IC12 Diabetes Mellitus Management Part 2

Question 1

What are incretins? Name two examples of incretins?

Answer 1

Incretins are naturally occurring hormones
released from the GI tract
* Glucagon-like peptide-1 (GLP-1)
* Glucose-dependent insulinotropic polypeptide (GIP)

Question 2

What is the MOA of GLP-1 Receptor Agonists?

Give an example of GLP-1 receptor agonist.

Answer 2

Act like endogenous GLP-1 and binds to receptors on Beta cells, leading to:
1. Gastric emptying is reduced
2. Glucose-dependent insulin biosynthesis and secretion is increased
3. Beta cell function improves
4. Food intake reduces

Liraglutide SC injection once daily (Common in hospitals)

Question 3

What are some ADRs of GLP-1 receptor agonists? What black box warning is there?

Answer 3

Lots of GI effects - N/V/D

Long acting agents - Less nausea/vomiting but more diarrhea

Acute pancreatitis

Dyspepsia

BLACK BOX WARNING: Thyroid C-cell tumors in animals. Human relevance unknown. Counsel patients regarding the risk of medullary thyroid carcinoma and the symptoms of thyroid cancers.

Question 4

What is GLP-1 receptor agonists HbA1c lowering effect?
Is it suitable for overweight patients?
When is it used?
What are its benefits?

Answer 4

Reduce HbA1c by 0.7-1.5%

Cause weight loss

Recommend over insulin as 1st line injectable when greater glucose lowering is needed

ASCVD benefit, but neutral for HF and minimal for CKD

Question 5

What are DPP-4 Inhibitors’ MOA?

Answer 5

Inhibition of DPP-4 enzyme from inactivating GLP-1 and thus increases concentrations of endogenous incretins

Question 6

What examples of DPP-4 inhibitors are there?

Which need dose adjustments?

Answer 6

Sitagliptin & linagliptin

Sitagliptin needs dose adjustment in CrCL < 50mL/min and severe ESRD

Question 7

What are ADRs of DPP-4 inhibitors?

Answer 7

Sitagliptin: Acute pancreatitis,HA, N/V, abdominal pain, skin reaction, angioedema

Linagliptin: Nasopharyngitis

Common - Severe joint pain (Warning and Precaution by FDA)

Question 8

What is the HbA1c lowering effect of DPP-4 Inhibitors?

Answer 8

Decrease by 0.5-0.9%

Question 9

What is DPP-4 inhibitors’ place in therapy?

Answer 9

2nd or 3rd line T2DM usually used as dual or triple therapy

Question 10

Which DPP-4 Inhibitor has been associated with pancreatitis?

Answer 10

Sitagliptin

Question 11

What are some advantages and disadvantages of DPP-4 inhibitors over GLP-1 agonists?

Answer 11

Lower incidence of GI ADR

But weight neutral, smaller HbA1c reduction, no big 3 benefits for ASCVD, HF, CKD

Question 12

What is SGLT2 inhibitor MOA?

Answer 12

Inhibition of SGLT2 glucose transporters located in the proximal kidney tubules leads to ↑renal glucose excretion, hence ↓ blood glucose

Question 13

What are some side effects of SGLT2 inhibitors?

Answer 13

• Hypotension, hypoglycaemia, renal impairment, ↑LDL, urinary urgency
• Genital mycotic infection/UTI (>5%)
• Increased risk of diabetic ketoacidosis - euglycemic DKA
• Fournier’s gangrene
• Canagliflozin specific: Amputations (BLACK BOX WARNING), hyperkalemia, fractures

Question 14

Why does KDIGO recommend SGLT2i only for eGFR > 30 mL/min? Can it be continued if eGFR drops lower than that?

Answer 14

Efficacy issue - SGLT2i needs to be filtered by the glomerulus in order to work on the SGLT2 glucose transporters on the renal tubules

May be CONTINUED even if eGFR drops but not started.

Question 15

What is SGLT2i HbA1c lowering effect, effect on weight loss and other benefits?

