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3152 Endocrine (DM + Thyroid) > DM Newer Therapeutic Drugs > Flashcards

DM Newer Therapeutic Drugs Flashcards

1
Q

What are incretins?

A

Incretins are endogenous gut hormones released after a meal due to stimulation of gastric motility

GIP: glucose-dependent insulinotropic polypeptide
GLP-1: glucagon-like peptide-1

They bind to recceptor on the pancreatic B cells and augment the secretion of insulin in a glucose-dependent manner:

  • Promote glucose dependent insulin release
  • Stimulate pancreas to release insulin (increase insulin secretion)
  • Inhibit release of glucagon, reduce hepatic glucose production
  • Slows gastric emptying and decreases appetite
  • Improve B cell function
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2
Q

[GLP-1 Agonist]

Name the most commonly used GLP-1 agonist and discuss its administration dose and route

A

Liraglutide

  • SC injection once daily, regardless of meals
  • Initiate at 0.6mg, then titrate to 1.2mg after 1 week. Can increase to 1.8mg.
  • No dose adjustment in renal impairment

*Think hormone - large protein/polypeptide, hence given via SC injection
*Semaglutide is the only oral GLP-1 agonist available

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3
Q

[GLP-1 Agonist]

What is its MOA?

A

GLP-agonist activates GLP-1 receptor (membrane GPCR) on pancreatic B cells, hence activates adenylate cyclase, increase cAMP, activates protein kinase A, and increase insulin secretion + decrease glucagon secretion by the pancreas

Eventually, insulin secretion subsides as blood glucose concentration decreases, approach euglycemia

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4
Q

[GLP-1 Agonist]

What is the structure of Liraglutide, and what does this confer?
How does this differ from endogenous GLP-1?

A

C16 fatty acid, offer cleavage protection from degradation by DPP-4 (dipeptidyl peptidase-4) enzyme, hence making it a long-acting peptide (half life of 13h)

*In contrast to endogenous GLP-1, half-life of 2h

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5
Q

[GLP-1 Agonist]

What is the absorption profile of Liraglutide?

A

Given SC, once daily dose
F = 55%

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6
Q

[GLP-1 Agonist]

What is the distribution profile of Liraglutide?

A

C16 fatty acid binds to plasma proteins (e.g., albumin)

Half life 13h (extended due to plasma protein binding, and protection from DPP-4 enzyme)

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7
Q

[GLP-1 Agonist]

What is the metabolism profile of Liraglutide?

A

Endogenously metabolized in a similar manner to large proteins
*protein degradation

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8
Q

[GLP-1 Agonist]

What is the excretion profile of Liraglutide?

A

6% renal, 5% feces

*No dose adjustment required in renal impairment

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9
Q

[GLP-1 Agonist]

What are the adverse effects?

A
  1. GI SEs: Nausea and vomiting, diarrhea (*longer acting agents have less nausea and more vomiting and diarrhea)
  2. Acute pancreatitis
  3. BBW: risk of medullary thyroid carcinoma (counsel pt on the risk + symptoms of thyroid cancers) (also avoid in pt with thyroid cancer)
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10
Q

[GLP-1 Agonist]

What is GLP-1 Agonist place in therapy with regards to HbA1c lowering and its benefits?

A

HbA1c:

  • Lowers by 0.7-1.5%
  • Marked reduction in PPG, moderate reduction in FPG

Weight:

  • Weight loss (think delayed gastric emptying and reduced appetite, N/V and diarrhea)

Benefits:

  • ASCVD - reduce atherothrombotic events like MI and stroke
  • CKD - minimal benefits
  • HF - NIL benefits

*Recommended as first line injectable over insulin, but it is expensive

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11
Q

[DPP-4 inhibitor]
*Dipeptidyl peptidase-4 inhibitor

What is its MOA?

