antihyperglycemic therapy (non-insulin)...o januvia® (sitagliptin) with pioglitazone o onglyza...

EFFECTIVE 1/1/2021

of 21 Pharmacy Benefit Clinical Criteria: P0098

Pharmacy Benefit Coverage Criteria

Effective Date ............................................ 1/1/2021 Next Review Date… ..................................... 1/1/2022 Coverage Policy Number ................................ P0098

Antihyperglycemic Therapy (Non-Insulin)

Table of Contents Medical Necessity Criteria ................................... 1 FDA Approved Indications ................................... 7 Recommended Dosing ...................................... 13 Background ........................................................ 18 References ........................................................ 20

Related Coverage Resources Quantity Limitations Step Therapy - (1109) Step Therapy - Standard/Performance Prescription

Drug Lists (Employer group plans) - (1801) Step Therapy - Value/Advantage Prescription Drug

Lists (Employer Group Plans) - (1802) Step Therapy - Legacy Prescription Drug Lists

(Employer Group Plans) - (1803)

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Medical Necessity Criteria This policy addresses coverage criteria for the following antihyperglycemic therapy classes:

Single-agent • Dipeptidyl Peptidase-4 (DPP-4) Inhibitors [refer to Appendix 1 for products] • Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) [refer to Appendix 2 for products] • Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors [refer to Appendix 3 for products]

Combination

• DPP-4 / SGLT2 Inhibitor Fixed-dose combinations [refer to Appendix 4 for products] • DPP-4 Fixed-dose Combinations [refer to Appendix 5 for products] • SGLT2 / Metformin Fixed-dose Combinations[refer to Appendix 6 for products] • SGLT2 / DPP-4 / Metformin Fixed-dose Combinations [refer to Appendix 7 for products]

‡ Note: The below metformin requirement criteria applies to new starts AND only for the specified antihyperglycemic therapies.

https://static.cigna.com/assets/chcp/pdf/coveragePolicies/pharmacy/ph_1201_coveragepositioncriteria_quantity_limits.pdf

https://static.cigna.com/assets/chcp/pdf/coveragePolicies/pharmacy/ph_1109_coveragepositioncriteria_step_therapy.pdf







EFFECTIVE 1/1/2021


Single-agent DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 RAs, and fixed-dose combinations of DPP-4 inhibitors/Metformin, SGLT2 inhibitors/Metformin, DPP-4/SGLT2 inhibitors, SGLT2/DPP-4 inhibitors/Metformin are medically necessary when ALL of the following criteria are met:

1. Documented ONE of the following: o Unable to achieve goal HbA1C despite metformin or metformin-containing regimen (meglitides,

sulfonylureas, or thiazolidinediones) at greater than or equal to 1,500 mg per day o Intolerance to metformin 1,500 mg per day despite appropriate dose titration duration (for

example, period of 8-12 weeks) o Contraindication to metformin per FDA label (for example, acute/chronic metabolic acidosis,

severe renal dysfunction) o Not a candidate for metformin (for example, hepatic impairment, moderate renal dysfunction,

unstable heart failure, individual is using an agent for a non-diabetic FDA-approved indication) o Initial metformin combination therapy is clinically appropriate for elevated HbA1C (for example;

HbA1C greater than 1.5% above goal) o Initial metformin combination therapy is clinically appropriate in an individual with co-morbid

conditions (such as ASCVD, heart failure, or CKD)

2. Individual will continue maximally tolerated metformin therapy, if not contraindicated per FDA label, intolerant, or otherwise not a candidate

3. Where coverage requires the use of preferred products, there is documentation of ONE of the following: o The individual has a contraindication according to FDA label OR significant intolerance to ALL of

covered alternatives* according to the table below OR

o The individual is not a candidate for ALL covered alternatives* according to the table below due to being subject to a warning per the prescribing information (labeling), having a disease characteristic, individual clinical factor[s], or other attributes/conditions or is unable to administer and requires this dosage formulation

*Coverage for antihyperglycemic therapy varies across plans. Refer to the customer’s benefit plan document for coverage details. Note: The below preferred product requirements apply to both new starts AND existing product users Employer Group Non-Covered Products and Preferred Covered Alternatives by Drug List:

Standard / Performance

Value / Advantage

Cigna Total Savings

Legacy

DPP-4 Inhibitors Alogliptin BOTH of the

following: • Metformin

requirement criteria‡

• sitagliptin (Januvia, Janumet / Janumet XR)

BOTH of the following: • Metformin





• linagliptin (Tradjenta, Jentadueto / Jentadueto XR)




Januvia® (sitagliptin)

Covered as Preferred Brand

(step therapy may

apply)


(step therapy may

apply)



• linagliptin (Tradjenta,


(step therapy may

apply)

EFFECTIVE 1/1/2021



Value / Advantage

Cigna Total Savings

Legacy

Jentadueto / Jentadueto XR)

Nesina (alogliptin)













Onglyza® (saxagliptin)













Tradjenta® (linagliptin)



• sitagliptin (Januvia, Janumet/Janumet XR)








