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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
[SGLT2i] Apart from lowering blood glucose levels, what other uses does SGLT2i have?
- BP reduction - Natriuresis effect (use in HF) etc.
26
[SGLT2i] Name 3 SGLT2i
Canagliflozin Empagliflozin Dapagliflozin
27
[SGLT2i] What is the absorption profile of Empagliflozin?
Oral, F: 60-80%
28
[SGLT2i] What is the distribution profile of Empagliflozin?
Half life: 12h Highly protein bounds ~90%
29
[SGLT2i] What is the metabolism profile of Empagliflozin?
Phase 2 glucuronidation
30
[SGLT2i] What is the excretion profile of Empagliflozin?
40% feces 55% urine
31
[SGLT2i] SGLT2i can be administered ______ meals
SGLT2i can be administered regardless of meals
32
[SGLT2i] Explain the initiation and continuation of SGLT2i wrt renal function
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
[SGLT2i] What is SGLT2i place in therapy with regards to HbA1c lowering and its benefits?
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
[SGLT2i] Which SGLT2i has been approved for use in HF for the general population?
Dapagliflozin and Empagliflozin
35
[SGLT2i] Which SGLT2i has been approved for use in CKD for the general population?
Dapagliflozin
36
[SGLT2i - Doreen] Where is SGLT1 and SGLT2 located?
SGLT1 - gut absorption of glucose, also in last third of proximal renal tubule SGLT2 - proximal renal tubule reabsorption of glucose
37
[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?
- 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
[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?
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
[SGLT2i - Doreen] What is SGLT2i role in HFpEF?
- Manage comorbidities (CKD, HTN, DM, obesity) - Improve diastolic function - Reduce inflammation and ROS
40
[SGLT2i - Doreen] What are the indications for SGLT2i?
- Congestive HF - Glycemic control or metabolic risk - Reduction in ASCVD - Diabetic kidney disease (kidney protective function) - Nondiabetic kidney disease (kidney protective function)
41
[SGLT2i] What are the adverse effects of SGLT2i? What are the Canagliflozin specific adverse effects?
- 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
[SGLT2i - Doreen] What infectious complications may occur as a result of DM? These complications are more common in? What are the counseling points?
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
[SGLT2i - Doreen] SGLT2i can contribute to the risk of diabetic ketoacidosis (DKA). What are the risk factors for SGLT2i-associated ketosis?
- >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
[SGLT2i - Doreen] In pt on SGLT2i with high risk of DKA, what should be done?
- Monitor urine ketones - Following acute illness, hold off SGLT2i and resume 24-48h following recovery
45
[SGLT2i - Doreen] What are the counseling points to prevent SGLT2i-associated ketosis?
- 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
[SGLT2i - Doreen] What advantages do the diuresis and natriuresis effects of SGLT2i have?
- 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
[SGLT2i - Doreen] What adverse effects do the diuresis and natriuresis effects of SGLT2i have? What are the counseling points to prevent this?
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
[SGLT2i - Doreen] Discuss the relationship b/w SGLT2i and AKI What are the renal effects of SGLT2i?
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
[SGLT2i - Doreen] How does the renal function of an individual change over time?
- 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
[SGLT2i INITIATION IN HF PATIENTS] When do we consider starting SGLT2i for patients with HF and T2DM
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
[SGLT2i INITIATION IN HF PATIENTS] If patient is hypervolemic: - Drug therapy - Counseling - Follow up - Monitoring
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
[SGLT2i INITIATION IN HF PATIENTS] If patient is euvolemic: - Drug therapy - Counseling - Follow up - Monitoring
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
[SGLT2i INITIATION IN HF PATIENTS] If patient is hypovolemic: - Drug therapy
Drug therapy - Decrease BP medications, reduce diuretic agents, liberalize fluid intake - Start SGLT2i only when euvolemic, to AVOID RISK OF AKI
54
Amongst all the old and new therapeutic agents, Which drugs have better HbA1c lowering potential of 1.5-2.0%?
Metformin (1.5-2.0%) Sulfonylureas (1.5%)
55
Amongst all the old and new therapeutic agents, Which drugs have moderate HbA1c lowering potential, above 1%?
GLP-1 agonist (0.7-1.5%) Thiazolidinediones (0.5-1.4%)
56
Amongst all the old and new therapeutic agents, Which drugs have low HbA1c lowering potential, more than 0.5%?
SGLT2i (0.8-1.0%) DPP4i (0.5-0.9%) a-glucosidase inhibitors (0.5-0.8%) *rmb all the inhibitors
57
Amongst all the old and new therapeutic agents, Which have weight loss effects, preferred for obese individuals?
- Metformin (slight) - GLP-1 agonist (N/V, diarrhea, loss of appetite) - SGLT2i (slight, diuretic effect)
58
Amongst all the old and new therapeutic agents, Which can cause weight gain?
Sulfonylurea (secrete insulin) Thiazolidinediones (risk of HF - sodium and fluid retention, edema)
59
Amongst all the old and new therapeutic agents, most are administered regardless of meals. What are the exceptions?
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
Amongst all the old and new therapeutic agents, which has greater effect on PPG than FPG?
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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