A

Dipeptidyl peptidase-4 enzyme degrades GLP-1

DPP-4 inhibitor binds to the DPP-4 enzyme and reduces GLP-1 degradation
Hence, increases the concentration and prolongs the action of endogenous incretins
=> secrete more insulin, less glucagon, less hepatic glucose pdn

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12
Q

[DPP-4 inhibitor]

Name two common DPP4-i

A

Sitagliptin
Linagliptin

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13
Q

[DPP-4 inhibitor]

What is the absorption profile of Sitagliptin

A

Oral, F = 87%

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14
Q

[DPP-4 inhibitor]

What is the distribution profile of Sitagliptin

A

half life 10-12h

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15
Q

[DPP-4 inhibitor]

What is the metabolism profile of Sitagliptin

A

Low liver metabolism

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16
Q

[DPP-4 inhibitor]

What is the excretion profile of Sitagliptin

A

80% excreted in urine

*Sitagliptin requires dose titration in renal impairment

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17
Q

[DPP-4 inhibitor]

What combi might DPP-4i be an add on to?

A

Metformin, sulfonylurea, thiazolidinedione

*DPP-4i is usually used as second or third line agent as dual or triple therapy, added when close to target

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18
Q

[DPP-4 inhibitor]
DPP-4 is taken ______ of meals

A

Regardless of meals

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19
Q

[DPP-4 inhibitor]

Between Sitagliptin and Linagliptin, which requires renal dose adjustment?

A

Sitagliptin - if CrCl <50ml/min

*Sitagliptin is subsidized, and hence pt who are no renally impaired should be given Sitagliptin as the choice of DPP-4i

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20
Q

[DPP-4 inhibitor]

What are the adverse effects of Sitagliptin?

A
  • Acute pancreatitis (counsel pt on S&S - abdominal pain, N/V, fever)
  • Nausea and vomiting
  • Headache
  • Abdominal pain
  • Skin reaction
  • Angioedema
  • FDA warning: rare severe joint pain, can be disabling

*lower incidence of GI SEs compared to GLP-1 agonist

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21
Q

[DPP-4 inhibitor]

What are the adverse effects of Linagliptin?

A
  • > =5% nasopharyngitis (runny nose, sore throat = flu-like symptoms)
  • FDA warning: rare severe joint pain, can be disabling
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22
Q

[DPP-4 inhibitor]

What is DPP-4 inhibitor place in therapy with regards to HbA1c lowering and its benefits?

A

HbA1c:

  • Lower by 0.5-0.9%
  • Moderate reduction in PPG, mild reduction in FPG (not as good as GLP-1 agonist)

Weight:

  • Weight neutral (unlike weight loss in GLP-1 agonist)

Benefits:

  • NIL big 3 benefits (CVD, CKD, HF)
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23
Q

[DPP-4 inhibitor]

(from Doreen eL)

DPP4-i have neutral effect on major adverse CV events, however Saxagliptin is a/w ____________

A

Saxagliptin a/w incr hospitalization for HF, and incr in cardiovascular mortality

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24
Q

[SGLT2i]

What is the MOA of SGLT2i?

A

Inhibit the sodium-glucose co-transporter 2 (SGLT2i) in the proximal renal tubules, hence decrease glucose reabsorption, decrease renal threshold for glucose, and increase renal glucose excretion

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25
Q

[SGLT2i]

Apart from lowering blood glucose levels, what other uses does SGLT2i have?

A
  • BP reduction
  • Natriuresis effect (use in HF)
    etc.
26
Q

[SGLT2i]

Name 3 SGLT2i

A

Canagliflozin

Empagliflozin

Dapagliflozin

27
Q

[SGLT2i]

What is the absorption profile of Empagliflozin?

A

Oral, F: 60-80%

28
Q

[SGLT2i]

What is the distribution profile of Empagliflozin?

A

Half life: 12h
Highly protein bounds ~90%

29
Q

[SGLT2i]

What is the metabolism profile of Empagliflozin?

A

Phase 2 glucuronidation

30
Q

[SGLT2i]

What is the excretion profile of Empagliflozin?