DPP-4 / SGLT2 Fixed-dose Combinations Glyxambi® (linagliptin-empagliflozin)

Covered as Preferred Brand (step therapy may apply)

Qtern® (saxagliptin-dapagliflozin)




• Glyxambi (empagliflozin-linagliptin) or Trijardy XR (empagliflozin-linagliptin-metformin)





Steglujan (sitagliptin- ertugliflozin)







Covered as Non-Preferred Brand (step therapy may apply)

EFFECTIVE 1/1/2021



Value / Advantage

Cigna Total Savings

Legacy

• BOTH of the following: o Glyxambi

(empagliflozin-linagliptin) or Trijardy XR (empagliflozin-linagliptin-metformin)

o Qtern

(dapagliflozin-saxagliptin)

• Glyxambi (empagliflozin-linagliptin) or Trijardy XR

(empagliflozin-linagliptin-metformin)


DPP-4 Fixed-dose Combinations

Alogliptin-metformin



• Janumet / Janumet XR (sitagliptin-metformin)






• Jentadueto / Jentadueto XR (linagliptin-metformin)




Alogliptin-pioglitazone

• Januvia® (sitagliptin) with pioglitazone


• Tradjenta® (linagliptin) with pioglitazone


Janumet® Janumet XR® (sitagliptin- metformin)

Covered as Preferred Brand (step therapy may

apply)


apply)





apply)

Jentadueto®

Jentadueto XR® (linagliptin- metformin)



• Janumet® /Janumet XR® (sitagliptin-metformin)



• Janumet®/ Janumet XR® (sitagliptin-metformin)


(step therapy may apply)



• Janumet® /Janumet XR® (sitagliptin-metformin)

Kazano (alogliptin-metformin)



• Janumet® / Janumet XR® (sitagliptin-metformin)










EFFECTIVE 1/1/2021



Value / Advantage

Cigna Total Savings

Legacy

Kombiglyze XR® (saxagliptin-metformin)



• Janumet XR® (sitagliptin-metformin)






• Jentadueto XR® (linagliptin-metformin)




Oseni (alogliptin-pioglitazone)



• Tradjenta® (linagliptin) with pioglitazone


GLP-1 Receptor Agonists Adlyxin (lixisenatide)

BOTH of the following: • Metformin requirement criteria‡ • ALL of the following:

o Bydureon® OR Byetta® (exenatide) o Ozempic (semaglutide) o Trulicity® (dulaglutide) o Victoza (liraglutide)

Covered as Non-Preferred Brand (step therapy may apply)

Byetta® (exenatide)


Bydureon® (exenatide)


Ozempic® (semaglutide)


Rybelsus®

(semaglutide) Covered as Preferred Brand

(step therapy may apply) Trulicity® (Dulaglutide)


Victoza® (liraglutide)


Metformin Products Fortamet®

(metformin extended release tablets)

BOTH of the following: • metformin ER (Glucophage® XR) • metformin immediate-release tablet

Glumetza®

(metformin extended release tablets)


Metformin ER osmotic tablets (Fortamet®)


Metformin ER tablets (Glumetza®)


SGLT2 Inhibitors Farxiga® (dapagliflozin)


EFFECTIVE 1/1/2021



Value / Advantage

Cigna Total Savings

Legacy

Invokana® (canagliflozin)


ALL of the following: • Diagnosis of Type 2 diabetes mellitus • Metformin requirement criteria‡ • ONE of the following:

o Documented contraindication per FDA label, intolerance or not a candidate for ALL of the following: Farxiga (dapagliflozin) Jardiance (empagliflozin) Steglatro (ertugliflozin)

o Cardiovascular disease (as defined by presence of coronary artery disease, stroke or peripheral artery disease) AND documented intolerance, contraindication per FDA label, or not a candidate for Jardiance

o Diabetic nephropathy with ALL of the following: Albuminuria greater than 300 mg

per day eGFR greater than or equal to 30

mL per minute Currently taking maximum

tolerated, daily dose of angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) (unless intolerant, not a candidate for, or contraindicated per FDA label


Jardiance® (empagliflozin)


Steglatro™ (ertugliflozin)


SGLT2 / Metformin Fixed-dose Combinations Invokamet® Invokamet XR® (canagliflozin-metformin)


BOTH of the following: • Metformin requirement criteria‡ • ALL of the following:

o Segluromet (ertugliflozin/metformin) o Synjardy / Synjardy XR

(empagliflozin/metformin) o Xigduo® XR (dapagliflozin/metformin)


Segluromet™ (ertugliflozin-metformin)


Synjardy® Synjardy XR® (empagliflozin-metformin)


Xigduo XR® Covered as Preferred Brand (step therapy may apply)

EFFECTIVE 1/1/2021



Value / Advantage

Cigna Total Savings

Legacy

(dapagliflozin-metformin)

SGLT2 / DPP-4 / Metformin Fixed-dose Combinations Trijardy™ XR (empagliflozin-linagliptin-metformin)


Initial and reauthorization is up to 12 months unless otherwise stated. When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy. Note: Receipt of sample product does not satisfy any criteria requirements for coverage. Documentation: When documentation is required, the prescriber must provide written documentation supporting the trials of these other agents. Documentation may include, but is not limited to, chart notes, prescription claims records, and/or prescription receipts. *If you’re a Cigna provider, please log in to the Cigna for Health Care Professionals website and search for specific patients to view their covered medications. FDA Approved Indications FDA Approved Indication

Brand Name Approved Indication DPP-4 Inhibitors Januvia (sitagliptin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Januvia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Januvia has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Januvia.

