1. Pharmacology Autumn Steen, PharmD, BCACP, CDE, CPP
Clinical Pharmacist, Diabetes Educator
Mission Diabetes Center

2. Disclosure
Nothing to disclose

3. Objectives
State basic mechanisms of action for each diabetes medication class
Identify and mitigate major side effects of pharmacotherapy for patients with diabetes
Recognize appropriate and inappropriate diabetes pharmacotherapy based on patient comorbidities
Provide appropriate counseling points for patients on insulin in order to ensure safe and effective use

4. Image taken from: http://care. diabetesjournals

5. Class: Biguanide Brand: Glucophage Generic: metformin
Reduces insulin resistance at the liver and reduces liver’s response to glucagon
Net result: Reduces hepatic glucose production at inappropriate times and reduces fasting blood sugar
Lowers A1c by 1-2%
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6. Class: Biguanide Brand: Glucophage Generic: metformin
Extra Benefits
Improves cholesterol
Lowers BP
Improves non-alcoholic fatty liver disease
Improves PCOS
Can reduce risk of developing diabetes in prediabetes population
Can reduce risk of heart attack and stroke
Potential anti-cancer benefits (?)

7. Class: Biguanide Brand: Glucophage Generic: metformin
Common Side Effects
Diarrhea*
Nausea and vomiting*
Flatulence*
B12 deficiency
Anemia, neuropathy
Monitor and supplement if needed
*Happens less with XR formulation
Warnings and Precautions
Lactic Acidosis
Renal impairment
eGFR < 30 ml/min – don’t use
eGFR ml/min – half dose
Iodinated contrast: discontinue if eGFR ml/min

8. Class: Thiazolidinedione (TZD) Brand: Actos Generic: pioglitazone
Reduces insulin resistance at the liver, muscle, and fat cells by improving ability to store fat in subcutaneous depots instead of visceral areas (liver, muscle, pancreas, etc)
Net result: Improves fasting and post-prandial BGs
Lowers A1c by 1-1.5%
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9. Class: Thiazolidinedione (TZD) Brand: Actos Generic: pioglitazone
Extra Benefits
Improves cholesterol
Lowers BP
Improves non-alcoholic fatty liver disease
Improves PCOS
Strong evidence to reduce prediabetes progression to diabetes
Reduces risk of heart attack, stroke, and death
Preserves beta cell function

10. Class: Thiazolidinedione (TZD) Brand: Actos Generic: pioglitazone
Common Side Effects
Weight gain*
Fluid retention
Bone fractures (women)
Pseudoanemia
*Less likely with diabetes medications that cause weight loss (GLP-1 RAs, SGLT2-is)
Warnings and Precautions
Heart failure
Osteoporosis
Bladder cancer
Macular edema

11. Class: Sulfonylureas Generics: glimepiride, glipizide, glyburide
Stimulates insulin secretion from the pancreas in a glucose-independent manner
Net result: reduces blood glucose in 2-3 hours (glipizide XL in 6-12 hours)
Lowers A1c by 1-2%
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12. Class: Sulfonylureas Generics: glimepiride, glipizide, glyburide
Extra Benefits
Cheap
Works quickly
Established therapy – no new side effects to be discovered

13. Class: Sulfonylureas Generics: glimepiride, glipizide, glyburide
Common Side Effects
Hypoglycemia
Weight gain
Sun sensitivity
Warnings and Precautions
Potentially increased CVD risk
Sulfa allergy
Chronic kidney disease (glipizide is preferred)

14. Class: DPP-IV Inhibitors Brands: Januvia, Onglyza, Tradjenta, Nesina Generics: sitagliptin, saxagliptin, linagliptin, alogliptin
Increases endogenous levels of GLP-1 and GIP (incretin hormones) which stimulates the pancreas to release insulin in response to food
Net result: reduces post prandial blood glucose
Lowers A1c by %
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15. Class: DPP-IV Inhibitors Brands: Januvia, Onglyza, Tradjenta, Nesina Generics: sitagliptin, saxagliptin, linagliptin, alogliptin
Extra Benefits
Weight neutral (sometimes loss)
No hypoglycemia
Few side effects
Safe in the elderly population
Weak evidence of preserving beta cell function

16. Class: DPP-IV Inhibitors Brands: Januvia, Onglyza, Tradjenta, Nesina Generics: sitagliptin, saxagliptin, linagliptin, alogliptin
Common Side Effects
Nasopharyngitis
Arthralgia
Headache
Warnings and Precautions
Bullous pemphigoid
Hypersensitivity
Chronic Kidney Disease
Except for Tradjenta (linagliptin)
Pancreatitis (?)
Bullous pemphigoid – report blisters or erosions, immunosuppressive therapy and referral to dermatology