A

40% feces
55% urine

31
Q

[SGLT2i]

SGLT2i can be administered ______ meals

A

SGLT2i can be administered regardless of meals

32
Q

[SGLT2i]

Explain the initiation and continuation of SGLT2i wrt renal function

A

SGLT2i should not be initiated if <30ml/min/BSA
SGLT2i can be continued if <30ml/min/BSA, unless it is not tolerated (ESRD) or kidney replacement therapy (dialysis) is initiated (*CI in ESRD or dialysis)

Why cannot initiate <30ml/min?

  • SGLT2i needs to be filtered into renal tubule to carry out its function (efficacy, not safety issue)

Why can continue if <30ml/min?

  • SGLT2i is beneficial in CKD, has renal protective effects (although blood glucose lowering potential may be reduced, it has other reason to continue use)

*MONITOR renal function
*NO dose adjustment
*Renal function is used to determine initiation of SGLT2i, NOT dose adjustment

33
Q

[SGLT2i]

What is SGLT2i place in therapy with regards to HbA1c lowering and its benefits?

A

HbA1c:

  • Lower by 0.8-1.0%
  • Moderate decrease in FPG, mild PPG

Weight:

  • Slight weight loss benefit

Benefits:

  • ASCVD: only Canagliflozin and Empagliflozin

=> reduce risk of major cardiac event in pt with atherosclerotic CVD

  • HF: class benefit
  • CKD: class benefit

=> reduce risk for a composite endpoint of worsening renal function, renal failure, or renal death

34
Q

[SGLT2i]

Which SGLT2i has been approved for use in HF for the general population?

A

Dapagliflozin and Empagliflozin

35
Q

[SGLT2i]

Which SGLT2i has been approved for use in CKD for the general population?

A

Dapagliflozin

36
Q

[SGLT2i - Doreen]

Where is SGLT1 and SGLT2 located?

A

SGLT1 - gut absorption of glucose, also in last third of proximal renal tubule

SGLT2 - proximal renal tubule reabsorption of glucose

37
Q

[SGLT2i - Doreen]

T2DM pt are 2.5x more likely to develop cardiac failure than non-diabetics
SGLT2i able to reduce the development via what postulated MOA?

A
  • Increase cardiac energy (ATP)
  • Better use of glucose oxidation
  • Ketone oxidation
  • Fatty acid oxidation
  • Glycolysis (break down glucose for energy)

=> Improve cardiac function, improved energy metabolism, decrease oxidative stress

38
Q

[SGLT2i - Doreen]

SGLT2i has been shown to have effects on the heart, kidney, vasculature, whole body
What are the conventional and novel mechanisms of SGLT2i?

A

Conventional mechanisms:

  • Diuresis, natriuresis, reduce BP => use in HF
    *SGLT2i BP lowering effect SBP/DBP: 3-5mmHg / 1-2mmHg
  • Improve glycemic control due to glycosuria => use in DM
  • Weight loss => use in DM
  • Incr in RBC mass and hematocrit (incr erythropoietin)

Novel mechanisms:

  • Improved myocardial energetics, decrease oxidative stress
  • Improved myocardial ionic hemostasis
  • Improved autophagy and lysosomal degradation
  • Altered adipokine regulation
  • Improve cardiac remodelling, decrease fibrosis
  • Inhibit sympathetic nervous system
39
Q

[SGLT2i - Doreen]

What is SGLT2i role in HFpEF?

A
  • Manage comorbidities (CKD, HTN, DM, obesity)
  • Improve diastolic function
  • Reduce inflammation and ROS
40
Q

[SGLT2i - Doreen]

What are the indications for SGLT2i?

A
  • Congestive HF
  • Glycemic control or metabolic risk
  • Reduction in ASCVD
  • Diabetic kidney disease (kidney protective function)
  • Nondiabetic kidney disease (kidney protective function)
41
Q

[SGLT2i]

What are the adverse effects of SGLT2i?

What are the Canagliflozin specific adverse effects?

A
  • Hypotension (diuresis)
  • Hypoglycemia
  • Renal impairment (diuretic, monitor kidney function)
  • Increase LDL
  • Urinary urgency (diuretic)
  • Genital mycotic infection / UTI (more likely in women)
  • Volume depletion
  • FDA warning: incr risk of DKA - euglycemic DKA w SGLT2i
  • FDA warning: Fournier’s gangrene (typically in males, life-threatening)
  • Canagliflozin specific: amputations, hyperkalemia, fractures
42
Q

[SGLT2i - Doreen]

What infectious complications may occur as a result of DM?
These complications are more common in?
What are the counseling points?

