1. Diabetes Medications: What to prescribe?
Rose M. Flinchum, MSEd., MS, CNS, RN, ACNS-BC, BC-ADM, CDE
Inpatient Diabetes CNS / Certified Diabetes Educator
Outpatient DSMES Quality Coordinator

2. Diabetes in our Practices
2015 Statistics
30.3 million Americans; 9.4% of the population
23.1 million were diagnosed; 7.2 million were undiagnosed
25.2% of seniors (diagnosed/undiagnosed)
34% of residents in nursing facilities
38% to 40% of hospital inpatients 
American Diabetes Association, 2017
CDC National Diabetes Statistics Report, 2017
Swanson, Potter, Kongable, Cook. Endocrine
Practice, 2017

3. Categories of Medications
Oral Medications
Injectable Medications
Biguanides
Sulfonylureas (SUs)
Meglitinide Derivatives
Alpha-glucosidase Inhibitors (AGIs)
Thiazolidinediones (TZDs)
Dipeptidyl Peptidase Inhibitors (DPP-4s)
SGLT-2 Inhibitors
Bile Acid Sequestrant
Dopamine Receptor Agonist
GLP-1 Receptor Agonists (GLP-1s)
Amylin-mimetic
Insulin (Injectable)
Rapid Acting
Short Acting
Intermediate Acting
Long Acting
U100, U200, U300, U500
Insulin / GLP-1 Combinations
Inhaled Insulin
Rapid acting

4. Algorithms: ADA, 2018 Type 1 Insulin
Multiple daily injections or insulin pump therapy
Amylin-mimetic may be added
Metformin, unless contraindicated/not tolerated
A1c >9%: Consider dual therapy
A1c >10%, BG > 300, symptomatic: Consider insulin therapy
Without ASCVD and not at goal within 3 months: Add another agent
With ASCVD: Incorporate empagliflozin or liraglutide A
Type 2

5. Algorithms: AACE, 2018 Insulin
Type 1
Insulin
Multiple daily injections or insulin pump therapy; Amylin-mimetic may be added
A1c <7.5%: Monotherapy (metformin/other)
A1c >7.5%, Dual therapy (includes basal insulin option)
If not at goal within 3 months: Proceed to Triple Therapy
If not at goal within 3 months: Proceed to or intensify insulin therapy
Type 2

6. Take into Consideration…
Drug’s indications / FDA approved uses
Drug’s mechanism of action
Is it addressing the individual’s problem/needs?
Type 1: Absolute insulin deficiency
Type 2: “Ominous Octet” to “Egregious Eleven”

7. Type 2 : Involved Tissues/ Defects “Egregious Eleven”
Pancreas – b-cell defect; apoptosis; insulin secretion
Gut – incretin effect
a-cell defect – glucagon secretion
Adipose tissue – insulin resistance; free fatty acid production;
lipolysis
Muscle – insulin resistance; glucose uptake
Liver – insulin resistance; endogenous glucose production
Brain – neurotransmitter dysfunction; insulin resistance
Colon; biome – abnormal microbiota; possible GLP-1 secretion
Immune dysregulation / inflammation
Stomach; small intestine – rate of gastric emptying / glucose absorption
Kidney – glucose reabsorption

8. Take into Consideration…
Is the problem:
Elevated fasting glucose?
Elevated post-prandial glucose?
< 7.3% % % %
> 10.2%
30% FPG
50%
FPG
55%
60%
70%
PPG
45%
40%
30%

9. Take into Consideration…
Safety
Propensity for causing hypoglycemia
Avoidance of hyperglycemia
Avoidance of glucose excursions
Cardiovascular considerations (+ & -)
Renal / hepatic function
Adverse reactions / side effects
Drug interactions
Warnings / precautions
Contraindications

10. Take into Consideration…
Impact on weight
Complexity vs. individual’s abilities / preferences
Cost / affordability
National Average Drug Acquisition Cost (NADAC)*
Average Wholesale Price (AWP)*
Patient preference
Efficacy
Can it deliver all that the individual needs?
Is dual, triple or more therapy needed to achieve the goals
*Costs adapted from ADA Clinical Guidelines, 2018

11. Drugs Affecting Glucose Levels
Increase Glucose Lowering of Insulin
Decrease Glucose Lowering of Insulin
Oral anti-diabetic products, pramlintide, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene, pentoxifylline, salicylates, somatostatin analogs, and sulfonamide antibiotics
Increase-Decrease
Beta-blockers, clonidine, lithium salts, and alcohol Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia
Corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), protease inhibitors and atypical antipsychotic medications (e.g. olanzapine and clozapine).

12. Glucose Targets: Adults from ADA, AACE/ACE, ACP 2018
Adults: ADA <7%
< 6.5% in select individuals
< 8% in select individuals
80 – 130 pre-prandial
< 180 peak post-prandial
Adults AACE < 6.5%; < 7% T2
> 6.5 current serious illness & risk for hypoglycemia
<100 TID pre-prandial
< 110 T2D pre-prandial
<140 post-prandial (both)
Adults ACP 7-8%
For most with type 2 DM
De-intensify meds if < 6.5%
Older Adults: ADA
< 7.5%
< 8% -8.5%
Hospitalized Individuals
140 – 180
110 – 140 in select individuals
Hospice / End-of-Life ADA
Stable: Little role for A1c
Organ Failure: Prevent hypoglycemia & dehydration
Dying:
Type 1: Perhaps small amount of basal insulin
Type 2: DC all diabetes meds

13. Glucose Targets: ADA Pregnant Women 6.0 – 6.5%
<6% in select individuals
<7% in select individuals
< 95 Fasting
<140 1 hr post- prandial
< hr post- prandial
Children
< 7.5%
< 7% in select individuals
90 – 130 pre-prandial
90 – 150 overnight