Nesina (alogliptin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Nesina is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

Onglyza (saxagliptin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use Onglyza is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

Tradjenta (linagliptin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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EFFECTIVE 1/1/2021


Brand Name Approved Indication Limitations of Use Tradjenta should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Tradjenta has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Tradjenta.

DPP-4 / SGLT2 Fixed-dose Combinations Glyxambi (linagliptin-empagliflozin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both empagliflozin and linagliptin is appropriate. Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. However, the effectiveness of GLYXAMBI on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established. Limitations of Use Glyxambi is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Glyxambi has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Glyxambi.

Qtern (saxagliptin- dapagliflozin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use Qtern is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.


Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate. Limitations of Use Steglujan is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Steglujan has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Steglujan.

DPP-4 Fixed-dose Combinations Janumet / Janumet XR (sitagliptin-metformin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin/metformin ER is appropriate. Limitations of Use Should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis.

Jentadueto / Jentadueto XR

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

EFFECTIVE 1/1/2021


Brand Name Approved Indication (linagliptin-metformin)

Limitation of Uses Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis.


Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both alogliptin and metformin is appropriate. Limitation of Use Kazano is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

Kombiglyze XR (saxagliptin-metformin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate. Limitation of Use Kombiglyze XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.


Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both alogliptin and pioglitazone is appropriate. Limitation of Use Oseni is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.


Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Adlyxin has not been studied in patients with chronic pancreatitis or a history of unexplained pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Adlyxin is not a substitute for insulin. Adlyxin is not indicated for use in patients with type 1 diabetes mellitus or for treatment of diabetic ketoacidosis. The concurrent use of Adlyxin with short acting insulin has not been studied and is not recommended. Adlyxin has not been studied in patients with gastroparesis and is not recommended in patients with gastroparesis.

Byetta (exenatide)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Byetta is not a substitute for insulin. Byetta should not be used for the treatment of type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Byetta with prandial insulin has not been studied and cannot be recommended. Based on postmarketing data, Byetta has been associated with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Byetta has not been

EFFECTIVE 1/1/2021


Brand Name Approved Indication studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Byetta. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.

Bydureon (exenatide extended-release)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Bydureon is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rat thyroid C-cell tumor findings to humans. Bydureon is not a substitute for insulin. Bydureon is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Bydureon with prandial insulin has not been studied. Bydureon has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.

Ozempic (semaglutide)

Indicated: • as an adjunct to diet and exercise to improve glycemic control in adults with type 2

diabetes mellitus. • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-

fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease.

Limitations of Use Ozempic is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Ozempic has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Ozempic is not a substitute for insulin. Ozempic is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis, as it would not be effective in these settings.

Rybelsus (semaglutide)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Rybelsus is not recommended as a first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of rodent C-cell tumor findings to humans. Rybelsus has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Rybelsus is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis, as it would not be effective in these settings.

Trulicity (dulaglutide)


diabetes mellitus

EFFECTIVE 1/1/2021


Brand Name Approved Indication • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes

mellitus who have established cardiovascular disease or multiple cardiovascular risk factors

Limitations of Use • Trulicity has not been studied in patients with a history of pancreatitis [see Warnings

and Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of pancreatitis.

• Trulicity should not be used in patients with type 1 diabetes mellitus. • Trulicity has not been studied in patients with severe gastrointestinal disease, including

severe gastroparesis and is therefore not recommended in these patients [see Warnings and Precautions (5.6)].

Victoza (liraglutide)

Indicated: • as an adjunct to diet and exercise to improve glycemic control in patients 10 years and

older with type 2 diabetes mellitus • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-

fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease

Limitations of Use Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza and prandial insulin has not been studied.

SGLT2 Inhibitors Farxiga (dapagliflozin)

Indicated: Type 2 Diabetes Mellitus:

• as an adjunct to diet and exercise to improve glycemic control. • to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes

mellitus and established cardiovascular disease or multiple cardiovascular risk factors.

Heart Failure:

• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV).

