Mixed – Glycemic Control Algorithm for Diabetes Type 2 (DM2)

Implement lifestyle interventions (including medically assisted weight loss)

Consider referral to Endocrinology if patient presents with
Start consistent DKA or severe/constant/recurrent hypoglycemia

A1C < 7.5% Yes metformin (Glucophage) If monotherapy is desired, metformin is preferred
Consider escalating to triple therapy or insulin if clinically indicated or if
A1C above contraindication to multiple antidiabetic agents based on individualized patient
Yes
target? care plan
No
Polydypsia, Polyurea, or Yes, A1C ≥ 9% INSULIN
7.5% ≤ A1C < 9% No A1C ≥ 9% Yes
Polyphasia symptoms? with symptoms (± other agents)
Yes, 7.5% ≤ A1C < 9% No, A1C ≥ 9% with no symptoms

DUAL THERAPY TRIPLE THERAPY

Indicators of high-risk or No ASCVD, HF, or Indicators of high-risk or established
No ASCVD, HF, or CKD
established ASCVD, CKD, or HF CKD ASCVD, CKD, or HF
Consider independently of baseline metformin Consider independently of baseline A1C or metformin ADD OR
A1C or individualized A1C target (Glucophage) individualized A1C target (Glucophage) INTENSIFY
preferred first line preferred first line INSULIN
ASCVD HF or CKD PLUS ASCVD HF or CKD PLUS 2 additional agents Refer to insulin
Predominates Predominates Predominates Predominates algorithm
SGLT-2i SGLT-2i
metformin metformin  empagliflozin metformin metformin  empagliflozin (Jardiance)
(Glucophage) (Glucophage) (Glucophage) (Glucophage)
(Jardiance)  canagliflozin (Invokana)
preferred first line preferred first line preferred first line preferred first line
 canagliflozin
PLUS PLUS PLUS 2 additional agents PLUS 2 additional agents
(Invokana) GLP-1 RA
PREFERABLY PREFERABLY SGLT-2i SGLT-2i  liraglutide (Victoza)
GLP-1 RA SGLT-2i GLP-1 RA  empagliflozin  empagliflozin  dulaglutide (Trulicity)
 liraglutide  empagliflozin  liraglutide (Victoza) (Jardiance) (Jardiance)
(Victoza) (Jardiance)  dulaglutide  canagliflozin (Invokana)  canagliflozin (Invokana) DPP-4i
 dulaglutide  canagliflozin (Trulicity)  sitagliptin (Januvia)
(Trulicity) (Invokana) GLP-1 RA GLP-1 RA  linagliptin (Tradjenta)
Or Or DPP-4i  liraglutide (Victoza)  liraglutide (Victoza)
SGLT-2i If eGFR less than  sitagliptin (Januvia)  dulaglutide (Trulicity)  dulaglutide (Trulicity) Sulfonylureas
 empagliflozin adequate, use  linagliptin  glipizide (Glucotrol)
(Jardiance) GLP-1 RA (Tradjenta) DPP-4i DPP-4i  glimepiride (Amaryl)
 canagliflozin  liraglutide  sitagliptin (Januvia)  sitagliptin (Januvia)
(Victoza) Sulfonylureas
(Invokana)  linagliptin (Tradjenta)  linagliptin (Tradjenta) Thiazolidinediones
 dulaglutide  glipizide (Glucotrol)  pioglitazone (Actos)
(Trulicity)  glimepiride (Amaryl) Sulfonylureas Basal Insulin
 glipizide (Glucotrol)  insulin glargine Basal Insulin
Thiazolidinediones  insulin glargine (Basaglar/
 glimepiride (Amaryl) (Basaglar/Lantus)
 pioglitazone (Actos)  insulin detemir Lantus)
Basal Insulin (Levemir)  insulin detemir (Levemir)
Check A1C  insulin glargine
every 3 months (Basaglar/Lantus) Rapid Acting Insulin
A1C above Yes, Proceed to  insulin detemir  insulin aspart (Novolog)
target? Triple Therapy  insulin lispro (Humalog)
(Levemir)
Thiazolidinediones Short Acting Insulin
 pioglitazone (Actos)  insulin human injection
Clinical Considerations of Pathway Drugs (Humulin R)
First line unless:  insulin human regular
eGFR < 30mL/min/1.73m2 (all)
metformin (Glucophage) eGFR < 45mL/min/1.73m2 (new) (Novolin R)
Inappropriate for use with DPP-4i
GLP-1 RA Caution for use with SU Yes, Consider adding/intensifying
Check A1C A1C above
liraglutide (Victoza) insulin therapy or
every 3 months target?
refer to Endocrinology
dulaglutide (Trulicity) Clinical Considerations of Pathway Insulin
Drugs Key
SGLT-2i Only one drug per patient,
Rapid Acting Insulin caution for use with TZD Hypoglycemia Atherosclerotic Cardiovascular Disease
empagliflozin (Jardiance)
insulin aspart (Novolog) Weight Bone
canagliflozin (Invokana)
insulin lispro (Humalog)
DPP-4i Inappropriate for use with GLP-1 RA Renal Ketoacidosis
Caution for use with SU
Only one drug per patient,
sitagliptin (Januvia) Short Acting Insulin caution for use with TZD Genitourinary Stroke
insulin human injection
linagliptin (Tradjenta) (Humulin R)
Gastrointestinal Peripheral Vascular Disease
Caution for use with GLP-1 RA
SU Caution for use with DPP-4i insulin human regular Heart Failure Non-Alcoholic SteatoHepatitis
Caution for use with Rapid/Short Acting Insulins
(Novolin R)
glipizide (Glucotrol) Known/likely adverse effects (increased monitoring and counseling)
Only one drug per patient,
Basal Insulin caution for use with TZD
glimepiride (Amaryl) Use with caution (increased monitoring and counseling)
insulin glargine
TZD Caution for use with Insulin (Basaglar/Lantus) Anticipated positive impact and/or favorable safety profile