14. Oral Diabetes Medications

15. Biguanide Metformin (Glucophage), Riomet Liquid Glucophage XR, Glumetza, Fortamet
FDA Approval
Adults, Children age 10 and above, Pregnancy: B
Mechanism of Action / Target
Lower hepatic glucose output; possible increased glucose uptake in muscles; activates AMP-kinase
Target: Fasting Glucose
Efficacy
Lowers A1c 1.5%; may lower up to 2%
Weight
Neutral / slight loss
Hypoglycemia Risk
Neutral (low risk)
Cardiovascular Risk
Neutral; do not use with unstable/hospitalized persons with HF. UKPDS: decreased cardiac events
Renal / Genitourinary
Contraindicated if GFR <30; do not start if <45
Hepatic Risk
Possible impaired lactate clearance; avoid in hepatic disease
Gastrointestinal
Moderate

16. Biguanide Metformin,(Glucophage), Riomet Liquid Glucophage XR Glumetza, Fortamet
Bone / Fracture Risk
Neutral
Cancer Risk
Lower risk being studied for pancreas, colon, hepatocellular, breast, endometrial, prostate
Ketoacidosis
Lactic Acidosis
Rare
Other Adverse Reactions
GI side effects
Lowers B12 Levels
Drug Interactions
Carbonic anhydrase inhibitors (i.e., topiramate)
Warnings / Precautions
Caution with alcohol abuse; binge drinking; intravenous radiologic contrast agents
Use caution in patients >age 80 with CrCl < 60
Contraindications
eGRF <30; acidosis, hypoxia, dehydration, DKA, HHS
Complexity
Low
Cost
NADAC: $2 - $5 / possibly free AWP: $4-$109

17. Sulfonylureas Glimepiride (Amaryl), Glipizide (Glucotrol / Glucotrol XL),Glyburide (Diabeta, Glynase)
FDA Approval
Adults: Y Pediatric: Safety not established. Pregnancy: Only glyburide (use with caution)
Mechanism of Action
Stimulate sustained insulin secretion; Closes K+ channels on b-cell plasma membranes
Efficacy
Lowers A1c 1.5 – 2%
Other: Decreased microvascular risk (UKPDS)
Weight
Gain
Hypoglycemia Risk
Moderate / Severe
Cardiovascular Risk
Increased HF Risk; ? Increased cardiovascular mortality Note: Decreased microvascular risk
Renal / Genitourinary
Increased hypoglycemia risk with reduced renal function. Dose conservatively; advance cautiously
Hepatic Risk
Dose conservatively; advance cautiously. Disulfiram-like alcohol reactions possible
Gastrointestinal
Neutral

18. Sulfonylureas Glimepiride (Amaryl), Glipizide (Glucotrol / Glucotrol XL),Glyburide (Micronase, Glynase)
Bone / Fracture Risk
Neutral
Cancer Risk
No known increased risk
Ketoacidosis
Neutral; does not cause
Other Adverse Reactions
Dermatologic; hematologic, including hemolytic anemia; hyponatremia/SIADH with some agents
Drug Interactions
NSAIDs, ACE-I, disopyramide, fluoxetine, clarithromycinsome azoles, salicylates, sulfonamides, chloramphenicol, probencid, coumarins, MAO inhibitors, beta blocking agents; oral miconazole? Fluoroquinolones; Rifampin; thiazides, corticosteroids, phenothiazines, INH

19. Sulfonylureas Glimepiride (Amaryl), Glipizide (Glucotrol / Glucotrol XL),Glyburide (Micronase, Glynase)
Warnings / Precautions
Hypoglycemia
Contraindications
Type 1 DM, DKA
Glyburide (Beers List; avoid in older adults); Glyburide: Patients treated with bosentan, Patients taking gemfibrozil
Ketoacidosis Risk
Complexity
Low
Cost
NADAC: $4-$17/ possible free (glipizide)
AWP: $48- $198

20. Meglitinides Repaglinide (Prandin) Nateglinide (Starlix)
FDA Approval
Adults with Type 2. Not approved in children
Pregnancy: C
Mechanism of Action / Target
Stimulate rapid insulin release
Target: Post-prandial glucose
Efficacy
Lowers A1c1.0 – 2.0%
Weight
Gain
Hypoglycemia Risk
Mild
Cardiovascular Risk
Incidence of total serious CV events higher for repaglinide than SUs
Renal / Genitourinary
Increased hypoglycemia risk with reduced renal function (especially with nateglinide)
Hepatic Risk
Use caution with liver impairment
Gastrointestinal
Neutral

21. Meglitinides Repaglinide (Prandin) Nateglinide (Starlix)
Bone / Fracture Risk
Neutral
Cancer Risk
No effects observed
Ketoacidosis
Other Adverse Reactions
Nateglinide: Increased uric acid
Drug Interactions
CYP3A4 agents(ketoconazole, itraconazole, erythromycin). CYP2C8 agents (trimethoprim (gemfibrozil; montelukast) and others (refampin, barbituates, carbamezapine, clarithromycin. Highly protien-bound drugs (NSAIDS, salicylates, sulfonamides, cyclosporine, chloramphenicol, coumarins, probenecid, MAO inhibitors, beta blockers).