17. Class: GLP-1 Receptor Agonists Brands: Byetta, Bydureon, Victoza, Trulicity, Adylxin, Ozempic Generics: exenatide, exenatide ER, liraglutide, dulaglutide, lixisenatide, semaglutide
Stimulates receptor for GLP-1, resulting in supraphysiologic downstream effects including: delayed gastric emptying, insulin secretion in response to food, decreased glucagon, increased satiety
Net result: decreased fasting and post prandial blood glucose levels
Lowers A1c by 1-1.5%
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18. Extra Benefits Weight loss Lowers BP Improves cholesterol
Class: GLP-1 Receptor Agonists Brands: Byetta, Bydureon, Victoza, Trulicity, Adylxin, Ozempic Generics: exenatide, exenatide ER, liraglutide, dulaglutide, lixisenatide, semaglutide
Extra Benefits
Weight loss
Lowers BP
Improves cholesterol
Strong evidence to prevent progression from prediabetes to type 2 diabetes
Reduces CVD risk
Reduces progression of diabetic kidney disease
Preserves beta cell function

19. Warnings and Precautions
Class: GLP-1 Receptor Agonists Brands: Byetta, Bydureon, Victoza, Trulicity, Adylxin, Ozempic Generics: exenatide, exenatide ER, liraglutide, dulaglutide, lixisenatide, semaglutide
Common Side Effects
Nausea
Diarrhea
Constipation
Vomiting
Headache
Increased heart rate
Warnings and Precautions
Chronic Kidney Disease
Gastroparesis
Pancreatitis (?)
Thyroid tumors (?)
Only seen in rats

20. Class: SGLT2 Inhibitors Brand: Invokana, Farxiga, Jardiance, Steglatro Generic: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
Inhibits sodium-glucose linked transporter 2 in the renal tubule, which reduces glucose reabsorption and increases glucose excretion into the urine
Net result: lowers fasting and post prandial blood glucose and glucose appears in the urine when BG > 100
Reduces A1c by 0.8-1%
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21. Class: SGLT2 Inhibitors Brand: Invokana, Farxiga, Jardiance, Steglatro Generic: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
Extra Benefits
Weight loss
Reduced BP
Reduces CVD risk
Reduces progression of diabetic kidney disease

22. Class: SGLT2 Inhibitors Brand: Invokana, Farxiga, Jardiance, Steglatro Generic: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
Common Side Effects
Genitourinary infections
Increased urine output and thirst
Dizziness
Hypotension
Warnings and Precautions
Increased serum K+
Chronic kidney disease
Osteoporosis
Increased risk of amputations
Fall risk

23. Image taken from: http://care. diabetesjournals

24. First Do No Harm – Patient Case
John Doe, 60 year old male, type 2 diabetes x 5 years, BMI 35 kg/m2
PMH: MI x 2, congestive heart failure, chronic kidney disease, hypertension, dyslipidemia
Labs: A1c 8.3%, SCr 1.8 mg/dl (eGFR 42 ml/min), total cholesterol 200, LDL 80, TG 180, HDL 35 (all else WNL)
Medications: atorvastatin, metoprolol, lisinopril, metformin 500 mg twice daily

25. First Do No Harm – Patient Case
His A1c goal is <7.5%. What would be the safest addition to his med profile?
Actos (pioglitazone) – a TZD
Invokana (canagliflozin) – a SGLT2 inhibitor
Victoza (liraglutide) – a GLP-1 receptor agonist
Glimepiride – a sulfonylurea
Tradjenta (linagliptin) – a DPP-IV inhibitor

26. Insulin

27. Basal and Bolus Definitions
Longer acting insulin formulations designed to keep blood glucose stable overnight and between meals
Bolus
Shorter acting insulin formulations designed to correct high blood glucose back to target and/or to prevent post prandial hyperglycemia

