Saxagliptin

Overview

Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.[1][2] WP

In April 2016, the U.S. FDA added a warning about increased risk of heart failure. This was based on data in an article that concluded "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."[3][4] WP

Uses, dosage and effects

Medical uses

Saxagliptin is used as monotherapy or in combination with other drugs for the treatment of type 2 diabetes. It does not appear to decrease the risk of heart attacks or strokes. One study showed a 3.5% risk of hospitalization for heart failure compared to 2.8% in a placebo-controlled group. Like other DPP-4 inhibitors, it has relatively modest HbA1c lowering ability, is associated with a relatively low risk of hypoglycemia, and does not cause weight gain.[4][5] WP

Saxagliptin improved mean HbA1c levels (relative to placebo) in a 24-week trial in people with type 2 diabetes. Combination therapy with saxagliptin and metformin was more effective than saxagliptin or metformin monotherapy. When the relative benefits of increasing the dose of a sulfonylurea or adding saxagliptin were assessed in a study of 768 patients, combination treatments were shown to have a significantly greater impact on fasting blood glucose than increasing the tested glibenclamide dose alone.[6][7] WP

Risks and side effects

Adverse effects

In those taking sulphonylureas there is an increased risk of low blood sugar.[8] WP

3 adverse reactions were seen higher in saxagliptin vs placebo. Table 1: Adverse Reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with ONGLYZA (saxagliptin tablets) 5 mg and More Commonly than in Patients Treated with Placebo.[9] WP⚠ A table follows this text in the source and is not copied here. Open the source to see it.

• The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue.[9] WP

In February 2012, Bristol-Myers/Astra Zeneca distributed additional safety information on saxagliptin use in South Africa. The package insert is to be edited for South Africa. Contraindications will now include a history of sensitivity to saxagliptin (or another DPP4 inhibitor) as well as pancreatitis. Spontaneously reported adverse events in South Africa have included anaphylaxis, angioedema and acute pancreatitis. WP⚠ Part of this sentence could not be copied from the source. Open the source to read it in full.

In a cardiovascular outcomes trial, saxagliptin treatment let to a small increase in the risk of being hospitalized for heart failure. Saxagliptin may cause joint pain that can be severe and disabling. Saxagliptin may increase the risk of heart failure.[4][10][11] WP

Tolerability

Both monotherapy and combination therapy with other agents was generally well tolerated in clinical trials.[6] WP

Pancreatitis and pancreatic cancer

An association of the DPP-IV inhibitor class with pancreatic problems has been proposed, mainly based on case reports associated with the DPP-IV inhibitor sitagliptin and several incretin mimetics including exenatide. A 2013 study of the DPP-4 inhibitor sitagliptin reported found "worrisome changes in the pancreases of the rats that could lead to pancreatic cancer". A second paper by the same authors reported an increase in precancerous lesions in the pancreases of organ donors who had taken GLP-1 inhibitors. In response to these reports, the United States FDA and the European Medicines Agency each undertook independent reviews of all clinical and preclinical data related to the possible association of DPP-IV inhibitors with pancreatic cancer. In a joint letter to the New England Journal of Medicines, the agencies stated that "Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data. The FDA and the EMA have not reached a final conclusion at this time regarding such a causal relationship. Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal."[12][13][14] WP

Lawsuits have been filed in which plaintiffs who developed pancreatic cancer claim that DPP-IV inhibitors or incretins had a causative role in the development of their cancers.[15] WP

Pharmacology

Pharmacology

Saxagliptin is part of a class of diabetes medications called dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 is an enzyme that breaks down incretin hormones. As a DPP-4 inhibitor, saxagliptin slows down the breakdown of incretin hormones, increasing the level of these hormones in the body. It is this increase in incretin hormones that is responsible for the beneficial actions of saxagliptin, including increasing insulin production in response to meals and decreasing the rate of gluconeogenesis in the liver.[16] WP

Dipeptidyl peptidase-4's role in blood glucose regulation is thought to be through degradation of GIP and the degradation of GLP-1.[17][18] WP

Because incretin hormones are more active in response to higher blood sugar levels (and are less active in response to low blood sugar), the risk of dangerously low blood sugar (hypoglycemia) is low with saxagliptin monotherapy. WP⚠ Wikipedia itself has flagged this text: citation needed.

Chemistry

Formula

C18H25N3O2 PC

CAS number

361442-04-8 PC

Molar mass (g/mol)

315.4 PC

IUPAC name (computed by PubChem)

(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile PC

SMILES

C1[C@@H]2C[C@@H]2N([C@@H]1C#N)C(=O)[C@H](C34CC5CC(C3)CC(C5)(C4)O)N PC

InChIKey

QGJUIPDUBHWZPV-SGTAVMJGSA-N PC

PubChem CID

11243969

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

1. Journal / agency Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han SP, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG. Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Journal of Medicinal Chemistry. July 2005. doi:10.1021/jm050261p · PMID 16033281
2. Other Bristol, Takeda Drugs Offer Alternatives to Januvia (Update2). 2008-06-07
3. Journal / agency Safety Alerts for Human Medical Products - Diabetes Medications Containing Saxagliptin and Alogliptin: Drug Safety Communication - Risk of Heart Failure
4. Journal / agency Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. The New England Journal of Medicine. October 2013. doi:10.1056/nejmoa1307684 · PMID 23992601
5. Journal / agency Ali S, Fonseca V. Saxagliptin overview: special focus on safety and adverse effects. Expert Opinion on Drug Safety. January 2013. doi:10.1517/14740338.2013.741584 · PMID 23137182
6. Journal / agency Dhillon S, Weber J. Saxagliptin. Drugs. October 2009. doi:10.2165/11201170-000000000-00000 · PMID 19791828
7. Journal / agency New Drugs: Saxagliptin. Australian Prescriber. June 2011
8. Journal / agency Salvo F, Moore N, Arnaud M, Robinson P, Raschi E, De Ponti F, Bégaud B, Pariente A. Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis. BMJ. May 2016. doi:10.1136/bmj.i2231 · PMID 27142267 · PMC4854021
9. Other Onglyza
10. Journal / agency DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication - May Cause Severe Joint Pain. 2015-08-28
11. Journal / agency FDA Drug Safety Communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin. 12 January 2017
12. Journal / agency Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, Butler AE, Butler PC. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes. July 2009. doi:10.2337/db09-0058 · PMID 19403868 · PMC2699878
13. Journal / agency Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. July 2013. doi:10.2337/db12-1686 · PMID 23524641 · PMC3712065
14. Journal / agency Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, Rosebraugh C. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. The New England Journal of Medicine. February 2014. doi:10.1056/NEJMp1314078 · PMID 24571751
15. Other IN RE: INCRETIN MIMETICS PRODUCTS LIABILITY LITIGATION. August 26, 2013
16. Other Emedtv. Onglyza
17. Journal / agency Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. European Journal of Biochemistry. June 1993. doi:10.1111/j.1432-1033.1993.tb17986.x · PMID 8100523
18. Journal / agency Ahrén B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. The Journal of Clinical Endocrinology and Metabolism. May 2004. doi:10.1210/jc.2003-031907 · PMID 15126524

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