22. Meglitinides Repaglinide (Prandin) Nateglinide (Starlix)
Drug Interactions, cont.
Thiazides, steroids, phenothiazines, thyroid agents, estrogens, OCAs, phytoin, nicotinic acid, sympathomimetics, Ca channel blockers, isoniazid. Nateglinide: St. John’s Wort, somatostatin, CYP2C9 inhibitors (fluconazole, amiodarone, moconazole, oxandrolone)
Warnings / Precautions
Hypoglycemia: Use caution in hepatic/renal insufficiency; elderly, debilitated/malnourished persons
Contraindications
DKA; Type 1 DM, Repaglinide: Do not co-administer with gemfibrozil or use in combination with NPH insulin;
Ketoacidosis Risk
Complexity
Moderate; tid dosing
Cost
NADAC: $40 - $56 AWP: $122 - $673

23. Alphaglucosidase Inhibitors Acarbose (Precose) Miglitol (Glyset)
FDA Approval
Adults. Not studied in children
Pregnancy: B
Mechanism of Action / Target
Delay carbohydrate digestion/absorption
Post-prandial glucose
Efficacy
Lowers A1c 0.5 – 1.0%
Weight
Neutral
Hypoglycemia
Neutral; may occur if dual therapy, etc. utilized.
Treat hypoglycemia with glucose tabs or milk
Cardiovascular Risk
Renal / Genitourinary
Neutral; avoid or use cautiously in those with renal issues (i.e., CC < 25 mL/min)
Hepatic Risk
Acarbose: Use cautiously in those with liver issues. May elevate serum transaminase levels. Hepatitis and liver damage (including fatalities reported

24. Alphaglucosidase Inhibitors Acarbose (Precose) Miglitol (Glyset)
Gastrointestinal
Moderate (pain, diarrhea, flatulence)
Bone / Fracture Risk
Neutral
Cancer Risk
Acarbose: Increase in renal tumors and benign Leydig cell tumors Miglitol: No evidence
Ketoacidosis
Other Adverse Reactions
Can potentiate hypoglycemia with SUs, insulin.
Elevated serum transaminase levels. Rash
Pneumatosis Cystoides Intestinalis (rare)
Drug Interactions
Acarbose: Metformin, digoxin; may require dose adjustment
Intestinal adsorbents (charcoal); digestive enzymes

25. Alphaglucosidase Inhibitors Acarbose (Precose) Miglitol (Glyset)
Warnings / Precautions
Hypoglycemia must be treated with oral glucose/dextrose
Contraindications
DKA, cirrhosis, inflammatory bowel disease and other intestinal, digestive, absorptive conditions
Miglitol: Not recommended in significant renal dysfunction CrCl <25 Acarbose: Cirrhosis, SrCr <2
Ketoacidosis Risk
Complexity
Moderate; tid dosing
Cost
NADAC: $25 Acarbose AWP: $

26. Thiazolidinediones Pioglitazone (Actos); Rosiglitazone (Avandia)
FDA Approval
Adults. Children:
Pregnancy: C
Mechanism of Action
Increase insulin sensitivity; activates PPAR-y
Efficacy
Lowers A1c 1.0 – 1.5%
Weight
Gain
Hypoglycemia Risk
Neutral
Cardiovascular Risk
Heart failure: Moderate increase
Atherosclerotic cardiovascular disease: May reduce stroke risk. Pioglitazone: Decrease triglycerides; decrease CVD.
Rosiglitazone: Increase LDL-C
Renal / GU
Neutral; no renal adjustment needed
Hepatic Risk
Neutral; may have benefit in nonalcoholic steatohepatisis. Reports of hepatic failure/death postmarketing

27. Thiazolidinediones Pioglitazone (Actos) Rosiglitazone (Avandia)
Gastrointestinal
Neutral
Bone / Fracture Risk
Moderate non-vertebral fracture risk (females)
Cancer Risk
Pioglitazone may increase risk of bladder cancer in men; avoid in active bladder cancer
Ketoacidosis
Other Adverse Reactions
Possible macular edema
Drug Interactions
CYP2C8 inhibitors (gemfibrozil) increase concentrations; CYP2C8 inducers (rifampin) decrease concentrations
Warnings / Precautions
Black Box Warning: Heart Failure, Should not be used in symptomatic HF. Obtain liver tests prior to initiation. Fluid retention; edema.

28. Thiazolidinediones Pioglitazone (Actos) Rosiglitazone (Avandia)
Contraindications
Symptomatic heart failure; NYHA Class III or IV; Type 1 DM ; DKA. Pio: ALT > 3X reference with serum total bilirubin > 2X reference range Rosi:
Active liver disease; ALT >2.5 upper limit)
Complexity
Low
Cost
NADAC: $5 - $314/ possibly free (pioglitazone)
AWP: $283 - $387

29. Dipeptidyl Peptidase 4 Inhibitors (DPP4 Inhibitors) Sitagliptin (Januvia), Saxagliptin(Onglyza), Linagliptin (Tradjenta), Alogliptin (Nesina)
FDA Approval
Adults Y Children: not established
Pregnancy: No studies Lactation: N
Mechanism of Action
Prolong action of gut hormones; increases incretin concentrations; Slow gastric emptying
Increases glucose-dependent insulin secretion
Efficacy
Lowers A1c 0.7%
Weight
Neutral
Hypoglycemia Risk
Neutral; low risk
Cardiovascular Risk
Heart Failure: Possible risk for saxagliptin & alogliptin
Athersclerotic cardiovascular disease: Neutral
May exacerbate underlying myocardial dysfunction
Renal / Genitourinary
Dose adjustment necessary with the exception of linagliptin; Reduction in albuminuria
Sitagliptin: post marketing acute renal failure

30. Dipeptidyl Peptidase 4 Inhibitors (DPP4 Inhibitors) Sitagliptin (Januvia), Saxagliptin(Onglyza), Linagliptin (Tradjenta), Alogliptin (Nesina)
Hepatic
No dose adjustment with linagliptin
Alogliptin: reports of hepatic failure
Gastrointestinal
Neutral; acute pancreatitis reported
Bone / Fracture Risk
Neutral
Cancer Risk
?Increased liver adenoma/carcinoma
Ketoacidosis
Other Adverse Reactions
Rare; severe arthralgia; possible angioedema/urticarial/facial edema and other immune-related effects; serious hypersensitivity reactions ? acute pancreatitis; bullous pemphigoid