Limitation of Use Farxiga is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Invokana (canagliflozin)


diabetes mellitus • to reduce the risk of major adverse cardiovascular events (cardiovascular death,

nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD)

• to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria > 300 mg/day

Limitation of Use Invokana is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

EFFECTIVE 1/1/2021


Brand Name Approved Indication Jardiance (empagliflozin)


diabetes mellitus • to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus

and established cardiovascular disease Limitation of Use Jardiance is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Steglatro (ertugliflozin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use Steglatro is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

SGLT2 / Metformin Fixed-dose Combinations (non-DPP4) Invokamet / Invokamet XR (canagliflozin-metformin)

Indicated: • As an adjunct to diet and exercise to improve glycemic control in adults with type 2

diabetes mellitus when treatment with both canagliflozin and metformin HCl is appropriate

• Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD). However, the effectiveness of Invokamet/Invokamet XR on reducing the risk of major cardiovascular events in adults with type 2 diabetes and cardiovascular disease has not been established

Limitation of Use Not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Segluromet (ertugliflozin-metformin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin. Limitations of Use Segluromet is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

Synjardy / Synjardy XR (empagliflozin-metformin)

Indicated: • As an adjunct to diet and exercise to improve glycemic control in adults with type 2

diabetes mellitus when treatment with both empagliflozin and metformin hydrochloride is appropriate

• Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. However, the effectiveness of Synjardy on reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has not been established

Limitation of Use Synjardy is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Xigduo XR (dapagliflozin-metformin)

Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin hydrochloride (HCL) is appropriate. Limitation of Use

EFFECTIVE 1/1/2021


Brand Name Approved Indication Xigduo XR is not recommended for patients with type 1 diabetes mellitus or diabetic ketoacidosis.


Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease. Limitations of Use Trijardy XR is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Trijardy XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Trijardy XR.

Recommended Dosing FDA Recommended Dosing

Brand Name Recommended Dosing DPP-4 Inhibitors Januvia (sitagliptin)

The recommended dose of Januvia is 100 mg once daily. Januvia can be taken with or without food.

Nesina (alogliptin)

The recommended dose of Nesina is 25 mg once daily. Nesina may be taken with or without food.

Onglyza (saxagliptin)

The recommended starting dose of Onglyza is 2.5 mg or 5 mg once daily taken regardless of meals. Onglyza tablets must not be split or cut.

Tradjenta (linagliptin)

The recommended dose of Tradjenta is 5 mg once daily. Tradjenta tablets can be taken with or without food.

DPP-4 / SGLT2 Fixed-dose Combinations Glyxambi (linagliptin-empagliflozin)

The recommended starting dose of GLYXAMBI is 10 mg empagliflozin/5 mg linagliptin once daily in the morning, taken with or without food. In patients tolerating GLYXAMBI, the dose may be increased to 25 mg empagliflozin/5 mg linagliptin once daily.

Qtern (saxagliptin- dapagliflozin)

The recommended starting dose of Qtern is a 5 mg dapagliflozin/5 mg saxagliptin tablet taken orally once daily in the morning with or without food.


The recommended starting dose of STEGLUJAN is 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning, with or without food. In patients tolerating STEGLUJAN, the dose may be increased to a maximum recommended dose of 15 mg ertugliflozin/100 mg sitagliptin, once daily, if additional glycemic control is needed.

DPP-4 Fixed-dose Combinations Janumet / Janumet XR (sitagliptin-metformin)

The maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Janumet • The starting dose of JANUMET should be based on the patient’s current regimen.

JANUMET should be given twice daily with meals • The recommended starting dose in patients not currently treated with metformin is 50

mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin

• The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken.

EFFECTIVE 1/1/2021


Brand Name Recommended Dosing • For patients taking metformin 850 mg twice daily, the recommended starting dose of

JANUMET is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily Janumet XR • In patients not currently treated with metformin, the recommended total daily starting

dose of Janumet XR is 100 mg sitagliptin and 1000 mg metformin hydrochloride (HCl) extended release. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose

• In patients already treated with metformin, the recommended total daily starting dose of Janumet XR is 100 mg sitagliptin and the previously prescribed dose of metformin.

• For patients taking metformin immediate-release 850 mg twice daily or 1000 mg twice daily, the recommended starting dose of Janumet XR is two 50 mg sitagliptin/1000 mg metformin hydrochloride extended-release tablets taken together once daily

• Maintain the same total daily dose of sitagliptin and metformin when changing between Janumet (sitagliptin and metformin HCl immediate-release) and Janumet XR. Patients with inadequate glycemic control on this dose of metformin can be titrated gradually, to reduce gastrointestinal side effects associated with metformin, up to the maximum recommended daily dose

Jentadueto / Jentadueto XR (linagliptin-metformin)

Jentadueto • In patients currently not treated with metformin, initiate treatment with 2.5 mg

linagliptin/500 mg metformin hydrochloride twice daily • In patients already treated with metformin, start with 2.5 mg linagliptin and the current

dose of metformin taken at each of the two daily meals (e.g., a patient on metformin 1000 mg twice daily would be started on 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily with meals)

• Patients already treated with linagliptin and metformin individual components may be switched to Jentadueto containing the same doses of each component

Jentadueto XR • In patients currently not treated with metformin, initiate Jentadueto XR treatment with 5

mg linagliptin/1000 mg metformin hydrochloride extended-release once daily with a meal

• In patients already treated with metformin, start Jentadueto XR with 5 mg of linagliptin total daily dose and a similar total daily dose of metformin once daily with a meal

• In patients already treated with linagliptin and metformin or Jentadueto, switch to Jentadueto XR containing 5 mg of linagliptin total daily dose and a similar total daily dose of metformin once daily with a meal

• Jentadueto XR should be swallowed whole. The tablets must not be split, crushed, dissolved, or chewed before swallowing.


