|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Legal status||POM (UK) ℞-only (US)|
|Mol. mass||315.41 g/mol|
| (what is this?)
Saxagliptin (rINN), previously identified as BMS-477118, is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.1 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. In June 2008, it was announced that Onglyza would be the trade name under which saxagliptin will be marketed.2
Saxagliptin does not appear to decrease the risk of heart attacks or stokes in those with type 2 diabetes. While it does decrease the HbA1C slightly it increases the risk of hospitalization for heart failure.3
Saxagliptin improving mean HbA1c levels (relative to placebo) in a 24-week trials people with type 2 diabetes.4 Combination therapy with saxagliptin and metformin was more effective than saxagliptin or metformin monotherapy.4 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.5
In 4148 patients studied, 3 adverse reactions were seen higher in saxaglyptin 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.6
|ONGLYZA 5 mg N=882||Placebo N=799|
|Upper respiratory tract infection||68 (7.7)||61 (7.6)|
|Urinary tract infection||60 (6.8)||49 (6.1)|
|Headache||57 (6.5)||47 (5.9)6|
- 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.6
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.
Both monotherapy and combination therapy with other agents was generally well tolerated in clinical trials.4
The DPP-4 enzyme is known to be involved in the suppression of certain malignancies, particularly in limiting the tissue invasion of these tumours. Inhibiting the DPP-4 enzymes may allow some cancers to progress.78 A study of DPP-4 inhibition in human non-small cell lung cancer (NSCLC) concluded that "DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells.9
The risk of cancer suppression with DPP-4 down-regulation applies to all the DPP-4 inhibitors on the market in addition to saxagliptin (sitagliptin and vildagliptin)
An in vitro study found that DPP-4 inhibitors, together with GLP-2, increased proliferation and migration of colon cancer cells, which might encourage cancer cells to metastasize,10
A 2013 study showed roughly a doubling of the risk of acute pancreatitis among users of the DPP-4 inhibitors. 11
In March of 2013, the FDA issued a Drug Safety Communication announcing investigations into DDP-4 inhibitors due to findings by academic researchers that could lead to new warnings and possible removal from the market if the findings are confirmed. 12 A few weeks later, the European Medicines Agency launched a similar investigation into GLP-1 agonists and DPP-4 inhibitors that could lead to similar warnings, restrictions or removals from market. 13
In August of 2013, a federal judiciary panel approved the consolidation of dozens of lawsuits against manufacturers of DPP-4 inhibitors before a judge in U.S. District Court in San Diego. Claims involving allegations of pancreatitis, pancreatic cancer and other side effects attributed to the use of Januvia, Janumet, Byetta and Victoza will continue to be eligible for review. The U.S. Judicial Panel on Multidistrict Litigation in its order described the common allegations: “Plaintiffs in all actions allege that the use of one or more of four anti-diabetic incretin based medications – Janumet (sitagliptin combined with metformin), Januvia (sitagliptin), Byetta (exenatide) and Victoza (liraglutide) – caused them or their decedent to develop pancreatic cancer,” the panel said. The order referenced the March 2013 FDA study announcement that included the drugs exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto). 1415
Dr. Peter C. Butler, Chief of Endocrinology at UCLA and former editor of Diabetes, the flagship journal of the American Diabetes Association, studied the DPP-4 inhibitor "Januvia" and found "found worrisome changes in the pancreases of the rats that could lead to pancreatic cancer". His follow-up studies now threaten the future of not only Januvia but all the drugs in its class (DPP-4 inhibitors). There are currently ore than 100 lawsuits representing 575 plaintiffs around the country are claiming injury from the DPP-4 inhibitor, Byetta, according to the latest quarterly regulatory filing from Bristol-Myers. Forty-three suits claim that another DPP-4 inhibitor, Januvia, caused pancreatic cancer, according to Merck. Dr. Butler and colleagues found far more cases of pancreatitis and pancreatic cancer reported for the [DPP-4 inhibitor] drugs than for Avandia. In Dr. Butler’s study of human pancreases obtained from 34 organ donors who had died for reasons unrelated to pancreatic disease, seven of the donors happened to have taken Januvia and one had taken Byetta. the pancreases of those eight people tended to have more precancerous lesions than the organs of the diabetics who had not taken those drugs, or those of the nondiabetics. There was also one case of a neuroendocrine tumor, a type of pancreatic cancer. Also, the pancreases of the incretin drug users were heavier, with faster growth of certain cells. “There were strange growths” that “you’d never see in a normal human pancreas,” Dr. Alexandra Butler said. 16
The synthesis of Saxagliptin by Bristol-Myers Squibb by the amide coupling of N-Boc-3-hydroxyadamantylglycine (2) and methanoprolineamide (3) with EDC. The former is commercially available, whereas the latter is available as the N-Boc analog. The prolineamide moiety is subsequently dehydrated with trifluoroacetic anhydride to give the cyanide as the trifluoracetate ester, which is hydrolyzed. Removal of the Boc protecting group, followed by neutralization gives the desired product (1):17
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 amount of glucose (sugar) that the liver produces.18
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.
