Diabetes Mellitus Oral Agents

Question 1

Definition of DM

Answer 1

• abnormal carbohydrate metabolism → hyperglycemia
  
  • due to relative or absolute impairment of insulin secretion
  • due to peripheral resistance to the action of insulin

Question 2

What does the Pancreas Produce

Answer 2

• insulin
• amylin
• glucagon

Question 3

Insulin resistance associated with CV risks such as?

Answer 3

• abd obestiy
• HTN
• dyslipidemia
• hypercoag
• hyperinsulinemia

Question 4

What cells are located in the Islet of Langerhans?

Answer 4

• Alpha Cells
  
  • release glucagon
    
    • increases blood glucose
• Beta Cells
  
  • release insulin and amylin
    
    • decreases blood glucose

Question 5

Fasting stage: insulin levels

Answer 5

43-186pMol/L

Question 6

Type II DM definition

Answer 6

• 90% of patients
• partial loss of insulin secretion
  
  • variable degree of deficiency
• peripheral insulin resistance
  
  • mostly in skeletal muscles & liver
    
    • not responsive to glucose uptake
    • can’t stop hepatic glucose production
• Present years before dx
• often asymptomatic
• hyperglycemia

Question 7

Type I DM

Answer 7

• 5-10% of pts
• absolute loss of insulin
  
  • due to autoimmune beta cell destruction
  • at time of diagnosis = 80-95% have been destroyed
  • Complete insulin dependency
• Honeymoon period:
  
  • Days to weeks after diagnosis experience remission
  • Lasts weeks – months
  • May need very low insulin supplementation
• DKA = initial presentation in 25% of adults
• genetic link: HLA-DR and HLA-DQ

Question 8

Vicious cycle of Type II DM

Answer 8

Question 9

Renal Glucose Threshold

Answer 9

180 mg/dL

Question 10

Diagnosis of Diabetes Mellitus WHO & ADA guidelines

Answer 10

Question 11

Medications that Affect Blood Glucose

Answer 11

Question 12

When to Screen for Type II DM: ADA guidelines

Answer 12

• adults without risk factors:
  
  • start at age 45
  • repeat q 3 yrs
  • more frequent if BMI ≥ 25 plus ≥ 1 risk factor
  • Fasting plasma glucose and A1C preferred over OGTT
• Children. at 10yo or onset of puberty with:
  
  • BMI > 85th percentile for age and sex
  • Wt for height > 85th percentile
  • wt > 120% of ideal height
  • plus ≥ risk factors
  • Screen Q 2yrs

Question 13

Glycemic Goals for DM patients: ADA

Answer 13

• A1C < 7% (normal 4-6%)
• preprandial plasma gluc: 70-130 mg/dL
• Postprandial plasma gluc: < 180mg/dL
• BP < 130/80

Question 14

Non-Pharm Tx of DM

Answer 14

• Diet:
  
  • counting carbs
  • reducing trans fat; cholesterol intake < 200mg/day
  • protein – 15-20% of daily caloric intake (animal and vegetables)
  • sodium: + CHF <2g/day
  • alcohol: NTE 2 drink/day; 1 drink = 12 oz of beer, 5oz wine, 1.5 oz of distilled alcohol
• Exercise:
  
  • starting goal = 150 min/week

Question 15

Categories for Oral Antihyperglycemics for DM II & A1C reduction %

Answer 15

• Biguanides: 1.5-2%
• Sulfonylureas: 1-1.5%
• Thiazolidinediones (TZD): 1-1.5%
• Non-sulfonylurea Secretagogues: 0.8-1%
  
  • (“Glinides” or Meglitinides)
• SGLT2 inhibitor: 0.8-1%
• Dipeptidyl Peptidase-4 (DPP-4) Inhibitors: 0.7-1%
• Alpha-Glucosidase Inhibitors 0.3-1%
• Bile Acid Sequestrant: 0.4% with metformin
• Dopamine Receptor agonists: 0.1-0.4%

Question 16

Sulfonylureas MOA

Answer 16

Block the ATP-sensitive K channels on beta cells → insulin secretion

• first class of PO antihyperglycemic agents approved in US
• Cross sensitivity with sulfa allergy
• all require renal adjustment, except tolbutamide
• hepatic metabolism - 2C9
• can’t stimulate insulin secretion at extremely high glucose levels (i.e. glucose toxicity)

Question 17

Sulfonylureas 1st generation

Answer 17

• Meds:
  
  • Chlorpropamide (Diabinese)
    
    • Avoid in Renal dysfunction or elderly
  • Tolazamide (Tolinase)
  • Tolbutamide (Orinase)
• SEs:
  
  • Hypoglycemia
  • weight gain
  • reduce efficacy over time
  • lower A1c by 1-1.5%
  • Not preferred by ADA or AACE

Question 18

Sulfonylureas 2nd Generation

Answer 18

• Meds:
  
