T2DM

A stepwise approach involving dietary and lifestyle changes along with medication(s) is recommended for the management of patients with type 2 diabetes.4,6 Metformin is the medication recommended first-line in most patients, unless contraindicated.4,6 After metformin, medication selection is determined by a variety of factors including glucose control, presence of cardiovascular disease, other patient-specific factors, (e.g., comorbidities, renal function, risk for hypoglycemia), patient preference, and cost.4,6 Some sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists have been shown to positively impact cardiovascular (CV) outcomes.4,6 Many times two, three, or more medications may be required to achieve glucose control. The GLP-1 agonists (dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) have been studied in combination with several other diabetes medications. The chart below reviews combination therapy with the GLP-1 agonists, including potential clinical benefits and limitations or practical issues to consider. GLP-1 agonists are expensive; therefore, cost is a potential limitation to any regimen containing a GLP-1 agonist.

GLP-1 agonist Combination

Comments

RECOMMENDED combinations

Glucagon-like peptide-1 (GLP-1) agonist plus insulin

Rationale for combo:
 GLP-1 agonists and insulin appear to have complementary mechanisms of action.

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

o Insulin: facilitates elimination of glucose and reduces hepatic glucose production.4
Potential benefits of combo:
 Adding a GLP-1 agonist to patients on insulin may improve glycemic control with less weight gain and a

similar risk of hypoglycemia compared to increasing insulin doses.6
When to consider combo:
 Consider adding a GLP-1 agonist to patients on basal insulin (with or without metformin) requiring

additional glucose lowering (with a mealtime insulin) who are at risk for hypoglycemia or who wish to avoid weight gain.4,6
o UseaGLP-1agonistwithprovenCVbenefits(e.g.,liraglutide[Victoza])inpatientswithCVdiseaseor

at high CV risk.4,6 Practical considerations:

 Consider using a combination product, especially if adherence is a concern to limit the number of injections. o Insulindegludec100units/mLandliraglutide3.6mg/mL(Xultophy)7,13
o Insulinglargine100units/mLandlixisenatide33mcg/mL(Soliqua[U.S.])7
o Comboproductshaveaninsulinmaxof50units/day(Xultophy)and60units/day(Soliqua).7,13

o Acombinationproductmaybemorecost-effectivevsusingaGLP-1agonistplusbasalinsulin separately.

More. . . July 2018 ~ Resource #340704

Combination Therapy with a GLP-1 Agonist

GLP-1 agonist Combination

Comments

RECOMMENDED combinations

Glucagon-like peptide-1 (GLP-1) agonist plus insulin

Rationale for combo:
 GLP-1 agonists and insulin appear to have complementary mechanisms of action.

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

similar risk of hypoglycemia compared to increasing insulin doses.6
When to consider combo:
 Consider adding a GLP-1 agonist to patients on basal insulin (with or without metformin) requiring

at high CV risk.4,6 Practical considerations:

o Acombinationproductmaybemorecost-effectivevsusingaGLP-1agonistplusbasalinsulin separately.

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3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com

More. . .

GLP-1 agonist Combination

Comments

RECOMMENDED combinations, continued

Glucagon-like peptide-1 (GLP-1) agonist plus metformin

Rationale for combo:
 GLP-1 agonists and metformin appear to have complementary mechanisms of action.

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

o Metformin: reduces hepatic glucose production.4
Potential benefits of combo:
 Adding a GLP-1 agonist to metformin may cause less hypoglycemia and less weight gain than adding other

medications (e.g., insulin, meglitinides, sulfonylurea).6
When to consider combo:
 Consider adding a GLP-1 agonist to patients on metformin requiring additional glucose lowering who are at

risk for hypoglycemia or who wish to avoid weight gain.4,6
o UseaGLP-1agonistwithprovenCVbenefits(e.g.,liraglutide[Victoza])inpatientswithCVdiseaseor

at high CV risk.4,6 Practical considerations:

 Patients may require teaching about proper injection technique.

Glucagon-like peptide-1 (GLP-1) agonist plus a sulfonylurea

Rationale for combo:
 GLP-1 agonists and a sulfonylurea have similar, but not identical mechanisms of action.

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

o Sulfonylureas: increase insulin secretion (non-glucose dependent).4
Potential benefits of combo:
 Adding a GLP-1 agonist (liraglutide or exenatide) to patients on a sulfonylurea (with or without metformin)

can improve glycemic control and possibly lead to weight loss, with limited incidence of major

hypoglycemia.10
When to consider combo:
 Consider adding a GLP-1 agonist to patients on a sulfonylurea requiring additional glucose lowering who

are at risk for hypoglycemia or who wish to avoid weight gain.4,6
o UseaGLP-1agonistwithprovenCVbenefits(e.g.,liraglutide[Victoza])inpatientswithCVdiseaseor

at high CV risk.4,6 Practical considerations:

 Patients may require teaching about proper injection technique.

More. . .

RECOMMENDED combinations, continued

Rationale for combo:
 GLP-1 agonists and metformin appear to have complementary mechanisms of action.

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

o Metformin: reduces hepatic glucose production.4
Potential benefits of combo:
 Adding a GLP-1 agonist to metformin may cause less hypoglycemia and less weight gain than adding other

medications (e.g., insulin, meglitinides, sulfonylurea).6
When to consider combo:
 Consider adding a GLP-1 agonist to patients on metformin requiring additional glucose lowering who are at

risk for hypoglycemia or who wish to avoid weight gain.4,6
o UseaGLP-1agonistwithprovenCVbenefits(e.g.,liraglutide[Victoza])inpatientswithCVdiseaseor

at high CV risk.4,6 Practical considerations:

 Patients may require teaching about proper injection technique.

