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233 2nd midterm > Type 2 Diabetes Part 2 > Flashcards

Type 2 Diabetes Part 2 Flashcards

1
Q

what post CV trial therapy can be used to overcome insulin resistance?

A

– Increase insulin secretion

➢Incretin-based therapies

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2
Q

what post CV trial therapy can be used to increase glucose excretion independent of insulin?

A

➢Sodium-glucose cotransporter-2 inhibitors

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3
Q

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors

Name 4 (ending)

A

Canagliflozin (Invokana®),
Dapagliflozin (Forxiga®),
Empagliflozin (Jardiance®),
Ertugliflozin (Steglatro®)

newest therapy for type 2 diabetes

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4
Q

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors

MOA?

A

– Inhibit SGLT2 (SGLT2 inhibitors induces glucosuria, gluc excretion)
• Our kidneys filter 160-180 grams of glucose/day
• The vast majority of this glucose (up to 99%) is
reabsorbed by the kidneys (proximal tubule)
• Hyperglycemia increases both the amount of filtered
glucose and reabsorbed glucose by the kidneys
• SGLT2 is the primary mediator of glucose reabsorption

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5
Q

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors

why do SGLT2 inhibitors in clinical practice only prevent ~50-60% of glucose reabsorption?

A
  • SGLT1 activity compensates for the inhibition of SGLT2
  • Early proximal tubule SGLT2 normally absorbs 97-99% of glucose
  • SGLT1 responsible for 3% , later in prox tubule
  • Reabsorb 40-60% of glucose filtered in kidneys
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6
Q

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors

where is SGLT1 expressed?

SLGT1?

A
  • First ones were not specific to SGLTs but it was thoguh SGLT2 was better because it is only in kidneys with no impact elsewhere
    • SGLT2 is expressed in the following tissues
    – Kidney
    – Islet α-cells
    • SGLT1 is expressed in the following tissues
    – Kidney
    – Heart
    – Small intestine
    ➢May delay intestinal glucose absorption
    ➢May enhance incretin hormone secretion
  • may be beneficial to inhibit SGLT1
  • canagliflozin shows some SGLT1 inhibitory action
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7
Q

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors

what advantages does it have? (4)

A

▪ Does not cause hypoglycemia (glucose independent)
▪ Can be prescribed with other therapies for diabetes
▪ Are effective at all stages of type 2 diabetes
▪ Have beneficial effects on the cardiovascular system
- Almost every SGLT inhibitor shows benefits for CV functions
- Empagliflozin (Jardiance®)shows best outcomes for CV, may be a heart disease drug

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8
Q

Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors

what disadvantages does it have? (4)

A

▪ *Increases genital and urinary tract infections
-increasing glucose in urine - conducive of bacterial growth

▪ May increase hepatic glucose production (via increasing glucagon secretion?)
- SGLT2 in alpha cells in islets increases glucagon sec

▪ *May increase ketoacidosis

  • can be due to increased fat oxidation with glucagon
  • ketone bodies may lead to increased CV benefits with increased signaling pathways

▪ *Increased risk of amputation (only seen with
canagliflozin)

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9
Q

describe the incretin effect?

A

β-cell exposure to equivalent circulating glucose
concentrations will stimulate a greater amount of insulin release if the glucose is administered orally vs. intravenously
- Islet beta cell exposed to same amount of glucose intravenously or orally
- The oral individuals have a larger rise in insulin than IV incretin effect

  • If glucose if given IV - it reaches pancreas and islet cells and secrete insulin
  • Eating food, before glucose gets to islet cells, it goes through GI
  • Enteroendocrine cells sense it and secrete GLP1 and GIP hormones (incretin hormones) and they augment insulin secretion
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10
Q

what are the pleiotropic effects of GLP-1 receptor agonism on glycemia?

5 locations

A

pancreas
- increase insulin (PRIMARY) and decrease glucagon secretion

liver
- dec glucagon reduce hepatic glucose production, decrease blood sugar levels

intestine
- GLP-1 is expressed in intestine, delay gastric emptying, delay absorption of sugar from eating

brain

  • Lower food intake, reductions in appetite
  • approved for obesity

adipose tissue
- decreased adiposity with low appetite

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11
Q

how do incretin-based therapies differ from secretagogues?

A
  • GLP-1 ability to enhance glucose-stimulated insulin secretion is glucose-dependent,
    • *Thus, the risk of hypoglycemia with GLP-1 is significantly less compared to other diabetic therapies (ie. Insulin, Sulfonylureas)
  • When blood sugar is high, GLP-1 based drug causes a lot of insulin secretion
  • Low blood sugar, opposite
  • As blood surgar gets normalized near the end, the insulin also lowers even though it is infused at the same rate
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12
Q

Incretin-Based Therapies - GLP-1 Receptor Agonists

MOA?
4 main actions

A

• promotes glucose stimulated insulin secretion
➢ Ability to enhance glucose-stimulated insulin secretion is glucose dependent, being more potent at higher plasma glucose levels
(low risk for hypoglycemia)
• inhibits glucagon secretion, which reduces hepatic
glucose production in patients with diabetes
• inhibits gastric emptying
➢ Delays appearance of nutrients (e.g. glucose) into the circulation
• inhibits appetite
➢ Leads to reductions in body weight and adiposity

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13
Q

Incretin-Based Therapies

what limitation does GLP-1 have?

