Sitagliptin Phosphate a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes by Ray Sahelian, M.D.
March 1 2016

Sitagliptin phosphate tablets are the first diabetes treatment approved in a new class of drugs known as DPP-4 inhibitors that enhances the body's own ability to lower elevated blood sugar. Sitagliptin is used daily to improve blood sugar levels in patients with type 2 diabetes, alone or in combination with two other commonly prescribed oral diabetes medications, metformin or a PPAR (peroxisome proliferator-activated receptor gamma) agonist, when either of these drugs alone, along with diet and exercise, don't provide adequate blood sugar control. Type 2 diabetes is the most common form of the disease, accounting for about 90 percent to 95 percent of all diagnosed cases of diabetes (21 million in 2005). For a list of natural supplements used in blood sugar control, see diabetes.

Sitagliptin and Diabetes research
Sitagliptin prescription medication was examined in a total of 2,719 patients with type 2 diabetes, in studies lasting from 12 weeks to more than a year. Sitagliptin was taken daily. Sitagliptin improved blood sugar control when used alone or in diabetes patients not satisfactorily managed with metformin or a PPAR agonist.

Sitagliptin side effects
The most common Sitagliptin side effects in clinical studies were upper respiratory tract infection, sore throat, and diarrhea.
   Dr. Sahelian comments: I am cautious about prescribing newly approved drugs. I prefer to wait a few years to make sure there are no Sitagliptin side effects of significance before exposing patients to a new drug. In the meantime, there are many other drugs and natural supplements that have been on the market longer, and I prefer to continue using them rather than sitagliptin. The email below mentions a sitagliptin side effect reported to us. Just because a drug is approved by the FDA does not make it immune to side effects that had not been reported previously. We learned with Vioxx that FDA can approve a drug that can later be found to have significant side effects. Sitagliptin may turn out to be safe, but why take the risk?

Medicine (Baltimore). 2015. Sitagliptin After Ischemic Stroke in Type 2 Diabetic Patients: A Nationwide Cohort Study. The cerebrovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus (T2DM) with ischemic stroke remains uncertain. The aim of this study was to assess the efficacy and safety of sitagliptin in patients with T2DM with recent ischemic stroke. We analyzed data from the Taiwan National Health Insurance Research Database between March 1, 2009, and December 31, 2011. Treatment with sitagliptin in type 2 diabetic patients with recent ischemic stroke was not associated with increased or decreased risks of adverse cerebrovascular outcomes.

Sitagliptin FDA approval
Sitagliptin is manufactured by Merckand Co., Inc., Whitehouse Station, N.J. Sitagliptin approval occurred in October 2006, and the FDA said the approval of sitagliptin meant also that this drug could be used either by itself or in combination with other drugs for blood sugar control.

Sitagliptin drug mechanism of action
Sitagliptin prolongs the activity of proteins that increase the release of insulin after blood sugar rises, such as after a meal. Sitagliptin does this by blocking an enzyme (dipeptidyl peptidase IV or DPP-IV) which breaks down these proteins, leading to better blood sugar control. Sitagliptin won U.S. approval in October, 2006 to treat adults with type 2 diabetes. Sitagliptin belongs to a new class of medicines called DPP-4 inhibitors that work by enhancing the body's own ability to lower blood sugar. It does not seem to weight gain, an advantage over some older diabetes treatments. Weight gain is considered an especially serious disadvantage, as patients who gain weight tend to stop taking their medications and as obesity is one of the leading causes of type 2 diabetes.

More on DPP-4 Inhibitor drugs
The dipeptidyl peptidase 4 (DPP-4) inhibitors enhance the body's own ability to control blood glucose by increasing the active levels of incretin hormones in the body. DPP-4 inhibitors control elevated blood glucose by triggering pancreatic insulin secretion, suppressing pancreatic glucagon secretion, and signalling the liver to reduce glucose production. DPP-4 inhibitors have shown HbA1c reductions up to 1 year of treatment and are thought to have a low risk of hypoglycemia, little or no effect on body weight, and the potential, based on animal and in vitro studies, for the regeneration and differentiation of pancreatic beta-cells. Several DPP4 inhibitors are currently being tested including vildagliptin (Galvus; LAF-237), sitagliptin (Januvia; MK-0431), and saxagliptin (BMS-477118).

Sitaglipin and metformin
Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes. Curr Med Res Opin. 2006. Merck Research Laboratories, Rahway, NJ, USA
As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions. Conclusions : In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.

Sitaglipin as monotherapy
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus.
Diabetologia. 2006. Diabetes Research Center, Hadassah University Hospital, Jerusalem, Israel.
The aim of this study was to assess the efficacy and safety of sitagliptin as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control on exercise and diet. A total of 521 patients aged 27-76 years with a mean baseline HbA(1c) of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. Conclusion: Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycemic control on exercise and diet.

Review
Rev Med Liege. 2013. Sitagliptin in the treatment of type 2 diabetes: insights five years after commercialisation. Sitagliptin (Januvia) was the first selective inhibitor of dipeptidyl peptidase-4 commercialized for the management of type 2 diabetes. It is also available as a fixed-dose combination with meformin (Janumet). Almost 5 years after its launch in Belgium, the present review summarizes the most recent data regarding the clinical efficacy of this antidiabetic agent, the controversy about its safety profile, its use at lower dosage in case of moderate to severe renal insufficiency, the various indications that have been successively accepted and reimbursed, and, finally, the perspectives offered by a large ongoing cardiovascular outcome trial (TECOS).