28. Activity Time of Insulins
Type of Insulin
Onset
Max Effect
When to Take It
Rapid Acting
Apidra® (Clear)
10 – 15 min
30-90 min
15 minutes before a meal
Humalog® (Clear)
min
60-90 min
Novolog® (Clear)
min
Fiasp® (Clear)
12-18 min
min
15 minutes before a meal, or up to 20 minutes after eating
Short Acting
(R) Regular (Clear)
30-60 min
2-3 hrs
30 minutes before a meal
Intermediate Acting
(N) NPH (Cloudy)
2-4 hrs
6-10 hrs
Once or twice daily. Ask healthcare provider.
Long Acting
Lantus® (Clear)
3-4 hrs
Usually once daily at bedtime. Ask healthcare provider.
Levemir® (Clear)
0.8 – 2 hrs
Toujeo® U-300 (Clear)
6 hours
Once daily. Ask healthcare provider.
Tresiba® U-100 and U-200 (Clear)
1 hour

29. Example Insulin Regimen
Basal: Lantus 40 units at bedtime Bolus: Novolog 10 units before each meal + sliding scale
Blood Glucose Level
Units of Novolog
Less than 150 2 4 6* 8*
>350
10*
*Call healthcare provider

30. Counseling Points
Do not take Novolog within 2 hours of previous dose to avoid insulin stacking and delayed hypoglycemia
Keep basal and bolus insulin separate or clearly labeled to avoid mixing them up
After opening the insulin pen or vial, may keep at room temperature for ~30 days (depends on the insulin)
Each blood glucose check is an opportunity to correct if you are on sliding scale insulin
Gently roll NPH (cloudy insulin) between hands before injecting. Never shake insulin.
Monitor for signs and symptoms of hypoglycemia and treat according to 15:15 rule
Always check blood sugar before going to bed, activity, or driving then treat as instructed
If taking NPH at night (either at supper or bedtime) check BG 4-6 hours later occasionally for a safety check
If you miss a dose of rapid or short-acting insulin and it’s been >15 mins since you ate, skip the meal dose, use sliding scale if BG is high

31. Prevention of Hypoglycemia with Exercise
Check BG before activity. If BG <100 mg/dl and exercising >30 minutes, eat small snack (~15-30g CHO)
Evidence that a 10-second sprint before or after a minute moderate intensity exercise can protect against exercise-induced hypoglycemia in type 1 diabetes (
45 minutes of resistance exercise before 45 minutes of aerobic exercise can reduce risk of hypoglycemia during aerobic activity (
Try not to exercise while insulin is at peak effect (1-2 hours rapid, 2-4 hours short, 4-6 hours NPH). If exercising after rapid acting insulin, either reduce dose or eat a snack
If exercising >60 minutes, will likely need dose reductions and snacks before and during activity. If strenuous will need to watch out for delayed hypoglycemia (6-12 hours later)

32. Recognize the Signs – Patient Case
Jane Doe has type 2 diabetes, current A1c is 6.7% and is on Lantus 60 units QHS, metformin 1,000 mg BID, and glimepiride 4 mg once daily
She recently started incorporating exercise into her weekly routine, doing seated exercises for 30 minutes 4 days per week with your help
Despite exercising more, she is noticing she is gaining weight. She reports snacking more often, and even gets up in the middle of the night feeling hungry. She often eats a lot at this time and says, “I could eat the whole refrigerator”
She checks her BG once daily in the morning, and it’s usually 80s-100s

33. Recognize the Signs – Patient Case
What would be your advice to help Jane lose weight?
Increase exercises to 5 days per week and take sleep aid
Discuss reducing doses of glimepiride and/or Lantus with provider
Eat a high protein snack before bed and take sleep aid
Reduce total calories in diet and slowly increase time of activity

34. Treatment of Severe Hypoglycemia
If a patient can’t drink or eat safely:
Call 911
Look for Glucagon Emergency Kit in patient’s bag
Follow mixing instructions found on inside panel
Cleanse site on buttock, arm, or thigh and inject
Turn patient on his/her side to prevent choking
If no response within 15 minutes, repeat
Once awake, give juice/soda then snack
Download the app:

35. Summary There are seven main classes of diabetes medications
Biguanide, sulfonylurea, TZD, DPP-IVi, GLP-1 RA, SGLT2i, insulin
Each work in a unique way and offer unique benefits as well as risks
Metformin is started first, and then additional therapy is chosen based on patient characteristics, preferences, and comorbidities
Sulfonylureas and insulin cause hypoglycemia
Patients should know the 15:15 rule of treatment, check blood glucose regularly, and be able to recognize the signs and symptoms before it’s too late
Everyone on basal-bolus therapy or hypoglycemia unawareness should have a glucagon emergency kit

36. Questions?
(828)

37. References
Diabetes Care 2018 Jan; 41(Supplement 1): S1-S159. Available at
Endocr Pract. 2018, doi: /CS
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