Rationale for combo:
 GLP-1 agonists and a sulfonylurea have similar, but not identical mechanisms of action.

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

can improve glycemic control and possibly lead to weight loss, with limited incidence of major

hypoglycemia.10
When to consider combo:
 Consider adding a GLP-1 agonist to patients on a sulfonylurea requiring additional glucose lowering who

are at risk for hypoglycemia or who wish to avoid weight gain.4,6
o UseaGLP-1agonistwithprovenCVbenefits(e.g.,liraglutide[Victoza])inpatientswithCVdiseaseor

at high CV risk.4,6 Practical considerations:

 Patients may require teaching about proper injection technique.

GLP-1 agonist Combination

Comments

ACCEPTABLE combinations (but still under investigation)

Glucagon-like peptide-1 (GLP-1) agonist plus a thiazolidinedione (TZD)

Rationale for combo:
 GLP-1 agonists and TZDs may have complimentary mechanisms of action.9

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

o TZDs: increases insulin sensitivity.4
Potential benefits of combo:
 The combination of liraglutide, metformin, and rosiglitazone significantly lowered A1C after 26 weeks of

therapy without major hypogylcemia.9
Potential downsides of combo:
 Warning with use of TZDs in patients with heart failure.4,6
 Potential for side effects (e.g., weight gain, fluid retention) with the TZDs.4,6
Ongoing clinical trial studying the combo:
 There is an ongoing clinical trial (NCT02887625) underway to evaluate this combination further: Exenatide

plus pioglitazone versus insulin in poorly controlled patients with type 2 diabetes mellitus (T2DM).8 Practical considerations:
 Patients may require teaching about proper injection technique.

Glucagon-like peptide-1 (GLP-1) agonist plus a “flozin” or sodium-glucose co-transporter 2 (SGLT2) inhibitor

Continued…

Rationale for combo:
 GLP-1 agonists and flozins may have complimentary mechanisms of action.1,2,3,5

o GLP-1 agonists: glucose-dependent increase in insulin secretion.4

o Flozins: increases glucosuria and blocks reabsorption of glucose in the kideny.4 Potential benefits of combo:

 Combination therapy with some GLP-1 agonists and flozins has the potential for additive CV benefits.2,5
o However,withoutlong-termdata,it’stoosoontosayifCVbenefitswillbeadditive.3,5

 GLP-1 agonists have been studied as add-on therapy to patients taking a flozin and added simultaneously
with a flozin leading to improved glucose control, weight loss, and small reductions in systolic blood pressure without significant hypoglycemia.1,2

o Additional studies are needed to determine the best way to combine these meds (e.g., simultaneous,

sequential).
When to consider combo:

 Consider adding a GLP-1 agonist to patients on a flozin requiring additional glucose lowering who are at risk for hypoglycemia or who wish to avoid weight gain.4,6
o UseaGLP-1agonistandflozinwithprovenCVbenefits(e.g.,liraglutide[Victoza],empagliflozin

[Jardiance], respectively) in patients with CV disease or at high CV risk.4,6

More. . . Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

GLP-1 agonist Combination

Comments

GLP-1 plus flozin, continued

Practical considerations:
 Patients may require teaching about proper injection technique.
 Cost-effective analyses need to be completed as GLP-1 agonists and flozins are both very expensive.3

NOT RECOMMENDED

Glucagon-like peptide-1 (GLP-1) agonist plus a “gliptin” or dipeptidyl peptidase-4 (DPP-4) inhibitor

Rationale for combo: 4,6,7  GLP-1 agonists and gliptins have similar mechanisms of action, involving incretin.

o GLP-1 agonists: Incretin mimetic (mimic incretin hormones) and cause a glucose-dependent increase in insulin secretion.4

o Gliptins: Incretin enhancer (prevent the breakdown of endogenous incretins) and cause a glucose- dependent increase in insulin secretion and a decrease in glucagon secretion.4

Potential downsides of combo: 4,6  Avoid combining GLP-1 agonists and gliptins [Evidence Level C].

patients already receiving metformin and sitagliptin.11
o Thiscombinationisexpensivewithoutprovidingasignificantbenefit. 12 o Though incidence is rare, pancreatitis has been seen with both GLP-1 agonists and gliptins.

unknown if combining these two groups would increase the risk of pancreatitis.

o DataarelackingtodemonstrateefficacywhencombiningGLP-1agonistsandgliptins.
 Limited data suggests only an additional 0.3% reduction of A1C when exenatide was added to

It is

Levels of Evidence

In accordance with our goal of providing Evidence- Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

Good-quality patient-oriented evidence.*

1. High-quality RCT 2. SR/Meta-analysis of

RCTs with consistent

findings
3. All-or-none study

Inconsistent or limited-quality patient-oriented evidence.*

1. Lower-quality RCT 2. SR/Meta-analysis

with low-quality clinical trials or of studies with inconsistent findings

3. Cohort study
4. Case control study

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).
RCT = randomized controlled trial; SR = systematic review
[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.%5D

Project Leader in preparation of this clinical resource (340704): Beth Bryant, Pharm.D., BCPS, Assistant Editor

References

1. Frias JP, Guja C, Hardy E, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised

controlled trial.

Lancet Diabetes Endocrinol

2016;4:1004-16.
2. Ludvik B, Frias JP, Tinahones FJ, et al. Dulaglutide

as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24 week, randomised, double-blind,

Cite this document as follows: Clinical Resource, Combination Therapy with a GLP-1 Agonist. Pharmacist’s Letter/Prescriber’s Letter. July 2018.