31. Dipeptidyl Peptidase 4 Inhibitors (DPP4 Inhibitors) Sitagliptin (Januvia), Saxagliptin(Onglyza), Linagliptin (Tradjenta), Alogliptin (Nesina)
Drug Interactions
Digoxin (no dosage adjustment recommended)
Onglyza: Dose adjustment with strong CYP3A4/5 Inhibitors (ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) Saxagliptin: Conivaptan, Fusidic acid, Idelalisib
Warnings / Precautions
Assess renal function prior to initiation
Observe for s/s of pancreatitis
Contraindications
Type 1; DKA. Not studied with history of pancreatitis
Complexity
Low
Cost
NADAC: $357 - $ AWP: $449 - $477

32. Sodium Glucose Cotransporter 2 Inhibitors (SGLT2 Inhibitors) Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance), Ertugliflozin (Steglatro)
FDA Approval
Adults. Pregnancy: C Not recommended in 2nd & 3rd trimesters
Mechanism of Action
Reduce glucose reabsorption in the kidney; inhibits SGLT-2 in the proximal nephron
Efficacy
Lowers A1c 0.5 – 1.0 %
Weight
Loss
Hypoglycemia
Neutral
Cardiovascular
Heart Failure: Possible benefit of empagliflozin
Atherosclerotic Cardiovascular Disease: Possible benefit of empagliflozin. Increased LDL-C. Hypotension; dizziness

33. Sodium Glucose Cotransporter 2 Inhibitors (SGLT2 Inhibitors) Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance), Ertugliflozin (Steglatro)
Renal / Genitourinary
Not indicated for eGFR <45 or <60 (Farxiga).
Genital mycotic/urinary infections; urosepsis / pyelonephritis). Canagliflozin: Incr. serum creatinine; decreased GFR during initial weeks. Possible benefit of empagliflozin
Hepatic
No dosage adjustment with mild/moderate impairment; not recommended with severe impairment (dapagliflozin: individual assessment with severe impairment)(empagliflozin may be used in hepatic impairment)
Gastrointestinal

34. Sodium Glucose Cotransporter 2 Inhibitors (SGLT2 Inhibitors) Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance), Ertugliflozin (Steglatro)
Bone / Fracture Risk
Canagliflozin warning; risk for amputation
Ertugliflozin: Consider risk of amputation prior to initiating
Cancer Risk
Dapagliflozin: imbalance in bladder cancer
Empagliflozin: No tumor increase
Euglycemia
Ketoacidosis
Rare, but serious. May occur in type 2 diabetes during stress
Other Adverse Reactions
Dehydration, potential hypotension; increased bone fractures (canagliflozin); hyperkalemia; UTIs/urosepsis; genital mycotic infections Canagliflozin: increased magnesium, phosphate, anaphylaxis, angioedema
Drug Interactions
Invokana: Rifampin; digoxin

35. Sodium Glucose Cotransporter 2 Inhibitors (SGLT2 Inhibitors) Canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance), Ertugliflozin (Steglatro)
Warnings / Precautions
Canagliflozin, Empagliflozin: Assess renal function before initiation. Consider reducing diuretic doses.
Do not use dapagliflozin with bladder cancer
Contraindications
Severe renal impairment, ESRD, dialysis
Canagliflozin, Empagliflozin eGFR < 45 ml/min
Dapagliflozin eGFR <60 ml/min
Complexity
Low
Cost
NADAC: $411 - $415 AWP: $512 - $517

36. Bile Acid Sequestrant Colesevelam (Welchol)
FDA Approval
Adults. Pregnancy: B
Children: Not studied in children < 10 or in girls who have not had a menstrual period
Mechanism of Action
Lowers cholesterol and glucose; mechanism unknown
Efficacy
Lowers A1c 0.5%
Weight
Neutral
Hypoglycemia Risk
Neutral/low risk
Cardiovascular Risk
Atherosclerotic Heart Disease: Benefit
Lowers LDL by 15-30%.
Renal / Genitourinary
Hepatic Risk
Pancreatitis; causes increase in triglycerides
Gastrointestinal
Mild – moderate side effects

37. Bile Acid Sequestrant Colesevelam (Welchol)
Bone / Fracture Risk
Neutral
Cancer Risk
?Increased pancreatic acinar cell adenoma; thyroid C-cell adenoma
Ketoacidosis
Other Adverse Reactions
Increased triglycerides/acute pancreatitis; vitamin deficiencies, constipation, fecal impaction dyspepsia, dysphagia nausea,
Drug Interactions
Cyclosporine, glimepiride, glipizide, glyburide, levothyroxine, certain birth control pills, olmesartan medoxomil, metformin extended release (ER), phenytoin (dose 4 hours prior to colesevelam). Has not been studied in combinatin with DPP4 Inhibitors

38. Bile Acid Sequestrant Colesevelam (Welchol)
Warnings / Precautions
Can decrease absorption of certain medications, vitamins A,D,E,K. Can elevated TSH (administer thyroid hormones 4 hours prior to colesevelam). May decrease INR in patients receiving warfarin. May decrease phenytoin levels.
Contraindications
Type 1 DM, DKA. Do not use with history of bowel issues: Obstruction or GI surgery, GI motility disorders, history of GI surgery, triglycerides >500
Complexity
Low
Cost
NADAC: $ AWP: $713

39. Dopamine Receptor Agonist Bromocriptine Mesylate Quick Release “QR”(Cycloset)
FDA Approval
Adults: Pediatrics: Not approved
Pregnancy: B
Mechanism of Action
Mechanism unknown; thought to reset circadian rhythm and decrease insulin resistance
Efficacy
Lowers A1c 0.6 – 0.9% Limited efficacy in combination with thiazolidinediones; efficacy not confirmed in combination with insulin
Weight
Neutral
Hypoglycemia Risk
Cardiovascular Risk
No increased risk for cardiovascular events or stroke; no unfavorable effect on hypertension; hypotension has been reported. No unfavorable effect on fasting lipids

