Addition of a dipeptidyl peptidase‐4 inhibitor, sitagliptin, to ongoing therapy with the glucagon‐like peptide‐1 receptor agonist liraglutide

Design

Randomized, double-blind, cross-over study 

N= 16

Objective

To determine whether the addition of sitagliptin to pre-existing therapy with liraglutide changes glycemic excursions after a mixed meal

Study Groups

Sitagliptin 100 mg (N= 16)

Placebo (N= 16)

Inclusion Criteria

Patients with type 2 diabetes treated with oral metformin (≥1500 mg/day for >1 month on a stable dose) and with subcutaneous liraglutide (1.2 mg/d for ≥2 weeks) only (no other glucose-lowering agent allowed)

None described 

Methods

Patients were randomized to be studied on two occasions after taking either sitagliptin 100 mg orally or placebo administered 60 minutes before a mixed meal. Each visit was separated by a washout period of at least 3 days.

Duration

Outcome Measures

Difference between incremental integrated glucose responses (iAUC) following a mixed meal between experiments with sitagliptin and placebo; full course time of glucose concentrations, insulin secretion, glucagon, GLP-1/GIP, gastric emptying, free fatty acids

Baseline Characteristics

Study population (N=16)

5 (31.3%)

Age, years

BMI, kg/m²

Diabetes duration, years

Metformin dose, mg/d

HbA1c, %

Results

Glucose concentrations: concentrations before and after ingestion of a mixed meal were not significantly altered by a single dose of sitagliptin. 

Insulin secretion: sitagliptin did not significantly alter insulin or C-peptide concentrations or insulin secretion rates through meal tests. However, there was a higher insulin secretion rate with sitagliptin in patients who were on the liraglutide/metformin regimen. 

Glucagon: meal stimulation increased glucagon concentrations which was not significantly altered by sitagliptin. 

GLP-1/GIP: intact GLP-1 and GIP increased significantly after meal ingestion. Total GLP-1 and GIP decreased but not significantly. 

Gastric emptying: tended to be more delayed with sitagliptin versus placebo. 

Free fatty acid: were suppressed after mixed meal ingestion with no difference in sitagliptin versus treatment. 

Adverse Events

None reported

Study Author Conclusions

A single dose treatment with sitagliptin in patients with type 2 diabetes treated with liraglutide induces similar changes in GLP-1 and GIP concentrations induced by mixed meal stimulation in the absence of GLP-1 receptor agonist treatment. However, this did not lead to significant changes. 

InpharmD Researcher Critique

Combination therapy with once-weekly glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a case series

Design

Retrospective chart review

N= 18

Objective

To describe the efficacy and safety of once-weekly GLP-1 RAs administered concomitantly with DPP-4 inhibitors in patients with type 2 diabetes

Study Groups

Concomitant GLP-1RA and DPP-4 inhibitor therapy (N= 18)

No insulin at start (n= 8)

On insulin at start (n= 10)

Inclusion Criteria

≥18 years old, diagnosed with type 2 diabetes, received concomitant DPP-4 inhibitor and once-weekly GLP-1 RA therapy, at least one HbA1c measurement within six months from index date (start of combination therapy)

Exclusion Criteria

Methods

This was a retrospective chart review from a free clinic in Virginia. The patients were followed starting on the date when both a GLP-1 RA and DPP-4 inhibitor were prescribed (index date).

Duration

Follow-up: 6 months

Outcome Measures

Baseline Characteristics

All patients (N= 18)

Age, years (interquartile range [IQR])

Female

BMI, kg/m² (IQR)

DPP-4 inhibitors

Sitagliptin

Saxagliptin

17 (94%)

1 (6%)

GLP-1 RAs

Albiglutide

Exenatide ER

12 (67%)

6 (33%)

Results

6 months

HbA1c, % (IQR)

Weight, kg (IQR)

Adverse Events

Study Author Conclusions

Concomitant use of once-weekly GLP-1 RAs and DPP-4 inhibitors provides only modest improvement in glycemic control with minimal weight loss benefits, which is similar to monotherapy with either agent. The combination is unlikely to provide synergistic effects and is not cost-effective.

These data support the current American Diabetes Association recommendations against the use of combined incretin therapy.

InpharmD Researcher Critique

Combination exenatide-sitagliptin therapy used with glipizide in a patient with type 2 diabetes mellitus

Design

Case presentation

A 55-year-old Caucasian female was diagnosed with type 2 diabetes mellitus and had a blood glucose concentration of 450 mg/dL, glycosylated hemoglobin (HbA1c) of 13.4%, and a weight of 204 lbs. Metformin hydrochloride 500 mg orally twice daily was initiated, but discontinued due to elevated liver function test values. Sitagliptin 100 mg orally once daily was initiated, followed by glipizide 2.5 mg orally once daily which was increased to 10 mg orally twice daily.

Three months after stable sitagliptin and glipizide use, the patient’s blood glucose concentration was still uncontrolled with an HbA1c of 9.3% and a weight of 218 lbs. Insulin therapy was discussed, but was refused by the patient due to fear of weight gain. Exenatide 5 μg subcutaneously twice daily was added to her existing therapy of sitagliptin 100 mg daily and glipizide 10 mg twice daily.

Seven months following the addition of exenatide, the patient’s HbA1c was reduced by 1.9% to a value of 7.4%, and she lost a total 11 lbs. The triple therapy was well-tolerated as the patient denied any hypoglycemic episodes. The patient also denied any lifestyle modifications including diet and exercise. The patient’s blood pressure remained at goal while taking losartan 100 mg orally once daily throughout triple therapy.

Study Author Conclusions

The use of exenatide (GLP-1 RA) and sitagliptin (DPP-4i) with glipizide therapy seemed safe and effective in a type 2 diabetes mellitus patient.

The study provides low quality of evidence considering it is a single case report, which cannot represent the population at large. Another limitation includes the report covering a relatively short duration of the therapy given that diabetes is a lifelong illness.