacodynamics

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01.

The label approves JANUVIA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Limitations of use: it should not be used in type 1 diabetes, and it has not been studied in patients with a history of pancreatitis. Sitagliptin slows inactivation of incretin hormones, raising concentrations of active GLP-1 and GIP. The label states that in patients with type 2 diabetes a dose produced DPP-4 inhibition over a 24-hour period and a 2-fold to 3-fold increase in circulating active GLP-1 and GIP after an oral glucose load or meal, and that in healthy subjects sitagliptin did not lower blood glucose or cause hypoglycemia.

Participants / model
Adults with type 2 diabetes; healthy subjects for the pharmacodynamic statement
Treatment
JANUVIA film-coated oral tablets
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

The label does not address use alongside injected peptides.

Read the original source
JANUVIA label PK: 87% bioavailability, 12.4 hour half-life, renal excretion

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01. Pharmacokinetics section.

Absolute oral bioavailability is approximately 87 percent, median Tmax 1 to 4 hours after a single oral dose in healthy subjects, with no food effect from a high-fat meal. Steady-state volume of distribution after a single intravenous dose is approximately 198 litres, and plasma protein binding is 38 percent. Approximately 79 percent is excreted unchanged in urine, metabolism is a minor pathway through CYP3A4 with contribution from CYP2C8, apparent terminal half-life is approximately 12.4 hours, and renal clearance is approximately 350 mL/min.

Participants / model
Healthy subjects in the label PK studies
Treatment
Oral and intravenous sitagliptin
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

Label PK in healthy subjects.

Read the original source
JANUVIA label warnings: pancreatitis, heart failure, renal failure, arthralgia, bullous pemphigoid

FDA prescribing information

DailyMed, U.S. National Library of Medicine. JANUVIA (sitagliptin) film-coated oral tablets, prescribing information, label version effective 14 November 2024. Set ID f85a48d0-0407-4c50-b0fa-7673a160bf01. Warnings and precautions, contraindications.

Postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis; heart failure, observed with two other members of the DPP-4 inhibitor class, with instruction to weigh risks and benefits in patients with heart-failure risk factors; acute renal failure sometimes requiring dialysis; increased hypoglycemia risk with insulin or an insulin secretagogue; serious hypersensitivity including anaphylaxis, angioedema and exfoliative skin conditions; severe and disabling arthralgia reported with DPP-4 inhibitors, with onset from one day to years and recurrence on rechallenge; and bullous pemphigoid requiring hospitalization. Contraindicated after a serious hypersensitivity reaction to sitagliptin.

Participants / model
Adults with type 2 diabetes in trials and postmarketing reports
Treatment
Oral sitagliptin
Follow-up
Label version effective 14 November 2024
Study design
FDA prescribing information
Funding
not stated in the source

The heart-failure warning is a class warning carried from two other DPP-4 inhibitors, not a sitagliptin finding. TECOS found no heart-failure excess.

Read the original source
Drugs@FDA: JANUVIA approved 16 October 2006

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 021995 (JANUVIA). Date read from the openFDA Drugs@FDA record.

FDA approved JANUVIA under NDA 021995 on 16 October 2006.

Participants / model
Not a clinical population
Treatment
Drug application
Follow-up
Approved 2006
Study design
FDA application record
Funding
not stated in the source

This record gives the approval date. Indications come from the product label.

Read the original source
741 patients, 24 weeks: HbA1c down 0.79 and 0.94 percent, weight not lower than placebo

Randomized controlled trial

Aschner P et al. Diabetes Care. 2006;29(12):2632-7. PMID 17130196.

Placebo-subtracted HbA1c reductions were -0.79 and -0.94 percent (P<0.001) and 2-hour postprandial glucose reductions -2.6 and -3.0 mmol/L. Body weight changed by -0.2 kg (100 mg) and -0.1 kg (200 mg) versus -1.1 kg on placebo, a difference significant in favor of placebo (P<0.01).

Participants / model
741 patients with type 2 diabetes (baseline HbA1c 8.0 percent)
Treatment
Oral sitagliptin 100 or 200 mg once daily, or placebo
Follow-up
24 weeks
Study design
Randomized double-blind placebo-controlled monotherapy study
Funding
not stated in the source

Sitagliptin is weight-neutral at best in this trial, which matters because supplier pages often place it next to weight-loss compounds.

Read the original source
TECOS: 14,671 patients, cardiovascular outcomes noninferior, no heart failure excess

Randomized controlled trial

Green JB et al. N Engl J Med. 2015;373(3):232-42. PMID 26052984.

The HbA1c difference was -0.29 percentage points (95% CI -0.32 to -0.27). The primary composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or hospitalization for unstable angina occurred in 11.4 versus 11.6 percent (hazard ratio 0.98, 95% CI 0.88 to 1.09, P<0.001 for noninferiority). Hospitalization for heart failure did not differ (hazard ratio 1.00, 95% CI 0.83 to 1.20, P=0.98), and there were no significant differences in acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32).