Healthcare providers should individualize the starting dose of Kazano based on the patient’s current regimen. Kazano should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. Kazano tablets must not be split before swallowing. The maximum total daily dose is 25 mg alogliptin/2000 mg metformin.

Kombiglyze XR (saxagliptin-metformin)

Kombiglyze XR should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin. The recommended starting dose of KOMBIGLYZE XR in patients who need 5 mg of saxagliptin and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin

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Brand Name Recommended Dosing In patients treated with metformin, the dosage of KOMBIGLYZE XR should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be treated with Kombiglyze XR 2.5 mg/1000 mg Patients who need 2.5 mg saxagliptin who are either metformin naive or who require a dose of metformin higher than 1000 mg should use the individual components.


The maximum total daily dose is 25 mg / 45 mg. Oseni should be taken once daily and can be taken with or without food. The tablets must not be split before swallowing. The recommended starting dose can be 25 mg/15 mg or 25 mg/30 mg. Oseni can be titrated up to a maximum of 25 mg/45 mg once daily based on glycemic response as determined by hemoglobin A1c (A1C).


The recommended starting dose of ADLYXIN is 10 mcg subcutaneously once daily for 14 days. Increase the dose to the maintenance dose of 20 mcg once daily starting on Day 15.

Byetta (exenatide)

The recommended starting dose of Byetta is 5 mcg administered twice daily (BID) at any time within the 60- minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Byetta should not be administered after a meal. Based on clinical response, the dose of Byetta can be increased to 10 mcg twice daily after 1 month of therapy.

Bydureon (exenatide extended-release)

The recommended dose of Bydureon is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals.

Ozempic (semaglutide)

The recommended starting dose of Ozempic is 0.25 mg subcutaneous injection once weekly for 4 weeks. The 0.25 mg dose is intended for treatment initiation and is not effective for glycemic control. After 4 weeks on the 0.25 mg dose, increase the dosage to 0.5 mg once weekly. If additional glycemic control is needed after at least 4 weeks on the 0.5 mg dose, the dosage may be increased to 1 mg once weekly. The maximum recommended dosage is 1 mg once weekly.

Rybelsus (semaglutide)

The recommended starting dose of Rybelsus is 3 mg once daily for 30 days. The 3 mg dose is intended for treatment initiation and is not effective for glycemic control. After 30 days on the 3 mg dose, increase the dose to 7 mg once daily. The dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dose. Taking two 7 mg Rybelsus tablets to achieve a 14 mg dose is not recommended.

Trulicity (dulaglutide)

• The recommended initiating dose of Trulicity is 0.75 mg injected subcutaneously once weekly.

• Increase the dose to 1.5 mg once weekly for additional glycemic control. • If additional glycemic control is needed, increase the dose to 3 mg once weekly after at

least 4 weeks on the 1.5 mg dose. • If additional glycemic control is needed, increase the dose to the maximum dose of 4.5

mg once weekly after at least 4 weeks on the 3 mg dose. • If a dose is missed, instruct patients to administer as soon as possible if there are at

least 3 days (72 hours) until the next scheduled dose. If less than 3 days remain before

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Brand Name Recommended Dosing the next scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.

• The day of weekly administration can be changed if necessary, as long as the last dose was administered 3 or more days before.

Victoza (liraglutide)

Adult Dosage • Initiate Victoza with a dose of 0.6 mg daily for one week. The 0.6 mg dose is a starting

dose intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control in adults. After one week at 0.6 mg per day, increase the dose to 1.2 mg daily

• If additional glycemic control is required, increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose

Pediatric Dosage • Initiate Victoza with a dose of 0.6 mg daily. • After at least one week at 0.6 mg daily, the dose may be increased to 1.2 mg daily if

additional glycemic control is required. • If additional glycemic control is required, increase the dose to 1.8 mg daily after at

least one week of treatment with the 1.2 mg daily dose. SGLT2 Inhibitors Farxiga (dapagliflozin)

Type 2 Diabetes Mellitus To improve glycemic control, the recommended starting dose of Farxiga is 5 mg orally once daily, taken in the morning, with or without food. In patients tolerating Farxiga 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily. To reduce the risk of hospitalization for heart failure in patients with type 2 diabetes mellitus and established CVD or multiple CV risk factors, the recommended dose of Farxiga is 10 mg orally once daily. Heart Failure The recommended dose of Farxiga is 10 mg orally once daily.

Invokana (canagliflozin)

The recommended starting dose of Invokana is 100 mg once daily, taken before the first meal of the day. In patients tolerating Invokana 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control, the dose can be increased to 300 mg once daily. In patients already initiated on therapy who meet the criterion of an eGFR < 30 mL/min/1.73 m2 with albuminuria greater than 300 mg/day, therapy can be continued at 100 mg once daily.

