Dr. Rabadaba: Part 2=T2DM

Question 1

T2DM

Answer 1

Life stycle changes is more effective than metformin for treatment of T2DM

Question 2

Metformin MOA

Answer 2

• Binds to Oct1 receptor on Hepatocyte membrane
• Mitochondria
  
  • inhibits complex 1 of ETC
  • causes increase in ADP and AMP/ATP ratio
    
    • Decrease ATP
    • increase ADP
• AMP activates AMPK
• AMPK:
  
  • inhibits gluconeogenesis
  • increases Lactate
    
    • decrease pyruvate
• Overal: Decrease hepatic Glucoxse production

Question 3

Metformin

Answer 3

• first line agent to prevent T2DM in:
  
  • prediabetes: A1C
  • w/T2DM-monotherapy if
    
    • A1c: 6.5-7.5
    • within 1.5% of established goal
  • Dual therapy:
    
    • A1C- 7.5-8.9 or goal is not attained within 3-6 months
  • Triple therapy
    
    • Asymptomatic patients w/A1c>8.9%
• Reduces insulin requirement but not A1c in T1DM

Question 4

Metformin: Contraindications

Answer 4

• Severe kidney disease
  
  • stage: 4-5
  • creatinine>1.7
  • eGFR<30
• Liver Diseases
  
  • due to accumulation of lactate in the liver
• Chronic Alcohol Consumption
  
  • women: 2 drinks a day
  • men: 4 drinks a day
• >80 y.o.
• Anemia-used with caution
• BUT 70% have at least 1 contraindication but lactic acidosis only ocurs in 6 per 100,000

Question 5

Metformin Advantages vs Disadvantages

Answer 5

• Advantages:
  
  • Reduces HbA1c by: 1-2%
  • rarely causes hypoglycemia
  • weight neutral (-2+ or +1%)
  • reduces major cardiac events including hospitalization for:
    
    • _​_acute Myocardial infarction (AMI)
    • ischemic stroke
    • hemorrhagic stroke
    • transient ischmic attack (TIA)
    • cardiovascular death
• Disadvantages:
  
  • causes GI discomforts
    
    • diarrhea, nausea, flatulence
    • decreaes overtime
    • reduced if taken with food
    • reduced risk with Metformin ER
  • Decreased vitamin B12 by 10-30%
  • Lactic acidosis
  • Accelerate kidney disease
    
    • 2x risk for dialysis

Question 6

SGLT2 inhibitors

Answer 6

• Sodium/glucose cotransporters inhibitors
• Early Proximal tubule
  
  • causes blood glucose to be elminated in urine
• Drugs: -Gliflozin
• Dual therapy:
  
  • Canagliflozin + Metformin or Metformin XR
  • Ertugliflozin + Metformin
• Triple Therapy:
  
  • Empagliflozin, linagliptin, metformin

Question 7

SGLT2 inhibitors: Advantages vs Disadvantages

Answer 7

• Advantages:
  
  • Reduce A1c by an extra 0.5-1.5%
  • Do not cause hypoglycemia
  • weight loss
  • Reduces MACE
    
    • canagliflozin only one FDA approved
  • Decrease CV death
    
    • Empagliflozine (decrease 35%)> Canagliflozine (decrease18%)
  • Slows the progression of CKD and HF
    
    • Empagliflozin and Canagliflozine> Dapagliflozin
• Disadvantages:
  
  • Volume depletion
    
    • caution in eldery and pts on thiazides or loop diuretcis
    • patient sit upright for 2m in before standing to avoid orthostatic hypotension
  • FDA warning:
    
    • Risk of euglycemic DKA
    • suspend before surgery
    • serious UTI’s
  • Canagliflozine
    
    • doubles the risk for toe/midfoot/leg amputations
    • increase risk of bone fracture

Question 8

SGLT2i: Favorable and Unfavorable effects in patients with T2DM

Answer 8

• Favorable:
  
  • prevent Heart Failure
  • Preserve renal function
  • reduce
    
    • major adverse cardiovascular events (MACE)
    • Blood pressure
  • weight loss
  • Glycemia improvement
• Unfavorable
  
  • Fractures
  • amputations
  • Genital infections
  • Diabetic Ketoacidosis

Question 9

GLP-1 agonists: Drugs

Answer 9

• 2nd line agents
• -tide

Question 10

GLP-1 Agonists: MOA

Answer 10

• Activates GLP-1 receptor on B-cells
  
  • Gs coupled
  • causes nutrient induced insulin release
• Promotes:
  
  • B-cell proliferation
  • insulin synthesis
• Decreases gastric emptying
• Increases satiety

Question 11

GLP-1 Agonists: Advantages vs disadvantages

Answer 11

• Advantages:
  
  • add 0.5-1% A1c
    
    • dulaglutide-most efficient
  • All reduce MACE
    
    • Dulaglutide, Liraglutide, Semaglutide are FDA approved
  • low progression of CKD
    
    • Exanatide, liraglutide, dulaglutide
  • May reduce foot amputation
  • substantial weight reduction
  • no hypoglycemia
• Disadvantages:
  
  • GI side effects
  • gastroporesis
  • pancreatitis
  • Avoid at eGFR<30
  • Semaglutide increases diabetic retionpathy
  • Exenatide-renal injury
  • DPP-4 inhibits need to be discontinuted

Question 12

DPP-4 antagonists

Answer 12

• -liptin
  
  • second line agents
• liptin + metformin
  
  • first line fix-dose combination

Question 13

DDP-4 antagonists: MOA

Answer 13

• Inhibit DPP-4 activity
  
  • prolongs endogenous release of GLP-1 and GIP
• increase glucose-induced insulin release
• inhibit glucagon release

Question 14

DDP-4 Antagonists: Advantages vs Disadvantages

Answer 14

• Advantages:
  
  • reduce A1c
  • help with postprandial glucose excursion
  • weight neutral
  • Hypoglycemia is rare
    
    • can be used with patients at risk for hypoglycemia (elderly, depressed)
• Disadvantages:
  
  • Upper respiratory tract infection
  • rhinitis
  • acute pancreatitis
  • joint pain
  • HF
  • rare hypersensitivity reactions