A

UTI, mycotic genital infections

  • Occur due to glucoruria
  • Most common in first months after initiating SGLT2i
  • More common in women and those with prior GMIs

Counseling:

  • Maintain genital hygiene, keep genital region dry
43
Q

[SGLT2i - Doreen]

SGLT2i can contribute to the risk of diabetic ketoacidosis (DKA).
What are the risk factors for SGLT2i-associated ketosis?

A
  • > 20% insulin dose reduction (pt were highly dependent on high dose insulin)
  • Lean body habitus
  • Women
  • Surgical stress
  • Trauma
  • Intercurrent illness (e.g., sepsis, pneumonia)
  • Alcohol abuse
  • Pt with latent autoimmune diabetes of adulthood

*Think T1DM type of presentation

44
Q

[SGLT2i - Doreen]

In pt on SGLT2i with high risk of DKA, what should be done?

A
  • Monitor urine ketones
  • Following acute illness, hold off SGLT2i and resume 24-48h following recovery
45
Q

[SGLT2i - Doreen]

What are the counseling points to prevent SGLT2i-associated ketosis?

A
  • Recognise signs and symptoms of DKA: vomiting, abdominal pain, SOB
  • Avoid >20% reduction in insulin dose, monitor following insulin dose changes
  • Discontinue SGLT2i during episodes of acute illness, vomiting, diarrhea, inability to eat or drink (extended periods w/o food)
  • Hold 2-3 days prior to scheduled surgery
46
Q

[SGLT2i - Doreen]

What advantages do the diuresis and natriuresis effects of SGLT2i have?

A
  • Osmotic diuresis additive to loop diuretics
  • Favourable properties in comparison to loop diuretics:
    => Reduction in serum uric acid (compared to thiazides or loop diuretics that incr uric acid and may precipitate gout)
    => Uncommon hypokalemia and hypomagnesium (unlike thiazides and loop diuretics)
  • Hemoconcentration (presumed to be secondary to volume contraction), accounts for 50% of cardiovascular benefit observed
47
Q

[SGLT2i - Doreen]

What adverse effects do the diuresis and natriuresis effects of SGLT2i have?

What are the counseling points to prevent this?

A

Adverse effect:

  • Pt may be at risk of volume depletion, esp during episodes of acute illness a/w nausea, vomiting, or diarrhea

Counseling points:

  • Sick day advice (hold off SGLT2i until resolution of symptoms)
  • Maintain fluid intake
  • Some patients including those with HF, may require liberalization of fluid intake if they are euvolemic, when initiating SGLT2i (DO NOT initiate if hypovolemic to avoid risk of AKI)
48
Q

[SGLT2i - Doreen]

Discuss the relationship b/w SGLT2i and AKI
What are the renal effects of SGLT2i?

A

AKI is not increased by SGLT2i

Renal effects:

  • Initial dip ~5ml/min/1.73m2 within 1-2 weeks (may appear as AKI)
  • Slowly returns to pre-treatment values over next 3-9months
  • Subsequently, rate of decline is slower than untreated individuals (long term renoprotective effects)

Therefore, fluid intake counseling is based on clinical assessment and judgement

49
Q

[SGLT2i - Doreen]

How does the renal function of an individual change over time?