pioglitazone (Actos) insulin detemir (Levemir) Neutral (the absence of an icon indicates neutral impact)

Progression of Disease
List of antidiabetic drugs on page 2.
Acknowledgements. Information contained herein is supported by recommendations and standards for glycemic control and insulin administration published by:
 AACE/ACE Garber AJ, Handelsman Y, Grunberger G, et al. Consensus Statement By The American Association Of Clinical Endocrinologists And American College Of Endocrinology On The Comprehensive Type 2 Diabetes
Management Algorithm – 2020 Executive Summary. Endocrine Practice. 2020;26(1):107- 139. doi:10.4158/cs-2019-0472.
 ADA The American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020. Diabetes Care. 2019;43(Supplement 1). doi:10.2337/dc20-s009.

This guide was prepared by Highmark Inc. as an informational resource only for medical professionals and is not intended as medical advice or as a substitute for the professional judgment of the clinician in patient care. The
list of medications may not be current or definitive and is not intended to be complete or exhaustive. Preferred agents were selected by clinician leadership, leveraging insights from evidence-based literature and formulary
status from common payors. The medications listed may not apply to all patients or all clinical situations. Medications may have different effects on different patients necessitating medical judgment of the clinician.
© 2020 Highmark Inc. All rights reserved. This material may not be reproduced or distributed in any form without express written permission of Highmark, Inc. 1
 Algorithm for Adding or Intensifying Insulin for Diabetes Type 2 (DM2)
Start Consider GLP-1 RA in most patients prior to insulin Intensity (prandial control)
Intensification of Therapy Blood Glucose Targets
Start Basal (long-acting Insulin)  Considerations for adjusting A1C and FBG targets should be
tailored to each individual patient and should include:
patient’s age, duration of disease, comorbidities, presence of
complications, and risk of hypoglycemia.
Begin prandial insulin Begin prandial insulin  For most patients with T2D their A1C target should be ≤7%
SGLT-2i
before largest meal before each meal and have a fasting or premeal BG of <130 mg/dL with
Fixed or weight- Weight-  empagliflozin (Jardiance)
 50% basal/50% prandial avoidance of hypoglycemia.
based regimen? based  canagliflozin (Invokana) Start: 10% of basal
Fixed (TDD 0.3-0.5 units/kg)
dose or 5 units
GLP-1 RA Start: 50% of TDD in Titrate insulin dose to achieve blood glucose targets
Start with 10 units A1C?  liraglutide (Victoza) Are three doses before (evaluate every 2-3 days)
once daily A1C < 8% A1C > 8%  dulaglutide (Trulicity) blood glucose targets
meals
 Increase by 2 units at goal?
No Basal Insulin Is 2-h postprandial
every 3 days if DPP-4i
TDD 0.1-0.2 U/kg TDD 0.2-0.3 U/kg  insulin glargine (Basaglar/ or next premeal glucose Yes
FBG >140mg/dL  sitagliptin (Januvia) Customize prandial insulin
frequency based on Lantus) > 140mg/dL?
 linagliptin (Tradjenta) individual patient needs  insulin detemir (Levemir)
Basal Insulin Increase individual prandial
 insulin glargine (Basaglar/Lantus) Discontinue Check Rapid Acting Insulin dose by 10% or 1-2 units,
Rapid Acting Insulin
 insulin detemir (Levemir) DPP-4i A1C
if adding  insulin aspart (Novolog)  insulin aspart (Novolog) whichever is greater
every Fasting
Prandial  insulin lispro (Humalog)  insulin lispro (Humalog)
3 months hypoglycemia Yes
insulin
Fasting Reduce TDD by: occurs?
hypoglycemia Yes  BG <70mg/dL: 10-20% Short Acting Insulin Short Acting Insulin
Are  insulin human injection  insulin human injection
occurs?  BG <40mg/dL: 20-40%
blood glucose targets No (Humulin R) Reduce TDD basal or prandial insulin by:
(Humulin R)
Check A1C every 3 months at goal?  10-20% if BG consistently < 70mg/dL
 insulin human regular  insulin human regular
(Novolin R)  20-40% if BG < 50mg/dL or Severe Hypoglycemia
No (Novolin R)
Are (requiring medical assistance from caretaker or
Check A1C every
blood glucose targets No other individual)
3 months
at goal?
Progression of Disease