40. Dopamine Receptor Agonist Bromocriptine Mesylate Quick Release “QR”(Cycloset)
Renal / Genitourinary
Neutral
Hepatic Risk
Gastrointestinal
Moderate; nausea
Bone / Fracture Risk
Cancer Risk
Unlikely any clinical significance
Ketoacidosis
Other Adverse Reactions
Headaches, fatigue, hypotension, syncope, somnolence, may exacerbate psychosis or reduce effectiveness of drugs, hallucinations, fibrotic complications. Neuroleptic malignant syndrome with abrupt dose reduction or withdrawal

41. Dopamine Receptor Agonist Bromocriptine Mesylate Quick Release “QR” (Cycloset)
Drug Interactions
Dopamine antagonists; dopamine receptor agonists. May increase the unbound fraction of highly protein-bound therapies; may increase ergot-related side effects/reduce effectiveness for migraines if administered within 6 hours. Avoid use with metoclopramide or sumatriptan; see package insert for more
Warnings / Precautions
Concomitant use with other dopamine receptor agonists not recommended. Use caution with strong inhibitors, inducers or substrates for CYP3A4
Contraindications
Type 1 DM; DKA; Type 2 requiring insulin therapy, syncopal migraines; lactation
Complexity
Low
Cost
NADAC: $ AWP: $784

42. Combination Oral Diabetes Medications
TZD + biguanide
Pioglitazone + metformin (ACTOplus Met)
Pioglitazone + metformin XR (ACTOplus Met XR)
Rosiglitazone + metformin (Avandamet)
TZD + sulfonylurea
Pioglitazone + glimepiride (Dietact)
Rosiglitazone + glimepiride (Avandryl)
Sulfonylurea + biguanide
Glyburide + metformin (Glucovance)
Glipizide + metformin (Metaglip)
SGLT-2 + DPP4- Inhibitor
Empagliflozin + linagliptin (Glyxmbi)
SGLT-2 + biguanide
Canagliflozin + metformin (Invokana)
Dapagliflozin + metformin (Xigduo)

43. Combination Oral Diabetes Medications
DPP4-Inhibitor + biguanide
sitagliptin + metformin (Janumet)
sitagliptin + metformin XR (Janumet XR)
linagliptin + metformin (Jentadueto)
alogliptin + metformin (Kazano)
saxagliptin + metformin XR (Kombiglyze)
DPP4-Inhibitor + TZD
alogliptin + pioglitazone (Oseni)
DPP4- Inhibitor + SGLT-2 Inhibitor
saxagliptin + dapagliflozin (Qtern)

44. Combination Oral Diabetes Medications
Meglitinide + biguanide
repaglinide + metformin (Prandimet)
SGLT-2 Inhibitor + DPP4- Inhibitor
ertugliflozin + sitagliptin (Stegujan)
SGLT-2 Inhibitor + biguanide
empagliflozin + metformin (Synjardy)
empalgiflozin + metformin XR (Synjardy XR)
ertugliflozin + metformin (Segluromet)
dapagliflozin + metformin (Xigduo XR)
DPP4 Inhibitor + Statin
Sitagliptin + Simvastatin (Juvisync)

45. Non-Insulin Injectable Medications and Insulin

46. GLP-1 Receptor Agonists Exenatide (Byetta), Exenatide ER (Bydureon B-Cise) Liraglutide (Victoza), Dulaglutide (Trulicity), Semaglutide (Ozempic), Lixisenatide (Adlyxin) [Albiglutide (Tanzeum) Discontinued 2018]
FDA Approval
Adults: Y Children: N Pregnancy: C May cause fetal harm Lactation: N
Mechanism of Action
Activate GLP-1 receptors; increase glucose release & decrease glucagon release (glucose dependent); slow gastric emptying; promote satiety. Target: Fasting and post-prandial glucose
Efficacy
Lowers A1c 0.8 – 2.0%
Weight
Loss of 1.6 – 6.0 kg Semalutide being studied for weight loss
Hypoglycemia
Rare; low risk with monotherapy

47. GLP-1 Receptor Agonists Exenatide (Byetta), Exenatide ER (Bydureon B-Cise) Liraglutide (Victoza), Dulaglutide (Trulicity), Semaglutide (Ozempic), Lixisenatide (Adlyxin) [Albiglutide (Tanzeum) Discontinued 2018]
Cardiovascular Risk
Reduces some CV risk factors/CV death, myo-cardial infarction, stroke (Victoza). Increased HR; possible prolongation of PRI
Renal / GU
May cause renal impairment; no dose adjustment
Hepatic Risk
Not expected (renal excretion); no dose adjustment
Gastrointestinal
Moderate: Nausea, vomiting, diarrhea, weight loss
Bone / Fracture
Cancer Risk
Thyroid C-cell hyperplasia/medullary tumor warning
Ketoacidosis
Other Adverse Reactions
? Acute pancreatitis; lipase, pancreatic amylase increase. Injection site reactions
Possible antibody development. Hypoglycemia when in combination with secretagogues/insulin

48. GLP-1 Receptor Agonists Exenatide (Byetta), Exenatide XR (Bydureon) Liraglutide (Victoza), Dulaglutide (Trulicity), Semaglutide (Ozempic), Lixisenatide (Adlyxin) [Albiglutide (Tanzeum) Discontinued 2018]
Drug Interactions
Warfarin (may increase INR) Delays gastric emptying; may affect absorption of oral medications
Warnings / Precautions
Black Box Warning: Thyroid C-cell tumor (exenatide XR, liraglutide, dulaglutide, semaglutide
Contraindications
Type 1 DM; DKA. Do not use in severe renal impairment/ESRD, intestinal diseases (i.e., gastroparesis) Personal/family history of medullary thyroid cancer, multiple endocrine neoplasia syndrome type 2
Complexity
High
Cost
NADAC: $500 - $ AWP: $626 - $968