A
  • Age related natural drop in renal function (1ml/min/1.73m2 per year)
  • Indiv with DM + CKD: rate of decrease is doubled (2ml/min/1.73m2 per year)
  • Indiv with DM + CKD + Macroalbuminuria: could exceed 3ml/min/1.73m2 per year
  • 20-40% DM pt incur GFR <60ml/min/1.73m2 mostly in older and poor DM control
50
Q

[SGLT2i INITIATION IN HF PATIENTS]

When do we consider starting SGLT2i for patients with HF and T2DM

A

If GFR >60ml/min/1.73m2 in pt with HF + T2DM, then we may assess volume status (euvolemic/hypervolemic/hypovolemic) and blood pressure to potentially start SGLT2i for HF

51
Q

[SGLT2i INITIATION IN HF PATIENTS]

If patient is hypervolemic:
- Drug therapy
- Counseling
- Follow up
- Monitoring

A

Drug therapy

  • Start SGLT2i, continue baseline ACEi/ARB/ARNI/MRA (fantastic 4)

Counseling

  • Sick day counseling to prevent volume depletion

Follow up/monitoring:

  • Blood work (renal panel, electrolytes, bicarbonates, creatinine) in 1-3 months [*consider earlier in higher risk pt - stage 3b CKD eGFR <45, prior episode of AKI, at risk of volume depletion]
  • Expect up to 30% incr in SCr (dcr in GFR) - [if >30% incr, reassess BP and volume status, and consider reducing diuretics, liberalizing fluid intake, holding SGLT2i]
52
Q

[SGLT2i INITIATION IN HF PATIENTS]

If patient is euvolemic:
- Drug therapy
- Counseling
- Follow up
- Monitoring

A

Drug therapy

  • Start SGLT2i, continue baseline ACEi/ARB/ARNI/MRA (fantastic 4)
  • Consider decreasing loop diuretic (since euvolemic)

Counseling

  • Sick day counseling to prevent volume depletion

Follow up/monitoring:

  • Blood work (renal panel, electrolytes, bicarbonates, creatinine) in 1-3 months [*consider earlier in higher risk pt - stage 3b CKD eGFR <45, prior episode of AKI, at risk of volume depletion]
  • Expect up to 30% incr in SCr (dcr in GFR) - [if >30% incr, reassess BP and volume status, and consider reducing diuretics, liberalizing fluid intake, holding SGLT2i]
53
Q

[SGLT2i INITIATION IN HF PATIENTS]

If patient is hypovolemic:
- Drug therapy

A

Drug therapy

  • Decrease BP medications, reduce diuretic agents, liberalize fluid intake
  • Start SGLT2i only when euvolemic, to AVOID RISK OF AKI
54
Q

Amongst all the old and new therapeutic agents,

Which drugs have better HbA1c lowering potential of 1.5-2.0%?

A

Metformin (1.5-2.0%)
Sulfonylureas (1.5%)

55
Q

Amongst all the old and new therapeutic agents,

Which drugs have moderate HbA1c lowering potential, above 1%?

A

GLP-1 agonist (0.7-1.5%)
Thiazolidinediones (0.5-1.4%)

56
Q

Amongst all the old and new therapeutic agents,

Which drugs have low HbA1c lowering potential, more than 0.5%?

A

SGLT2i (0.8-1.0%)
DPP4i (0.5-0.9%)
a-glucosidase inhibitors (0.5-0.8%)

*rmb all the inhibitors

57
Q

Amongst all the old and new therapeutic agents,

Which have weight loss effects, preferred for obese individuals?

A
  • Metformin (slight)
  • GLP-1 agonist (N/V, diarrhea, loss of appetite)
  • SGLT2i (slight, diuretic effect)
58
Q

Amongst all the old and new therapeutic agents,

Which can cause weight gain?

A

Sulfonylurea (secrete insulin)
Thiazolidinediones (risk of HF - sodium and fluid retention, edema)

59
Q

Amongst all the old and new therapeutic agents, most are administered regardless of meals.

What are the exceptions?

A

Metformin - regardless, but with/after meals to reduce stomach upset and GI adverse effects

Sulfonylurea - 15-30min before food (skip if no food)

a-Glucosidase inhibitor - with food (skip if no food)

60
Q

Amongst all the old and new therapeutic agents, which has greater effect on PPG than FPG?

A

Sulfonylurea
TZD (same)
a-Glucosidase inhibitor (PPG only)
GLP-1 agonist
DDP4 inhibitor

*Only MET and SGLT2i (FPG > PPG)

3152 Endocrine (DM + Thyroid) (11 decks)

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