A New Drug Application for saxagliptin in the treatment of type 2 diabetes was submitted to the FDA in June 2008. It was based on a drug development program with 8 randomized trials: 1 phase 2 dose-ranging (2.5–100 mg/d) study; 6 phase 3, 24-week controlled trials with additional controlled follow-up from 12 to 42 months, double-blinded throughout; and one 12-week mechanism-of-action trial with a 2-year follow-up period.21 The FDA approved Saxagliptin with brand name Onglyza on July 31, 2009.22
Bristol-Myers Squibb announced on 27 December 2006 that Otsuka Pharmaceutical Co. has been granted exclusive rights to develop and commercialize the compound in Japan. Under the licensing agreement, Otsuka will be responsible for all development costs, but Bristol-Myers Squibb retains rights to co-promote saxagliptin with Otsuka in Japan.23 Further, on 11 January 2007 it was announced that Bristol-Myers Squibb and AstraZeneca would work together to complete development of the drug and in subsequent marketing.24
- Augeri D et al. (2005). "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 48 (15): 5025–5037. doi:10.1021/jm050261p. PMID 16033281.
- "Bristol, Takeda Drugs Offer Alternatives to Januvia (Update2)". Bloomberg. 2008-06-07.
- 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; the SAVOR-TIMI 53 Steering Committee and, Investigators (2013 Oct 3). "Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus.". The New England journal of medicine 369 (14): 1317–1326. PMID 23992601.
- Dhillon, S; Weber, J. (2009). "Saxagliptin". Drugs 69 (15): 2103–2114. doi:10.2165/11201170-000000000-00000. PMID 19791828.
- "New Drugs: Saxagliptin". Australian Prescriber (34): 89–91. June 2011.
- "Onglyza". RxList. Retrieved 2012-01-31.
- Pro B, Dang NH (October 2004). "CD26/dipeptidyl peptidase IV and its role in cancer". Histol. Histopathol. 19 (4): 1345–51. PMID 15375776.
- Wesley UV, McGroarty M, Homoyouni A (February 2005). "Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway". Cancer Res. 65 (4): 1325–34. doi:10.1158/0008-5472.CAN-04-1852. PMID 15735018.
- Wesley, U; et al (2004). "Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells.". Int J Cancer 109 (6): 855–866. doi:10.1002/ijc.20091. PMID 15027119.
- Masur, K; Schwartz, F; Entschladen, F; Niggemann, B; Zaenker, K (2006). "DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells". Regulatory Peptides 137 (3): 147–55. doi:10.1016/j.regpep.2006.07.003. PMID 16908079.
- Singh, Sonal (February 25, 2013). "Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus". JAMA Internal Medicine. American Medical Association. Retrieved 2013-02-25.
- "FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes". FDA. U.S. Food and Drug Administration. March 3, 2013. Retrieved 2013-03-14.
- "European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes". EMA. European Medicines Agency Sciences Medicines Health. March 26, 2013. Retrieved 2013-03-26.
- "Latest Januvia Lawsuits Alleging Pancreatic Cancer Help: Resource4thePeople Reports Cases Continue To Be Filed in Federal Multidistrict Litigation". DG. DigitalJournal.com. October 14, 2013. Retrieved 2013-10-14.
- "IN RE: INCRETIN MIMETICS PRODUCTS LIABILITY LITIGATION". USJP. United States Judicial Panel on Multidistric Litigation. August 26, 2013. Retrieved 2013-08-26.
- Pollack, Andrew (May 30, 2013). "A Lone Voice Raises Alarms on Lucrative Diabetes Drugs". New York Times Business Day. The New York Times Company. Retrieved 2013-05-30.
- Savage, Scott A.; Jones, Gregory S.; Kolotuchin, Sergei; Ramrattan, Shelly Ann; Vu, Truc; Waltermire, Robert E. (2009). "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor". Org. Process Res. Dev. 13: 091016152805096. doi:10.1021/op900226j.
-  Diabetes info
- Mentlein, R; Gallwitz, B; Schmidt, WE (15 June 1993). "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 214 (3): 829–835. doi:10.1111/j.1432-1033.1993.tb17986.x. PMID 8100523.
- Ahrén, Bo; Landin-Olsson, Mona; Jansson, Per-Anders; Svensson, Maria; Holmes, David; Schweizer, Anja (May 2004). "Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes". Journal of Clinical Endocrinology & Metabolism 89 (5): 2078–2084. doi:10.1210/jc.2003-031907. PMID 15126524. Retrieved 2007-01-11.
- Robert Frederich, MD, PhD et al. (May 2010). "A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 Diabetes". Postgraduate Medicine. 122 (3): 16–27. doi:10.3810/pgm.2010.05.2138. PMID 20463410.
- Telegram (2 August 2009). "FDA approves diabetes drug from two area manufacturers". Worcester Telegram & Gazette Corp. Retrieved 2009-08-02.
- "Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. Announce Exclusive Licensing Agreement for Diabetes Compound Saxagliptin in Japan" (Press release). Bristol-Myers Squibb. December 27, 2006. Retrieved 2006-12-27.
- Associated Press (11 January 2007). "AstraZeneca teams with Bristol-Myers on diabetes drugs". Delaware News-Journal. Retrieved 2007-01-11.dead link
- Official site
- Banting and Best Diabetes Centre at UT dpp4
- The race to get DPP-4 inhibitors to market - Forbes.com
- Walker, Emily P. "Saxagliptin First Diabetes Drug to Pass FDA Cardiovascular Safety Review".