49. Insulin-GLP-1 RA Combinations Xultophy (IDegLira), Soliqua (iGlarLixi)
Black Box Warning: Do not use with family history of medullary thyroid cancer or multiple endocrine neoplasia type 2; rise of thyroid C-cell tumors
Name
Combinations
Additional Information
Xultophy
(IDegLira)
Insulin degludec (IDeg or Tresiba Ultra Long Insulin) + Liraglutide (Victoza) GLP-1 RA
100 units IDeg/3.6 mg liraglutide per ml
iGlarLixi
(Soliqua)
Insulin glargine (Lantus) Long Acting Insulin +
Lixisenatide (Adlyxin) GLP-1 RA
100 units Lantus/33 mcg Lixisenatide per ml
Contraindications, precautions, side effects include
those of the individual components
Cost: NADAC: $404 AWP: $508 - $763

50. Amylin-mimetic Pramlintide (Symlin)
FDA Approval
Adults (Types 1 and 2 on insulin therapy). Pregnancy: C Children: N
Mechanism of Action
Slows gastric emptying; promotes satiety; suppresses glucagon Target: Post-prandial glucose
Efficacy
Lowers A1c 0.2 – 0.7%
Weight
Loss
Hypoglycemia Risk
Severe risk, especially in Type 1 DM. Reduce prandial insulin dose by 50% upon initiation of drug
Cardiovascular Risk
Renal / Genitourinary
No renal dosing required. Not studied in ESRD
Hepatic Risk
Not studied
Gastrointestinal
Moderate risk for nausea, vomiting; anorexia

51. Amylin-mimetic Pramlintide (Symlin)
Bone / Fracture Risk
Cancer Risk
None identified
Ketoacidosis
Other Adverse Reactions
Black Box Warning: Severe hypoglycemia risk 3 hours post-injection. Decrease insulin dose when initiating pramlintide.
Drug Interactions
Slows gastric motility; administer oral meds 1 hour prior or 2 hours after pramlintide. Drugs that may increase hypoglycemia when taken with pramlintide: Anti-diabetic products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, propoxyphene, salicylates, somatostatin analogs, and sulfonamide antibiotics.

52. Amylin-mimetic Pramlintide (Symlin)
Contraindications
A1c > 9%. Hypoglycemia unawareness; confirmed gastroparesis; poor medication compliance; use of drugs that stimulate gastric emptying
Complexity
High
Cost
Average Wholesale Price: $2,336

53. Insulin Injected & Inhaled
FDA Approval
Adults: Y Dependent upon the agent in children and pregnancy (Lantus: Pregnancy C; children: Age 6 and above with type1)
Mechanism of Action / Target
Activates insulin receptors; increases glucose disposal; decreases hepatic glucose; suppresses ketogenesis. Target: Basal = FPB Bolus = PPG
Efficacy
Lowers A1c as much as required
Weight
Edema; weight gain; Levemir < NPH; ? Levemir < Lantus; Toujeo < Lantus; Tresiba ?= Lantus
Hypoglycemia
Moderate-to-severe; risk increased with renal insufficiency, hypoglycemia unawareness. Less excursions and hypoglycemia with Toujeo & Tresiba
Cardiovascular Risk
Heart failure: Increased risk. Possibly contributes to hypertension, dyslipidemia; atherosclerotic cardiovascular disease being studied

54. Insulin Injected & Inhaled
Microvascular
Reduced microvascular risk
Renal /
Genitourinary
Increased risk for hypoglycemia with decreased renal function; may require insulin dose reduction
Hepatic
Increased hypoglycemia risk with decreased hepatic function; may require insulin dose reduction
Gastrointestinal
Neutral
Respiratory
Inhaled insulin: Pulmonary toxicity
Bone / Fracture Risk
Cancer Risk
No evidence of increased cancer risk
Ketoacidosis
Neutral; used to prevent/treat in type 1 diabetes

55. Insulin Injected & Inhaled
Other Adverse Reactions
Injection site reactions/infections; lipoatrophy; lipohypertrophy. Blurred vision with therapy initiation; immunologic (antibody formation); during treatment for DKA, may lead to low phosphate, magnesium, potassium
Drug Interactions
Signs of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine. Reduce dose when initiating pramlintide. See next slide
Warnings / Precautions
Use caution with concentrated insulins, adjusting doses, renal/hepatic insufficiency, etc.
Contraindications
Reduced lung function (inhaled insulin)
Complexity
Moderate-to-High
Cost
Varies from $143 - $341 (pens, newer meds more
*$25/vial at one chain pharmacy
Inhaled: AWP: $544 - $911

56. FDA Approved Meds - Pregnancy
Insulin
Rapid Acting
Aspart – B
Lispro –B
Apidra – B
Short Acting
NovoLIN R – B
HumuLIN R – B
Intermediate
NovoLIN N – B
Humulin N – B
Insulin
Long Acting
Detemir – B
Glargine – C
Ultra Long
Degludec – No rating; animal studies similar to Human NPH
Oral Meds
Metformin - B
Glyburide – B
DiaBeta - C

57. FDA Approved Meds - Pediatrics
Insulin
Rapid Acting
Apidra age 4/+
Lispro age 3/+
Aspart age 2/+
Short Acting
NovoLIN R age 2/+
HumuLIN R Yes / ?
Intermediate Acting
HumuLIN N
- not studied
NovoLIN N no information
Insulin
Long Acting
Glargine age 6/+
Detemir age 2/ +
Ultra Long Acting
Degludec age 1/+
Oral Meds
Metformin
Age 10 /+

58. Insulin Injected & Inhaled
Category
Type of Insulin
Bolus
Ultra-Rapid-Acting, Rapid-Acting and Short Acting Analogs
Bolus Inhaled
Rapid-Acting
Basal
Intermediate, Long-Acting and
Ultra-Long Acting
Basal + Bolus
(Premix)
Rapid-Acting + Intermediate,
Short-Acting +Intermediate,
Rapid-Acting + Ultra Long-Acting
Concentrated
U200 Rapid-Acting
U-500 Short-Acting
U-300 Long-Acting
U-200 Ultra Long-Acting