Participants / model
14,671 adults with type 2 diabetes and established cardiovascular disease
Treatment
Oral sitagliptin or placebo added to usual care
Follow-up
Median follow-up 3.0 years
Study design
Randomized placebo-controlled cardiovascular outcome trial (NCT00790205)
Funding
not stated in the source

Patients with type 2 diabetes and established cardiovascular disease.

Read the original source
In human plasma, DPP-IV makes the first cut in growth hormone releasing hormone

Cell study

Frohman LA et al. J Clin Invest. 1989;83(5):1533-40. PMID 2565342.

In human plasma, the primary proteolytic cleavage of growth hormone releasing hormone at the 2 to 3 amino acid bond is a single-step dipeptidylpeptidase IV cut, blocked by the DPP IV inhibitor diprotin A and prevented by D-amino acid substitution at position 1 or 2. GRH(1-44)-NH2, GRH(1-40)-OH, GRH(1-32)-NH2 and GRH(1-29)-NH2 were all rapidly cleaved; GRH(2-32)-NH2 was not. The authors concluded that GRH degradation in plasma occurs primarily by DPP IV and to a lesser extent by trypsin-like enzymes.

Participants / model
Human plasma in vitro; endogenous immunoreactivity from a human GRH transgenic pig
Treatment
Not a therapeutic route; enzyme incubation
Follow-up
Not applicable
Study design
In vitro mechanistic study
Funding
not stated in the source

This is in vitro plasma enzymology, not a statement that inhibiting DPP-4 in a person changes a peptide's clinical effect.

Read the original source
39 healthy adults, 29 women: higher stimulated GH and free IGF-1 in women, acute

Randomized controlled trial

Wilson JR et al. J Am Heart Assoc. 2018;7(5). PMID 29478970.

Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free IGF-1 (P<0.001 after adjustment for baseline) in women, and enhanced vasodilation (P=0.01) and tissue plasminogen activator (P<0.001) in women only.

Participants / model
39 healthy adults, 29 of them women
Treatment
Oral sitagliptin or placebo on two separate days, with intravenous arginine 30 g to stimulate GH
Follow-up
Two separate study days
Study design
Two-part double-blind randomized placebo-controlled crossover study (NCT01701973)
Funding
not stated in the source

The effect was reported in women, used a pharmacologic arginine stimulus, and was measured acutely, not over a dosing course. It should not be generalized to men.

Read the original source
60 patients with type 2 diabetes: IGF-1 did not differ, 18 on DPP-4 inhibitors

Human study

Teti C et al. J Endocrinol Invest. 2020;43(3):389-393. PMID 31473983.

Absolute IGF-1 values and IGF-1 SDS did not differ significantly between the three groups. The authors concluded that DPP-4 inhibition does not significantly influence the GH/IGF-1 system.

Participants / model
60 adults with type 2 diabetes grouped by the drugs taken over the previous 4 months: 17 on exenatide or liraglutide plus metformin, 18 on sitagliptin or vildagliptin plus metformin, 25 on metformin
Treatment
Oral DPP-4 inhibitors or injectable GLP-1 agonists plus metformin, as taken in care
Follow-up
Drugs taken over the previous 4 months
Study design
Cross-sectional observational comparison
Funding
not stated in the source

This is a cross-sectional comparison, not a randomized trial, and it had 18 patients in the DPP-4 inhibitor group.

Read the original source
Growing pigs, 10 in total: 90% DPP-IV inhibition did not raise IGF-1, GHRH did

Animal study

Faidley TD et al. Exp Biol Med (Maywood). 2006;231(8):1373-8. PMID 16946406.

Plasma inhibitor concentrations held at 1 micromolar, producing 90 percent inhibition of circulating DPP-IV activity. Relative to the predose 24-hour period, IGF-1 AUC tended to be lower with the inhibitor than in controls (P=0.062), while GHRH infusion raised IGF-1 AUC (P=0.049 versus controls, P=0.001 versus inhibitor). The authors concluded that DPP-IV inhibition does not alter circulating IGF-1 in the growing pig.

Participants / model
Growing pigs (78 kg), 10 in total across three arms: saline (n=2), inhibitor (n=4), GHRH (n=4)
Treatment
Intravenous infusion of a DPP-IV inhibitor closely related to sitagliptin, or of GHRH, versus saline
Follow-up
72-hour inhibitor infusion; 48-hour GHRH infusion
Study design
Controlled animal experiment
Funding
The experiment was run by the sponsor of sitagliptin.

The inhibitor was closely related to sitagliptin, not sitagliptin itself. Ninety percent enzyme inhibition did not reproduce what giving the peptide itself did.

Read the original source

Why is Sitagliptin in A tier?

A fits an approved drug promoted for an off-label use. Sitagliptin has been FDA-approved since 2006, with randomized efficacy trials and a 14,671-patient cardiovascular outcome trial with a neutral result. The supplier's use alongside injected peptides rests on a real enzyme premise, but the searches run on 9 October 2026 found no study that co-administered it with an injected peptide.