A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co-Administration of Sitagliptin with Intensively Titrated Insulin Glargine

Kingsley Onokalah, PharmD candidate 2015, Mercer University College of Pharmacy

Type 2 diabetes mellitus (T2DM) is a group of metabolic disorders characterized by elevated blood glucose levels. The underlying cause may be due to lower insulin secretion, a decrease in insulin sensitivity, or both. It is a chronic condition that may result in microvascular, macrovascular, and neuropathic disorders if glycemic control is not achieved.1

The general approach to treatment for T2DM includes goal setting for blood glucose levels, blood pressure, lipid levels, and dietary and exercise modifications.1 Long-term glycemic control is measured through hemoglobin A1c (HbA1c), which reflects glycemic control for the prior two to three months.1 The ADA recommends a goal HbA1c of <7% in most patients.2

The American Diabetes Association (ADA) guidelines recommend that all patients with T2DM be initiated on metformin if it not contraindicated. If the HbA1c target is not achieved after three months, the ADA recommends that metformin be combined with one of the following six treatment options: dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium/glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or basal insulin.1

The focus of the following study is on sitagliptin, a DPP-4 inhibitor, in addition to basal insulin.3 Sitagliptin and other drugs in its class work to inhibit the DPP-4 enzyme, leading to a decrease in the release of glucagon and subsequent increase in insulin secretion to decrease blood glucose levels.1 While the risk of hypoglycemia does not increase with this drug class, headache and nasopharyngitis may be slightly more common.1

Title: A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co-Administration of Sitagliptin with Intensively Titrated Insulin Glargine
Design Multicenter, randomized, double-blind, placebo-controlled clinical trial
Objective To assess the effect of sitagliptin on insulin dose in patients with inadequately controlled T2DM
Study Groups Sitagliptan 100 mg daily (n= 330) or placebo (n= 330)
Methods Patients with uncontrolled type 2 diabetes on insulin, with or without metformin (> 1500 mg daily) or sulfonylurea, randomized to receive sitagliptin or placebo.  Patients could remain on metformin but not sulfonylurea after randomization.
Duration January 16, 2012 to June 7, 2013
Primary Outcome Measure Change in daily insulin dose following 24 weeks of therapy
Baseline Characteristics Sitagliptin: Age 59.3 + 8.9 years, 45.9% male, 72.3% white race, 13.2 + 6.0 years duration of type 2 diabetes

Placebo: Age 58.3 + 9.7 years, 49.8% male, 66.9% white race, 13.7 + 6.4 years duration of type 2 diabetes

Results Change from baseline in daily insulin dose at week 24 of therapy

Sitagliptan group: 19.0 (95% confidence interval 16.5 – 21.6)

Placebo group: 23.8 (95% confidence interval 21.3 – 26.3)

P= 0.009 vs placebo

Adverse Events Common Adverse Events:  Only hypoglycemia reported: occurred in 28.3% of sitagliptin group at least once, occurred in 43.8% of placebo group at least once.
Serious Adverse Events: Not reported
Percentage that Discontinued due to Adverse Events: 0% in sitagliptin group, 0.6% in placebo group
Study Author Conclusions As demonstrated in this study, the concurrent administration of sitagliptin with a treat-to-target insulin titration regimen reduced the insulin dose requirement while providing superior glycemic efficacy and a reduced incidence of hypoglycemia compared to the treat-to-target insulin-only titration regimen.

The study results confirmed the investigators’ hypothesis that sitagliptin, compared to placebo, would allow the study participants to achieve glycemic control with a lower dose of basal insulin. Sitagliptin may prove advantageous for patients since study results showed there is a lower risk of hypoglycemia if their insulin dose doesn’t have to be increased as often to maintain appropriate control of blood glucose.3 Future studies could investigate effect of sitagliptin on basal insulin titration for a longer amount of time than 24 weeks.


  1. Triplitt CL, Repas T, Alvarez C. Chapter 57. Diabetes Mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com/content.aspx?bookid=689&Sectionid=45310509. Accessed April 3, 2015.
  2. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. Available at: http://care.diabetesjournals.org/content/37/Supplement_1/S14.extract. Accessed April 2, 2015.
  3. Mathieu C, Shankar RR, Lorder D, et al. A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co-Administration of Sitagliptin with Intensively Titrated Insulin Glargine. Diabetes Ther. March 28, 2015. [Epub ahead of print]. doi:10.1007/s13300-015-0105-3.

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