Jardiance (empagliflozin)

The recommended starting dose of Jardiance is 10 mg once daily in the morning, taken with or without food. In patients tolerating Jardiance, the dose may be increased to 25 mg.

Steglatro (ertugliflozin)

The recommended starting dose of Steglatro is 5 mg once daily, taken in the morning, with or without food. In patients tolerating Steglatro 5 mg once daily, the dose may be increased to a maximum recommended dose of 15 mg once daily if additional glycemic control is needed.

SGLT2 Fixed-dose Combinations (non-DPP4) Invokamet / Invokamet XR (canagliflozin-metformin)

The maximum recommended daily dose is canagliflozin 300 mg and metformin HCl 2,000 mg in patients with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2 or greater. Invokamet dosing is one tablet, twice daily with meals.

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Brand Name Recommended Dosing Invokamet XR dosing is two tablets, once daily with the morning meal. Swallow each tablet whole and never crush, cut, or chew. Patients Currently not Treated with Either Canagliflozin or Metformin HCl • Invokamet: One tablet, twice daily, each tablet containing canagliflozin 50 mg and

metformin HCl 500 mg • Invokamet XR: Two tablets, once daily, each tablet containing canagliflozin 50 mg and

metformin HCl 500 mg Patients on Metformin • Invokamet: One tablet, twice daily, where the total daily dose contains canagliflozin

100 mg and the same, or nearest appropriate, daily dose of metformin HCl • Invokamet XR: Two tablets, once daily, where the total daily dose contains

canagliflozin 100 mg and the patient’s same, or nearest appropriate, daily dose of metformin HCl

Patients on Canagliflozin • Invokamet: One tablet, twice daily, where the total daily dose contains the same daily

dose of canagliflozin and metformin HCl 1,000 mg • Invokamet XR: Two tablets, once daily, where the total daily dose contains the

patient’s same daily dose of canagliflozin and metformin HCl 1,000 mg Patients Already Treated with Canagliflozin and Metformin • Invokamet: One tablet, twice daily, where the total daily dose contains the same daily

dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl

• Invokamet XR: Two tablets, once daily, where the total daily dose contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin HCl

Segluromet (ertugliflozin-metformin)

The maximum recommended total daily dose is 15 mg ertugliflozin and 2,000 mg metformin. Take Segluromet twice daily with meals, with gradual dose escalation for those initiating metformin to reduce the gastrointestinal side effects due to metformin In patients on metformin, switch to Segluromet tablets containing 2.5 mg ertugliflozin, with a similar total daily dose of metformin. In patients on ertugliflozin, switch to Segluromet tablets containing 500 mg metformin, with a similar total daily dose of ertugliflozin. In patients already treated with ertugliflozin and metformin, switch to Segluromet tablets containing the same total daily dose of ertugliflozin and a similar daily dose of metformin.

Synjardy / Synjardy XR (empagliflozin-metformin)

The maximum recommended today daily dose is 25 mg empagliflozin and 2,000 mg of metformin. The dose of metformin hydrochloride should be gradually escalated to reduce the gastrointestinal side effects due to metformin hydrochloride. Take Synjardy twice daily with meals. Take Synjardy XR orally once daily with a meal in the morning. Swallow Synjardy XR tablets whole. Do not split, crush, dissolve, or chew before swallowing. In patients on metformin hydrochloride, switch to Synjardy XR containing a similar total daily dose of metformin hydrochloride and a total daily dose of empagliflozin 10 mg; In patients on empagliflozin, switch to Synjardy XR containing the same total daily dose of empagliflozin and a total daily dose of metformin hydrochloride extended-release 1000 mg

EFFECTIVE 1/1/2021


Brand Name Recommended Dosing In patients already treated with empagliflozin and metformin hydrochloride, switch to Synjardy XR containing the same total daily doses of empagliflozin and a similar total daily dose of metformin hydrochloride.

Xigduo XR (dapagliflozin-metformin)

The maximum total daily dose is 10 mg dapagliflozin and 2,000 mg metformin. Take Xigduo XR once daily in the morning with food. Swallow Xigduo XR tablets whole and never crush, cut, or chew. For patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is 5 mg once daily. For patients requiring a dose of 5 mg dapagliflozin and 2000 mg metformin hydrochloride (HCl) extended-release, use two of the 2.5 mg dapagliflozin/1000 mg metformin HCl extended-release tablets.


Individualize the starting dose of Trijardy XR based on the patient’s current regimen: • In patients on metformin HCl, with or without linagliptin, switch to Trijardy XR

containing a similar total daily dose of metformin HCl and a total daily dose of empagliflozin 10 mg and linagliptin 5 mg;

• In patients on metformin HCl and any regimen containing empagliflozin, with or without linagliptin, switch to Trijardy XR containing a similar total daily dose of metformin HCl, the same total daily dose of empagliflozin and linagliptin 5 mg.

Monitor effectiveness and tolerability, and adjust dosing as appropriate, not to exceed the maximum recommended daily dose of empagliflozin 25 mg, linagliptin 5 mg and metformin HCl 2000 mg. Trijardy XR is taken orally, once daily with a meal in the morning.