A

GLP-1 has a very short half-life (2 min)
• Dipeptidyl-peptidase 4 (DPP-4) is the enzyme responsible for the inactivation of GLP-1
- cleaves any protein with Ala or Pro in 2nd aa position
- can’t just use recombinant GLP-1
- Degradation-resistant GLP-1R agonists and DPP-4
inhibiton needed

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14
Q

Incretin-Based Therapies - GLP-1 Receptor Agonists

name 6 GLP-1 analogs that are resistant to DPP-4

what is their dosage form?

A

➢Exenatide (Byetta®) [T1/2 ~ 2 hours]
❖Synthetic version of the Gila monster salivary hormone, exendin-4
- DPP-4 can’t access

➢Liraglutide (Victoza®) [T1/2 ~ 12 hours]
❖Acylated GLP-1 analog that noncovalently binds to
albumin
- alanine still there but bind to albumin so DPP-4 can’t access

➢Albiglutide (Tanzeum®) [T1/2 ~ 4-7 days]
❖GLP-1 dimer fused to albumin

➢Lixisenatide (Lyxumia®) [T1/2 ~ 2.5 hours]
❖Structurally related to exendin-4

➢Semaglutide (Ozempic®) [T1/2 ~ 1 week]
❖Longer-acting alternative to liraglutide

• Proteins, therefore must be injected
➢ Can lead to formation of neutralizing antibodies
(exenatide)
- oral recently approved

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15
Q

Incretin-Based Therapies - GLP-1 Receptor Agonists

Advantages (3)

A

▪ Also cause body weight loss (liraglutide approved for
obesity)
▪ Less risk of hypoglycemia (do not promote insulin
secretion when circulating glucose levels are low/normal)
▪ Reduced cardiovascular risk with GLP-1R agonists (seen with all GLP-1R agonists for most part except lixisenatide and exenatide)

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16
Q

Incretin-Based Therapies - GLP-1 Receptor Agonists

Disadvantages (3)

A

▪ Primarily gastrointestinal concerns (nausea, diarrhea,
vomiting), transient
▪ *Increase in heart rate, no CV risk
▪ *Pancreatitis???
▪ Increased risk of hypoglycemia if co-prescribed with
sulfonylureas

17
Q

Incretin-Based Therapies - DPP-4 Inhibitors

name 5

dosage form?

A 
➢Sitagliptin (Januvia®, Janumet®)
➢Vildagliptin (Galvus®)
➢Saxagliptin (Onglyza®, Komboglyze®)
➢Alogliptin (Nesina®, Kazano®, Oseni®)
➢Linagliptin (Tradjenta®, JentaDueto®)

Oral Administration (tablets taken once/day)

18
Q

Incretin-Based Therapies - DPP-4 Inhibitors

MOA?

A

– Inhibit DPP-4 activity to prevent the breakdown of
endogenously released GLP-1
• Also improve glycemia by preventing breakdown of GIP (also increases insulin secretion)

19
Q

Incretin-Based Therapies - DPP-4 Inhibitors

Advantages (2)

A

Less risk of hypoglycemia (do not promote insulin
secretion when circulating glucose levels are low/normal)
▪ Oral versus injectable (patient preference)

20
Q

Incretin-Based Therapies - DPP-4 Inhibitors

Disadvantages (5)

A

▪ Primarily gastrointestinal concerns (nausea, diarrhea,
vomiting)
▪ *Pancreatitis???
▪ Increased risk of hypoglycemia if co-prescribed with
sulfonylureas
▪ Increased risk of hospitalization for heart failure (only seen with the DPP-4 inhibitor saxagliptin)
▪ Don’t cause weight loss like GLP-1 receptor agonists, no improvement of CV outcomes

21
Q

Incretin-Based Therapies

Why the Difference in Cardiovascular Outcomes
with the Incretin-Based Therapies?

A

– DPP-4 inhibitors only prevent the degradation of
endogenously released GLP-1 but GLP-1 agonist is given in pharmacologic conc (physiological versus
pharmacological activity)
– DPP-4 degrades a large number of different
peptides (many of which we are still learning about), many other substrates (complex)

22
Q

Polypharmacy in the Obese Individual

You have the following obese individual with type 2
diabetes, hypertension and mild heart failure being treated with the following drugs

  • Hydrochlorothiazide
  • Losartan
  • Glyburide
  • Metformin

take off which med?

A

Want to take off glyburide - increases insulin which causes weight gain

ideal replacement: liraglutide (approved for weight lost), GLP agonist

23
Q

what drugs promote glucose excretion form urine?

A

SGLT2 inhibitors

24
Q

which drugs augment insulin only when blood glucose levels are elevated?

A

GLP-1 receptor agonists and DPP-4 inhibitors

233 2nd midterm (13 decks)

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