  • Glyburide
    
    • more hypoglycemia
      
      • not recommended by ADA
  • Glipizide
    
    • less weight gain than glyburide
  • Glimepiride
    
    • less weight gain than glyburide
• SEs:
  
  • weight gain
  • hypoglycemia
  • 2^nd line tx (ADA) after metformin
  • add on therapy
  • inexpensive
  • start low & slow in elderly

Question 19

Non-Sulfonylurea Secretagogues (Glinides): Overview

Answer 19

• block ATP-sensitive K channels
• produce same effect as sulfonylureas,
  
  • but shorter onset & duration
• bind to receptor adjacent to the sulfonylureas receptor
• cannot be used together with sulfonylureas
• Advantage:
  
  • reduce post-meal gluc level
• **Lowers A1C 0.8-1%**
• take 15-30min before meal

Question 20

Non-Sulfonylurea Secretagogues (Glinides): Meds

Answer 20

• Lowers A1C by 0.8-1%
• Meds:
  
  • Meglitinide
  • Nateglinide (Starlix)
  • Repaglinide (Prandin) + Metformin (PrandiMet)
    
    • more effective for lowering A1C than Starlix
• SEs:
  
  • weight neutral
  • hypoglycemia
  • 2nd line according to ADA
    
    • 1st line if metformin contraindicated
• can use instead of sulfonylureas
• used in combo with others

Question 21

Biguanide

Answer 21

Metformin

lowers A1C by 1.5-2% and FBG by 60-80mg/dL

• MOA:
  
  • unclear
  • decreases hepatic glucose production & increases insulin sensitivity → liver, fat, & muscles
  • does not affect insulin release
• used as monotherapy
• reduced LDL by 18.7%; TG by 12%
  
  • increased HDL by 1.2%
• SEs:
  
  • GI: N/Diarrhea (=most common)
    
    • decreased appetite
  • Lactic Acidosis → rare
  • inhibits mitochondrial oxidation of lactic acid
  • Renal impairment elderly :
    
    • CrCl ≤ 30ml/min
    • hypoxemia, sepsis, dehydration
  • interferes with B12 absorption
    
    • monitor B12 levels
• Considerations:
  
  • withhold tx when pt undergoes surgery or radiocontrast dye
  • renal fxn: assess within 48 hours after procedure → normal → restart
  • avoid in liver disease:
    
    • Check LFTs

Question 22

Alpha-Glucosidase Inhibitors MOA & Meds

Answer 22

lowers A1C by 0.3-1%

• MOA: delay absorption of carbohydrates (by inhibiting alpha-glucoside at the brush border of the small intestine)
  
  • →reduce post-prandial BG
  • act as osmotic to draw water into GI lumen
  • pt can skip dose if they skip a meal/do not eat carbs
• Meds:
  
  • Acarbose (Precose)
    
    • not as effective as Miglitol
    • 3rd line – ADA
  • Miglitol (Glyset)
  • **GIVEN WITH MEALS** (BOTH)
• SEs:
  
  • GI:
    
    • flatulence, abd discomfort, diarrhea
• contraindicated:
  
  • short bowel syndrome
  • irritable bowel syndrome
  • SCr >2mg/dL
• Wt neutral
• take with Meals

Question 23

Dosage of Metformin

Answer 23

• 500mg PO BID or 850mg Qday
• Max: 2550 mg/day (Glucophage)
• Max: 2000mg/day (Glucophage XR)

Question 24

Thiazolidinediones: MOA, Considerations, SEs

Answer 24

lowers A1C by 1-1.5%; reduce FPG by 60-70mg/dL

aka TZDs or “glitazones”

• MOA:
  
  • stimulate peroxisome proliferator-activated receptor gamma (PPAR-gamma) → nuclear receptor
    
    • increase sensitivity to insulin
    • decrease plasma fatty acid levels
• Onset: delayed → takes several weeks, up to 12 weeks for max effects
• SEs:
  
  • fluid retention
    
    • increased when combined with insulin tx
    • contraindicated in HF
  • hepatotoxicity – reversible within weeks after d/c
    
    • check LFTs at baseline & PRN
    • if baseline ALT 2.5x UNL → do not start
    • if ALT 3x UNL after taking TZD → d/c
  • Promotes ovulation → unwanted pregnancy
  • increased incidence of upper & lower limb fracture
  • increases risk of bladder cancer after 1 yr → dose related
    
    • contraindicated with h/o bladder cancer
  • Weight gain
  • low risk of hypoglycemia

Question 25

Thiazolidinediones: Meds

Answer 25

lowers A1C by 1-1.5%

• Meds:
  
  • Pioglitazone (Actos)
    
    • • metformin
    • • glimepiride
    • +alogliptin
  • Rosiglitazone (avandia)
    
    • • metformin
    • +glimepiride
      
      • greater risk of MI
• 2nd line according to ADA
• SEs:
  