• Take Trijardy XR 10 mg/5 mg/1000 mg or Trijardy XR 25 mg/5 mg/1000 mg as a single tablet once daily.

• Take Trijardy XR 5 mg/2.5 mg/1000 mg or Trijardy XR 12.5 mg/2.5 mg/1000 mg as two tablets together once daily.

• Swallow Trijardy XR tablets whole. Do not split, crush, dissolve, or chew. Background Professional Societies/Organizations American Diabetes Association (ADA) The 2019 ADA: Standards of Medical Care in Diabetes recommends, for the pharmacological management of type 2 diabetes mellitus (T2DM), metformin as the initial therapy, and that metformin should be continued when used in combination with other agents, including insulin, if not contraindicated and if tolerated. Among patents with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), sodium–glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide 1 (GLP-1) receptor agonists with demonstrated cardiovascular disease benefit are recommended as part of the antihyperglycemic regimen. Among patients with ASCVD at high risk of heart failure (HF) or in whom heart failure coexists, SGLT2 inhibitors are preferred. For patients with T2DM and chronic kidney disease (CKD), consider use of a SGLT2 inhibitor or GLP-1 receptor agonist shown to reduce risk of CKD progression, cardiovascular events, or both. For patients without established ASCVD or CKD, the choice of a second agent to add to metformin is not yet guided by empiric evidence. Drug choice should be based on avoidance of side effects, particularly hypoglycemia and weight gain, cost, and patient preferences. ADA does not recommend one DPP-4 inhibitor over another. (ADA, 2019) American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) The 2019 Consensus Statement on the Comprehensive Type 2 Diabetes Management Algorithm states that if T2DM is recent onset or mild hyperglycemia (HbA1C < 7.5%), lifestyle therapy plus antihyperglycemic monotherapy (preferably with metformin) is recommended. In patients who do not reach their glycemic target on

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metformin monotherapy, metformin should be continued in combination with other agents, including insulin. Patients who present with an A1C >7.5% (whether newly diagnosed or not) and who are not already taking any antihyperglycemic agents should be started initially on metformin plus another agent in addition to lifestyle therapy. In those with cardiovascular disease (CVD) and/or CKD, GLP-1 receptor agonists and SGLT2 inhibitors with proven CVD and/or CKD benefits is preferred as add-on therapy to metformin. Additionally, if individual has coronary heart disease (CHD), a GLP-1 receptor agonist or SGLT2 inhibitor should be included in antihyperglycemic treatment regimen. (AACE/ACE, 2019) Metformin Current guidelines recommend, along with lifestyle interventions, that metformin should be the initial pharmacologic therapy for T2DM in the absence of specific contraindications. Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death. Metformin has a low risk of hypoglycemia, can promote modest weight loss, and has good antihyperglycemic efficacy at doses of 1,000 to 2,000 mg/day. (AACE/ACE, 2019; ADA, 2019) In most DPP-4, GLP-1, and SGLT2 metformin add-on studies, the target metformin dose was 1,500 mg/day or greater. (Adlyxin PI, 2016; Bydureon/Byetta PI, 2018; Farxiga PI, 2019; Invokana, 2018; Januvia, 2019; Jardiance, 2018; Nesina, 2019; Onglyza, 2019; Ozempic, 2019; Steglatro, 2018; Tradjenta, 2019; Trulicity, 2019; Victoza, 2019). In the cardiovascular outcome trials for respective GLP-1 (liraglutide) and SGLT2 (canagliflozin, empagliflozin) agents that carry such risk reduction indication, the vast majority of individuals had metformin as part of their pre-trial antihyperglycemic regimen in those for whom metformin was not contraindicated or was tolerated (percent of patients on metformin therapy: 73% to 77%). (Marso, 2016; Neal, 2017; Zinman, 2015) Single-agents Appendix 1

DPP-4 Inhibitors alogliptin (Nesina)

linagliptin (Tradjenta) saxagliptin (Onglyza) sitagliptin (Januvia)

Appendix 2

GLP-1 RAs dulaglutide (Trulicity)

exenatide (Byetta, Bydureon) liraglutide (Victoza)

lixisenatide (Adlyxin) semaglutide (Ozempic) injectable semaglutide (Rybelsus) oral tablet

Appendix 3

SGLT2 Inhibitors canagliflozin (Invokana) dapagliflozin (Farxiga)

empagliflozin (Jardiance) ertugliflozin (Steglatro)

Appendix 4

DPP-4 / SGLT2 Inhibitors Fixed-dose Combinations linagliptin-empagliflozin (Glyxambi)

saxagliptin-dapagliflozin (Qtern) sitagliptin-ertugliflozin (Steglujan)

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Appendix 5

DPP-4 Inhibitor Fixed-dose Combinations alogliptin-metformin (Kazano) alogliptin-pioglitazone (Oseni)

linagliptin-metformin (Jentadueto / Jentadueto XR) saxagliptin-metformin (Kombiglyze XR)

sitagliptin-metformin (Janumet / Janumet XR) Appendix 6

SGLT2 Inhibitors / Metformin Fixed-dose Combinations

canagliflozin-metformin (Invokamet / Invokamet XR) dapagliflozin-metformin (Xigduo XR) empagliflozin-metformin (Synjardy / Synjardy XR) ertugliflozin-metformin (Segluromet)