Clinical Considerations of Pathway Clinical Considerations of Pathway Insulin Drugs Clinical Considerations of Pathway Drugs Key
Insulin Drugs Only one drug per patient,
Atherosclerotic
Inappropriate for use with DPP-4i
Basal Insulin caution for use with TZD GLP-1 RA Known/likely adverse
Only one drug per patient, Caution for use with SU Hypoglycemia
Rapid Acting Insulin caution for use with TZD Cardiovascular Disease effects (increased
insulin glargine (Basaglar/Lantus) liraglutide (Victoza) monitoring and counseling)
insulin aspart (Novolog) Weight Bone
insulin detemir (Levemir) dulaglutide (Trulicity) Use with caution (increased
insulin lispro (Humalog) Renal Ketoacidosis monitoring and counseling)
Short Acting Insulin Only one drug per patient, Clinical Considerations of Pathway Drugs SGLT-2i Anticipated positive impact
caution for use with TZD Genitourinary Stroke
Inappropriate for use with GLP-1 RA empagliflozin and/or favorable safety
insulin human injection DPP-4i Peripheral Vascular
Caution for use with SU profile
(Humulin R) (Jardiance) Gastrointestinal
Disease
sitagliptin (Januvia) Neutral (the absence of
insulin human regular canagliflozin Heart Failure
Non-Alcoholic an icon indicates neutral
(Novolin R) linagliptin (Tradjenta) (Invokana) SteatoHepatitis impact)