  • Fluid retention
  • increased ovulation
  • long bone fractures
  • hepatotoxicity
  • bladder cancer

Question 26

Functions of GIP & GLP-1

Answer 26

• GLP-1:
  
  • increase insulin
  • decrease glucagon
  • decrease Beta cell apoptosis
  • increase beta cell proliferation
• GIP:
  
  • increase insulin
  • increase glucagon
  • decrease beta cell apoptosis
  • increase beta cell proliferation
• DDP-4 enzyme breaks down GLP-1 and GIP

Question 27

DPP-4 Inhibitors (dipeptidyl peptidase-4 inhibitors): MOA, SEs, general info

Answer 27

lowers A1C by 0.7-1%

• MOA:
  
  • inhibit DDP-4 therefore less GIP & GLP-1 is broken down and more is available
• General Info:
  
  • less hypoglycemia
  • weight neutral
  • 2nd line tx
• SEs:
  
  • HA
  • nasopharyngitis
  • pancreatitis??

Question 28

DPP-4 Inhibitors: Meds

Answer 28

-gliptins

lowers A1C by 0.7-1%

• Sitagliptin: case report of acute pancreatitis, including hemorrhagic and necrotizing
  
  • CrCl <50 mL/min → max dose: 50mg/d
  • CrCl <30 mL/min → max dose: 25mg/d
• Saxagliptin:
  
  • CrCl <50 mL/min
  • Strong 3A4 inhibitor
• Linagliptin
  
  • substrate of 3A4
  • no adjustment needed for renal/hepatic impairment
• Alogliptin
  
  • CrCl 30-59: 12.5 mg/day
  • CrCl <30: 6.25mg/day

Question 29

Dopamine Receptor Agonist and DM

Answer 29

lowers A1C by 01-0.4%

• Bromocriptine (Cycloset)
  
  • unknown MOA
  • AM admin improves insulin sensitivity
  • 3rd line tx
• SEs:
  
  • rhinitis/sinusitis
  • HA/dizziness
  • syncope
  • nausea
  • hypotension
• Contraindications
  
  • Lactation
  • Syncopal migraine

Question 30

Bile Acid Sequestrant and DM

Answer 30

lowers A1C by 0.4% when used with metformin

• Colesevelam (Welchol)
  
  • binds to bile acid in GI lumen
  • unclear MOA for lowering glucose
  • lowers LDL by up to 20%
• SEs:
  
  • nausea/bloating/constipation
  • increased TGs
  • dyspepsia
• DDI:
  
  • prevents absorption of:
    
    • levothyroxine, OC, phenytoin
    • warfarin, digoxin
    • **separate by 4 hours**
• Malabsorption of fat-soluble vitamins: A, D, E, K

Question 31

SGLT2 Inhibitor (Sodium-Glucose Co-transporter 2): MOA, general info, SEs

Answer 31

• MOA:
  
  • reduce reabsorption of filtered glucose
• benefits:
  
  • weight loss
  • BP reduction (slight)
  • less hypoglycemia
• general info:
  
  • may increase LDL
  • expensive
  • only added onto metformin
• SEs:
  
  • renal dysfunction do not use
  • fungal infx of genitals
  • UTI
  • increased urination
  • hypotension

Question 32

SGLT2 Inhibitor: Meds

Answer 32

• “if you use SGLT2 inhibitors you may sucCEED in losing weight”
• Canagliflozin (Invokana)
  
  • • Metformin (invokamet)
  • Do Not Use if CrCl <45 mL/min
  • may increase risk of stroke
• Dapagliflozin (Farxiga)
  
  • +Metformin (Xigduo XR)
  • Do Not Use if CrCl <60 mL/min
  • contraindicated with h/o bladder cancer
  • may increase risk of bladder cancer
• Empagliflozin (Jardiance)
  
  • +Linagliptin (Glyxambi)
  • +Metformin (Synjardy)
  • Do Not Use if CrCl <45 mL/min
• Ertugliflozin (Steglatro)
  
  • +sitagliptin (Steglujan)
  • +metformin (Segluromet)
  • Do Not Use if CrCl <30 mL/min

Question 33

Glycemic Goals of Tx in DM

Answer 33

• Non-Pregnant:
  
  • A1C <7%
    
    • Preprandial BG: 80-130 mg/dL
    • Postprandial BG <180 mg/dL
  • May target A1C <6.5%:
    
    • DM2 tx with lifestyle mods or metformin only
    • long life expectancy
    • no significant CV disease
    • pregnancy (<6% = optimal without hypoglycemia)
  • May target A1C < 8%
    
    • H/o severe hypoglycemia
    • Limited life expectancy
    • Advanced micro or macrovascular
    • Complications extensive comorbidities
    • Long standing DM—difficult to achieve
    • Has been on appropriate doses on multiple agents and monitoring

Question 34

Summary of Glucose Lowering Interventions (Chart)

Answer 34