Answer 15

• 0.8-1.0% reduction
• Slight weight loss from urination
• ASCVD (Cana and Empa only), HF (Dapa and Empa), CKD (Dapa)

Question 16

What class of medication is finerenone?
When is it indicated?
What is its side effects?

Answer 16

• Mineralocorticoid receptor antagonist
• Indicated to slow CKD progression, reduce the risk of kidney failure, heart attack, heart failure hospitalization and cardiovascular death in adult patients with CKD associated with T2DM
• Side effects: Hyperkalemia, hypotension, lesser risk of gynecomastia compared to spironolactone

Question 17

What class of medication is tirzepatide?
When is it indicated?
What about its effect on weight?

Answer 17

• GIP and GLP-1 receptor agonist
• Once-weekly injection indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
• Although approved as a DM drug (for now), has tremendous weight loss potential.
• First investigational medicine to deliver >20% weight loss on average in a phase 3 study

Question 18

What is the drug of choice in pregnant patients with DM?

Answer 18

Insulin

Question 19

What is insulin’s MOA and HbA1c lowering effect?

Answer 19

Regulate carbohydrates, fat, and amino acids
▪ Glucose: facilitating uptake of glucose in muscle and adipose tissue and by inhibiting hepatic glucose output (glycogenolysis and gluconeogenesis)
▪ Fat: enhancing fat storage (lipogenesis) and inhibiting the mobilization of fat for energy in adipose tissue (lipolysis and free fatty acid oxidation)
▪ Protein: increasing protein synthesis and inhibiting proteolysis in muscle tissue

↓ HbA1c up to 2.5%! (highest out of all agents)

Question 20

Describe the ADME of Insulin (PK)

Answer 20

Absorption - Onset is faster and shorter duration for IV > IM > SQ; rate limiting step occurs after SQ administration for depot formation

Distribution - Enter bloodstream directly

Elimination - Exogenous insulin is renally excreted; endogenous insulin is hepatically metabolized

Question 21

Rank the injection sites from fastest to slowest rate of absorption by SC route of insulin injection

Answer 21

Abdomen > Outer upper arms > Top and outer thighs > Buttocks

Question 22

What factors can alter insulin absorption

Answer 22

• Temperature – Heat (↑), Cold (↓)
• Massage (↑)
• Exercise (↑)
• Jet injectors (↑) – via pressure rather than needle
• Lipodystrophy (↓) or (↑)
  – Lipoatrophy (↑): concavity or pitting of adipose tissue due to immune response due to pork and beef insulin (Rare nowadays due to phasing out of pork/beef insulin; mostly synthetic human insulin now)
  – Lipohypertrophy (↓ ): bulging of adipose tissue due to not rotating injection sites.
• Others (↓) or (↑)
  – Needle size/gauge, administration technique (if IM then ↑), insulin preparations, mixtures, concentration, dose, insulin stability

Question 23

Name the 4 types of insulin,
the examples of insulin,
the target BG,
the onset of insulin,
the peak effect,
the duration of action and
the administration

Answer 23

Rapid-acting
1. Aspart, Lispro, Glulisine
2. PPG
3. Onset 5-15 min
4. Peak 1-2 hours
5. Duration 3-5 hours/1 injection per meal

Short-acting
1. Regular
2. PPG
3. Onset 30-60 min
4. Peak 2-4 hours
5. Duration 6-8 hours/1 injection per meal

Intermediate acting
1. NPH (Insulatard®)
2. FPG
3. Onset 1-2 hours
4. Peak 6-12 hours
5. Duration 10-16 hours/2 injections for 24h
coverage

Long-acting
1. Detemir, Lantus Glargine (U-100)
2. FPG
3. 0.8-2 hours | 1.5 hours
4. Hill | Peakless
5. 12 hrs for 0.2 units/kg; 20-24h for 0.4 units/kg (2 injections better coverage) | ~24 hours/1 injection for 24h coverage