59. Insulin Action Profiles
Bolus
Insulin
Bolus
Insulin
Bolus
Insulin
Basal Insulin
Rapid
Ultra Rapid
Short
Intermediate
Long
Ultra Long

60. Insulin: Onset, Peak and Duration
Type
Insulin
Onset
Peak
Duration
Ultra Rapid
Analog
Aspart (Fiasp)
2.5 min
60 min
3-5 hr
Rapid
Analogs
Aspart (NovoLOG)
Lispro HumaLOG/Admelog)
Glulisine (Apidra)
5-15 min
30-90 min
<5 hrs
Short
(Regular) HumuLIN R, NovoLIN R,
Relion R
30 – 60 min
2-3 hrs
5-8 hrs
Inter-mediate
(NPH)
HumuLIN N, NovoLIN N
Relion N
2-4 hrs
4-10 hrs
10-16 hrs
Long
Detemir (Levemir)
Glargine (Lantus/Basaglar)
3-8 hrs
No peak
6-24 hrs
20-24 hrs
Ultra Long
Deglucec (Tresiba)
1 hour
<42 hrs

61. Insulin: Onset, Peak and Duration
Type
Insulin
Onset
Peak
Duration
Premix:
Intermediate + short
(NPH + Regular)
HumuLIN 70/30
NovoLIN 70/30
Relion 70/30
30-60 min
Dual
Peaks
10-16 hrs
Premix: Intermediate + rapid
(NPH + Rapid AnaLOG)
HumaLOG 75/25
NovoLOG 70/30
5-15
min
Dual Peaks
Premix;
Ultra Long
+ rapid
(Degludec + Aspart)
Ryzodeg Mix 70/30
5-15 min
24 hrs

62. Insulin: Onset, Peak and Duration
Concentrated Insulin
U200 (Bolus)
HumuLOG
U200 KwikPen
3 ml pen – 28 days
U300 (Basal)
Glargine (Lantus)
U300 SoloStar Pen
1.5 ml pen – 42 days
U300 (Ultra Long Basal)
Degludec (Tresiba)
U300 FlexTouch Pen
3 ml pen – 8 weeks
U500 (Bolus/Basal)
Regular
U500 KwikPen or Vial
20 ml vial – 40 days

63. Inhaled Insulin: Onset, Peak and Duration
Type
Insulin
Onset
Peak
Duration
Rapid Acting
Regular human insulin
(Afrezza)
15 min
1 hour
3 hours
Doses: 4, 8, 12 unit cartridges; take before meals
Assess lung function at baseline, 6 months, then yearly
May need dose reduction if combined to DPP4 or GLP-1 therapies
May require dose reduction in renal, hepatic impairment
Pregnancy: C Children: Not studied
Black Box Warning: Do not use in patients
With asthma, COPD or chronic lung disease
(see product insert for detailed information)

64. Additional Notes on Insulin
GLP-I RAs are not FDA approved for use with rapid acting insulins
U-200 (rapid acting)insulin may not be administered IV
Lantus not approved for use in pregnancy/children under age 6
Tresiba and Toujeo shown to have less hypoglycemia risk

65. What to prescribe? Major Area of Concern Drug(s) to Consider
Drug(s) to Avoid / Use with Caution
Avoidance of Hypoglycemia
Metformin, DPP4-Inhibitors, GLP-1 RAs
Sulfonylureas; Insulin; Amylin-mimetic (along with insulin)
Decreased Renal Function
Liraglutide, Empagliflozin, DPP4s (with dose adjustment, except for Linagliptin)
Metformin (GFR <30), Exenatide (CrCl <30)
SUs, Meglitinides, Insulin (incr. risk of hypos)
History of Pancreatitis, Bowel Obstruction
GLP-1 RAs, Bile Acid Sequestrant
Gastrointestinal
SGLT2s, DPP4s,TZDs, SUs, Meglitinides
Biguanide, GLP1-RAs, AGIs, Amylin-mimetic, Bile Acid Sequestrant, Dopamine Agonist
GU Infections
All others neutral
Avoid SGLT-2s

66. What to prescribe? Major Area of Concern Drug(s) to Consider
Drug(s) to Avoid / Use with Caution
Cardiac
HF: Empagliflozin, Liraglutide
ASCVD: GLP1-RAs, SGLT-2s, TZDs, Dopamine Agonist, Bile Acid Sequetrant
HF: TZDs, Saxagliptin, Alogliptin, SUs, Metinglinides, Insulin
ASCVD: SUs, Meglitinides
Cancer
DPP4-Inhibitors (thyroid)
Bone Fracture
All others neutral
Canagliflozin, TZDs
Weight
Biguanide, SGLT-2s, GLP-1 RAs, amylin-mimetic
TZDs, Sulfonylureas, Meglitinides, Insulin
Cost
Metformin, sulfonylureas
Human Insulin (N, R, LIN premix)
Insulin analogs, concentrated insulin
GLP-1 Ras, SGLT-2s,
Complexity / Adherence
Monotherapy dly/bid; basal insulin only; weekly GLP1 RAs
Insulin intensive regimens; insulin pump; GLP1 RAs (bid/dly); dual/triple/etc. therapy

67. Prescribing Insulin When
All persons with type 1 diabetes
Basal-bolus insulin with correction or insulin pump therapy almost always required
May need adjustments during times of infection, stress, changes in activity and/or intake
May need significant decrease during the “honeymoon period”
Individuals with type 2 diabetes, gestational diabetes
A1c > 10% >9% with symptoms (AACE/ACE)
Intolerance of oral medications and/or GLP-1 RAs