Appendix 7

SGLT2 Inhibitors / DPP-4 Inhibitors / Metformin Fixed-dose Combinations

empagliflozin-linagliptin-metformin (Trijardy XR) References 1. AACE/ACE Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the American

Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2019 Executive Summary. Endocr Pract. 2019 Jan. Available at: https://www.aace.com/publications/algorithm

2. ADA Standards of Medical Care in Diabetes, Diabetes Care January 2019;42(Suppl. 1):S90–S102. Available at: http://care.diabetesjournals.org/content/42/Supplement_1/S90

3. Adlyxin (lixisenatide) [package insert]. Bridgewater, NJ. Sanofi-Aventis. July 2016. 4. Ahmann AJ, Capehorn M, Charpentier G et al. Efficacy and safety of once-weekly semaglutide versus

exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): A 56-week, open-label, randomized clinical trial. Diabetes Care. 2018;41(2):258-266.

5. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomized, open-label study. Lancet. 2013;381(9861):117-124.

6. Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day vs exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39-47.

7. Bydureon/Byetta (Exenatide) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals LP. December 2018.

8. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide in metformin-treated patients with Type 2 diabetes (AWARD-6): a randomized, open-label, phase 3, non-inferiority trial. Lancet. 2014;384(9951):1349-1357.

9. Farxiga (dapagliflozin) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals LP. January 2020. 10. Glyxambi (linagliptin and empagliflozin) [package insert]. Ridgefiled, CT. Boehringer Ingelheim

Pharmaceuticals, Inc. July 2019. 11. Invokana (canagliflozin) [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc. October 2019. 12. Invokamet/Invokamet XR (canagliflozin and metformin/metformin ER) [package insert]. Titusville, NJ.

Janssen Pharmaceuticals, Inc. October 2018. 13. Januvia (sitagliptin) [package insert]. Whitehouse Stating, NJ. Merck & Co., Inc. July 2019. 14. Janumet/Janumet XR (sitagliptin and metformin/metformin ER) [package insert]. Whitehouse Station, NJ.

Merck & Co., Inc. July 2019.

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15. Jardiance (empagliflozin) [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. December 2018.

16. Jentadueto/Jentadueto XR (linagliptin and metformin/metformin ER) [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. July 2019.

17. Kazano (alogliptin and metformin) [package insert]. Deerfield, IL. Takeda Pharmaceuticals America, Inc. February 2017.

18. Kombiglyze (saxagliptin and metformin) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals LP. July 2019.

19. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016a;375(4):311-322.

20. Neal B, Perkovic V, Mahaffey KW, et al.; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.

21. Nesina (alogliptin) [package insert]. Deerfield, IL. Takeda Pharmaceuticals America, Inc. July 2019. 22. Onglyza (saxagliptin) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals LP. July 2019. 23. Oseni (alogliptin and pioglitazone) [package insert]. Deerfield, IL. Takeda Pharmaceuticals America, Inc. July

2019. 24. Ozempic (semaglutide) [package insert]. Plainsboro, NJ. Novo Nordisk Inc. January 2020. 25. Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2

diabetes (SUSTAIN 7): a randomized, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6(4):275-286.

26. Qtern (saxagliptin and dapagliflozin) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals LP. July 2019

27. Rosenstock J, Raccah D, Korányi L, Maffei L, Boka G, Miossec P, Gerich JE. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care. 2013;36(10):2945-2951.

28. Rybelsus (semaglutide) [package insert]. Plainsboro, NJ. Novo Nordisk Inc. Novemeber 2019. 29. Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in

combination with metformin compared to sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2010;26(7):540-9.

30. Segluromet (ertugliflozin and metformin) [package insert]. Whitehouse Station, NJ. Merck & Co., Inc. October 2018.

31. Steglatro (ertugliflozin) [package insert]. Whitehouse Station, NJ. Merck & Co., Inc. October 2018. 32. Steglujan (sitagliptin and ertugliflozin) [package insert]. Whitehouse Station, NJ. Merck & Co., Inc. July 2019. 33. Synjardy (empagliflozin and metformin/metformin ER) [package insert]. Ridgefield, CT. Boehringer Ingelheim

Pharmaceuticals, Inc. October 2018. 34. Tradjenta (linagliptin) [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. July

2019. 35. Trijardy™ XR [prescribing information]. Ridgefield, CT: Boehringer Ingelheim; January 2020. 36. Trulicity (Dulaglutide) [package insert]. Indianapolis, IN. Eli Lilly and Company. September 2020. 37. Victoza (liraglutide) [package insert]. Plainsboro, NJ. Novo Nordisk Inc. June 2019. 38. Xigduo XR (dapagliflozin and metformin) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals

LP. February 2019. 39. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2

diabetes. N Engl J Med. 2015;373(22):2117-2128.

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