Preferred pathway drugs

List of Antidiabetic Drugs Non-preferred drugs
Not meant to be a comprehensive list of clinical considerations
Biguanides; ~1% A1C Reduction Alpha-glucosidase inhibitors (AGi); 0.7%-0.8% A1C Reduction
metformin PO QD- PO TID Pros: low risk of hypoglycemia (monotherapy), weight neutral
Black Box Warnings acarbose (Precose)‡ж (w/meals)
(Glucophage)‡Фж TID Pros: weight neutral, low risk of hypoglycemia Cons: GI disturbances (flatulance, diarrhea), frequent dosing (with
metformin ER PO QD- Lactic Acidosis PO TID
Cons: GI (diarrhea, nausea, dyspepsia, constipation, miglitol (Glyset)ж (w/meals) meals)
(Glucophage XR)‡Фж BID (death, hypothermia, hypotension, and
vomiting), B12 deficiency
metformin ER-Osmotic PO QD- resistant bradyarrhythmias have been Meglitinides (GLN); 0.7%-1.1% A1C Reduction
(Fortamet)‡Фж BID Contraindications: Lactic acidosis, DKA, metabolic acidosis,
reported due to metformin-associated lactic
metformin ER-Gastric PO QD- renal failure repaglinide (Prandin)‡Фж PO BID-QID Pros: flexible dosing (skip dose if skipping meal)
(w/meals)
(Glumetza)‡Фж BID acidosis) Cons: risk of hypoglycemia, weight gain, frequent dosing (TID)
PO TID
nateglinide (Starlix)ж (w/meals) Contraindications: diabetic ketoacidosis
Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RA); ~1% A1C Reduction
liraglutide (Victoza) SQ QD Others
Contraindications: basilar/hemiplegic migraine, breast-feeding,
dulaglutide (Trulicity) SQ QW Pros: weight loss, low risk of hypoglycemia, ASCVD benefits bromocriptine (Cycloset) PO QD
eclampsia, ergot alkaloid hypersensitivity, preeclampsia, pregnancy
semaglutide (Ozempic) SQ QW Cons: GI (diarrhea, nausea, dyspepsia, constipation,
colesevelam (WelChol)ж PO QD-BID Contraindications: GI obstruction, hypertriglyceridemia, pancreatitis
vomiting), fatigue Black Box Warnings
semaglutide (Rybelsus) PO QD Contraindications: history of angioedema, medullary Thyroid C-cell tumors SQ w/each Contraindications: cresol hypersensitivity, gastroparesis,
pramlintide (Symlin) major meal hypoglycemia awareness
lixisenatide (Adlyxin)Ф SQ QD thyroid carcinoma (MTC), multiple endocrine neoplasia (except lixisenatide (Adlyxin))
syndrome type II (MEN 2), thyroid C-cell tumors, Insulins
exenatide ER (Bydureon/ SQ QW
Bydureon BCise)Ф pancreatitis Rapid Acting Insulin
exenatide (Byetta)Ф SQ BID insulin aspart (Novolog)ж U-100; Vials, Pre-Filled Pens, Penfill
Sodium-Glucose Co-Transporter 2 Inhibitor (SGLT-2i); ~0.4%-0.7% A1C Reduction U-100, U-200; Vials, Cartridge, Pre-
insulin lispro (Humalog)ж Filled Pens
empagliflozin (Jardiance)Ф PO QD Pros: weight loss, daily oral dosing (dose reduction in renal disease) insulin glulisine (Apidra) U-100; Vials, Pre-Filled Pens
Black Box Warnings
Cons: genitourinary infections, DKA, increased urination, hyperlipidemia,
canagliflozin (Invokana)Ф PO QD dizziness, hypotension, bone fracture, dose reduction in renal disease Risk of lower limb insulin lispro (Admelog) U-100; Vials, Pre-Filled Pens
amputations in patients with
dapagliflozin (Farxiga) Ф PO QD Contraindications: dialysis, renal failure, lower limb amputations established CVD or risk of CV insulin aspart (Fiasp) U-100; Vials, Pre-Filled Pens, Penfill
(canagliflozin only), avoid in patients with diarrhea, hypotension, or
ertugliflozin (Steglatro)‡Ф PO QD dehydration (canagliflozin (Invokana) only) insulin human (Afrezza) Inhaled; Inhalation powder Pros: reduce effects of
hyperglycemia (fatigue, frequent
Dipeptidyl-Peptidase IV Inhibitors (DPP-4i); ~0.5%-0.7% A1C Reduction Short-acting Insulin urination, etc.), decrease risk of
sitagliptin (Januvia)Ф PO QD insulin human injection (Humulin R) U-100; Vials micro/macrovascular
Pros: low risk of hypoglycemia (monotherapy), weight neutral, daily oral dosing, generally well tolerated complications
linagliptin (Tradjenta) PO QD (less GI ADE) insulin human injection (Novolin R) U-100; Vials, Pre-Filled Pens
Cons: weight gain, potential for
alogliptin (Nesina)‡Фж PO QD Cons: may be associated with pancreatitis, may cause severe joint pain insulin human injection (Humulin R) U-500; Vials, Pre-Filled Pens hypoglycemia, caution in heart
Contraindications: history of angioedema, serious rash failure
saxagliptin (Onglyza)Ф PO QD Intermediate-acting Insulin Precautions (all): hypoglycemia
Sulfonylureas (SU); 0.7%-1.3% A1C Reduction insulin NPH (Humulin N) U-100; Vials, Pre-Filled Pens Contraindications (Afrezza only):
PO QD- asthma, COPD, pulmonary
glipizide (Glucotrol)‡Фж insulin NPH (Novolin N) U-100; Vials, Pre-Filled Pens
BID Pros: orally administered disease, acute bronchospasm
glimepiride (Amaryl)‡Фж PO QD Cons: risk of hypoglycemia, weight gain, short-lived efficacy Basal Insulin
PO QD- Contraindications: diabetic ketoacidosis
glyburide (Glynase)‡Фж BID insulin glargine (Basaglar) U-100; Pre-Filled Pens