68. Insulin Regimen/Titration Type 1
ADA
AACE/ACE
Starting Basal Dose 0.4 or 0.5 – 1 units/kg/day
Titrate dose
Prandial (Nutritional)
Insulin : Carb Ratio
Correction
Insulin Sensitivity Factor
Being studied for application in Type 1
Metformin
GLP-1 Receptor Agonists
SGLT2-Inhibitors
Starting Basal Dose units/kg/day
Titrate dose
Prandial (Nutritional)
Insulin : Carb Ratio
Usually 1:5 to 1:20
Correction
Insulin Sensitivity Factor
1800/TDD = mg/dL glucose will lower per 1 unit of insulin
I:C Ratio Formula:
500/TDD

69. Insulin Regimen/Titration Type 2
ADA
AACE/ACE
Basal:
10 units/day or units/kg/day
Adjust 10-15% or 2-4 units once or twice weekly
If dose-related hypoglycemia occurs, reduce by 10-20% or by 4 units
Prandial (Nutritional)
4 units at largest meal or 0.1 units/kg 04 10% basal dose
Titrate up 1-2 units or % 1-2X weekly
Add additional meals if not at goal
Other options: Add GLP- 1 RA or move to premix bid or tid ac
Basal
A1c < – 0.2 units/kg/day
A1c > – 0.3 units/kg/day
Increase by 2 units every 2-3 days if not at target (or use adjustable regimen)
Decrease by 10-20% if <70
Decrease by 20 – 40% if <40
Prandial
May add GLP-1 RA, SGLT2, or DPP4 or add prandial insulin
5 units or 10% of basal; add additional meals if not at goal or 50% of TDD divided by 3 meals
Titrate every 2-3 days; increase by 10% or 1-2 units if 2 hr PP > 140

70. What to Prescribe: Inpatient
Oral Medications: ADA
Insulin / Injectables: ADA
Insulin is the preferred treatment for glycemic control
In some circumstances, it may be appropriate to continue home anti- hyperglycemic medications
If oral medications are held in the hospital, there should be a protocol for resuming them 1– 2 days before discharge
Non-critically ill: Basal plus bolus correction insulin, with the addition of nutritional insulin in patients who have good nutritional intake
Critically ill: Continuous insulin infusion
Sole use of sliding scale insulin in the inpatient hospital setting is strongly discouraged
Premixed insulin not generally recommended inpatient
Increased risk of hypoglycemia

71. Ending Thoughts… Individualize
Don’t over treat! Relax targets appropriately
Elderly, frail, those who live alone, hypoglycemia unawareness…
Anticipate and avoid hypoglycemia…and not just in those with diabetes!
Avoid inertia! Advance therapy when indicted
Pens much easier and safer for persons to use; prescribe whenever possible
Basal bolus is most physiologic and gives much better results in those with type 1 and many persons with type 2
If glucose isn’t responding to insulin, check their pen/syringe preparation and injection techniques
Don’t be afraid of insulin pump therapy; it changes lives
Remember to refer to Diabetes Self-Management Education Services

72. Thank You! Rose M. Flinchum Office: 219.326.1234 Ext. 7162
Cell:

73. References 14: 464. https://doi.org/10.1007/s11892-013-0464-y
American Association of Clinical Endocrinologists. (2018). Glycemic management in type 2 diabetes.
Retrieved from
American Association of Clinical Endocrinologist. (2018). AACE Diabetes Resource Center Treatment of
Type 1 Diabetes. Retrieved from
American Diabetes Association (2017). Statistics about diabetes. Retrieved from:
American Diabetes Association (2018). Standards of Medical Care in Diabetes Older adults.
Diabetes Care. 41 (Supplement1) S119 – S125. Retrieved from
American Diabetes Association (2018). Standards of Medical Care in Diabetes Children and adolescents. Diabetes Care. 41(Supplement 1): S126-S136. Retrieved from
American Diabetes Association (2018). Standards of Medical Care in Diabetes – Glycemic targets. 41(Supplement 1): S55-S64.

74. References
American Diabetes Association (2018). Standards of Medical Care in Diabetes Management of diabetes in pregnancy. Diabetes Care(Supplement 1): S137-S143. Retrieved from American Diabetes Association (2018). Standards of Medical Care in Diabetes – Pharmacologic approaches to glycemic treatment. Diabetes Care (Supplement 1): S73-S85. Retrieved from S008 Burke, S. (2017). Updates to managing diabetes in the long-term care setting. Medscape Education Diabetes and Endocrinology. Accessed at Bzowyckyj, A. , Cornell, S. (2016). Eleven things every clinician should know about the “egregious eleven.” iForumRx. Retrieved from Centers for Disease Control and Prevention (2017). National diabetes statistics report, Retrieved from:

75. References
Garber, A., Abrahamson, A., Barzilay, J., Blonde, L., Bloomgarden, Z., Bush, M.… and Umpierrez, G. (2018). Consensus statement by the American association of clinical endocrinologists and American college of endocrinology on the comprehensive type 2 diabetes management algorithm – 2018 executive summary. Endocrine Practice. Retrieved from Doi: /CS Indiana University Physicians. ( Adult diabetes practice guidelines pharmaceutical management algorithms, 8th edition. McCulloch, D., & Munshi, M. (2017). Treatment of type 2 diabetes mellitus in the older patient. Up-to-Date. Retrieved from older-patient.

76. References
Munshi, M., Florez, H. Huang, E., Kalyani, R. Mupanomunda, M., Pandya, N., …Haas, L. (2016). Diabetes in long term care and skilled nursing facilities: A position statement of the American Diabetes Association. Diabetes Care. 39 (2) Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA, et al. Hemoglobin A1c targets for glycemic control with pharmacologic therapy for nonpregnant adults with type 2 diabetes mellitus: A guidance statement update from the american college of physicians. Ann Intern Med. [Epub ahead of print 6 March 2018] doi: /M Swanson, C., Potter, D., Kongable, G., and Cook, C. Update on inpatient glycemic control in hospitals in the United States.(2017). Endocrine Practice. 17(6),

77. References
United States Department of Health and Human Services Administration, U.S. Food & Drug Administration. (2018) fda approved drug products. Accessed March 24, 2018
from