Thiazolidinediones (TZD); 0.8%-0.9% A1C Reduction insulin glargine (Lantus) U-100; Vials, Pre-Filled Pens

pioglitazone (Actos)‡ж PO QD Pros: low risk of hypoglycemia (monotherapy) Black Box Warnings insulin detemir (Levemir) U-100; Vials, Pre-Filled Pens
PO QD- Cons: weight gain, edema, increased risk of fracture, caution in hepatic impairment May cause or
rosiglitazone (Avandia)‡ BID Contraindications: heart failure exacerbate CHF insulin glargine (Toujeo) U-300; Pre-Filled Pens

List of Combination Products (Refer to individual agent for clinical information) insulin degludec (Tresiba) U-100, U-200; Vials, Pre-Filled Pens
sitagliptin/metformin (Janumet, Janumet XR); alogliptan/metformin (Kanzo)ж; linagliptan/metformin (Jentaduetto, Dosing Considerations Dosing Abbreviations
DPP-4i/metformin
Jentaduetto XR); saxagliptan/metformin (Kombiglyze XR) Refer to prescribing information for PO = by mouth, SQ = Subcutaneous
individual drugs QD = once daily, BID = twice daily, TID = three times daily,
meglitinide/metformin repaglinide/metformin (PrandiMet)ж QID = four times a day
Hepatic = ‡
empagliflozin/metformin (Synjardy, Synjardy XR; canagliflozin/metformin (Invokamet, Invokamet XR); dapagliflozin/ Renal = Ф QW = once weekly
SGLT-2i/metformin Generic Availability = ж
metformin (Xigduo XR); ertugliflozin/metformin (Segluromet)
Acknowledgements. Information contained herein is supported by recommendations and standards for glycemic control and insulin administration published by:
SU/metformin glipizide/metformin (Metaglip)ж; glyburide/metformin (Glucovance)ж  AACE/ACE Garber AJ, Handelsman Y, Grunberger G, et al. Consensus Statement By The American Association Of Clinical Endocrinologists And American College
Of Endocrinology On The Comprehensive Type 2 Diabetes Management Algorithm – 2020 Executive Summary. Endocrine Practice. 2020;26(1):107- 139.
TZD/metformin pioglitazone/metformin (ActoPlus Met ж, ActoPlus Met XR); rosiglitazone/metformin (Avandamet) doi:10.4158/cs-2019-0472.
 ADA The American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020. Diabetes Care.
SGLT-2i/DPP-4i empagliflozin/linagliptan (Glyxambi); dapagliflozin/saxagliptan (Qtern); ertugliflozin/sitagliptan (Steglujan) 2019;43(Supplement 1). doi:10.2337/dc20-s009.

DPP-4i/TZD alogliptan/pioglitazone (Oseni)ж This guide was prepared by Highmark Inc. as an informational resource only for medical professionals and is not intended as medical advice or as a substitute for
the professional judgment of the clinician in patient care. The list of medications may not be current or definitive and is not intended to be complete or
pioglitazone/glimepiride (Duetact)ж exhaustive. Preferred agents were selected by clinician leadership, leveraging insights from evidence-based literature and formulary status from common
TZD/SU payors. The medications listed may not apply to all patients or all clinical situations. Medications may have different effects on different patients necessitating
medical judgment of the clinician.
GLP-1 RA/basal insulin lixisenatide/insulin glargine (Soliqua); liraglutide/insulin degludec (Xultophy) © 2020 Highmark Inc. All rights reserved. This material may not be reproduced or distributed in any form without express written permission of Highmark, Inc.
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