Question 24

Name the ultra-short acting (with excipients) and ultra-long acting insulins

Answer 24

Ultra short:
1) Insulin aspart (Fiasp®)
▪ Vitamin B3 – increase speed of initial absorption
▪ L-arginine – stabilizes formulation

2) Insulin lispro-aabc (Lyumjev®)
▪ Treprostinil – enhances absorption via vasodilation
▪ Citrate – enhances vascular permeability

Ultra long
1) Degludec
2) Glargine (U-300)

Question 25

What are the peak effects, duration of action and administration for ultra long acting insulins

Answer 25

Insulin Degludec
➢Peakless with a duration of action of 42 hours
➢Inject subcutaneously once daily at any time of day

Insulin Glargine (U-300)
➢Peakless with a duration of action of 36 hours
➢once daily at the same time every day.

Question 26

Which insulins are incompatible for mixing?

Answer 26

Glargine (Lantus), Glulisine, Detemir

Question 27

What insulins give stable mixes

Answer 27

➢ Regular + NPH
➢ Rapid-acting + NPH
➢ Rapid-acting (aspart) + degludec (Mixed prior to administration)

Question 28

What are some pre-mixed insulin?

Answer 28

NovoMix 30 (Aspart 30%, Aspart Protamine 70%)

Humalog Mix 75/25 (Lispro 25%, Lispro Protamine 75%)

Mixtard 70/30 (NPH 70%, Regular 30%)

Mixtard 50/50 (NPH 50%, Regular 50%)

Question 29

What are pre-mixed insulin products for? How many times a day for administration and when?

Answer 29

Meals/snack and basal coverage

2 times a day before meals (15-30min)

Question 30

Why is it challenging to titrate and adjust insulin dose?

Answer 30

➢ Both basal and prandial coverage adjusted together!
➢ But not impossible if know patients and their lifestyle
➢ Easier to optimize drug therapy if patients perform self monitored blood glucose (SMBG) at home

Question 31

What oral therapies should be continued or discontinued when injectables are started?

Answer 31

Continue - Metformin, SGLT2i

Discontinue
- TZD (When insulin started), or reduce dose
- SU (Effectiveness will wear off & rely on insulin)
- DPP-4i (When GLP-1 agonist started)

Question 32

General rule of thumb in insulin dosing conversion.

How much dose reduction for high risk of hypoglycemia?

Answer 32

Mostly 1:1 unit
Mixtard® 30 or Insulatard®
- 16 units AM and 8 units PM

Can be switched to:
NovoMix® 30
- 16 units AM and 8 units PM (vice versa)

10 to 20% dose reduction

Question 33

Exceptions in insulin dosing conversion that require dose reduction (MUST)

Answer 33

Intermediate to Long Acting (FBG):
➢Decrease by 20% when switching from
1) Twice daily NPH to
2) Once daily glargine/detemir

▪ Eg: 20 units NPH twice daily -> 32 units of glargine once daily

Ultra long acting to intermediate/long acting:
➢Decrease by 20% when switching from
1) U-300 glargine to
2) Other alternative basal insulin analog

▪ Eg: 40 units of U-300 glargine -> 32 units of U-100 glargine/detemir

Question 34

What are some insulin ADRs?

Answer 34

Hypoglycemia: BG ≤ 4.0 mmol/L (70 mg/dL)
➢ S/Sx (including but not limited to): blurry vision, sweating, tremor, hunger, confusion, anxiety, shaking, rapid HR, dizziness, headache, weakness & fatigue, irritability
➢ Nocturnal: nightmares, restless sleep, profuse sweating, morning headache

Weight gain
➢ More than patients on SUs
➢ Type 1: weight gain of 4.6 kg more at 5 years when compared to those patients in the conventional therapy group (DCCT)
➢ Type 2: Weight gain was 4 kg more at 10 years when compared to patients
in the conventional treatment group (UKPDS)
* Benefits of glycemic control outweigh weight gain ➢ Always remind patients regarding diet, exercise and losing weight

Lipodystrophy
➢ Lipoatrophy: concavity or pitting of adipose tissue due to immune
response due to pork and beef insulin
➢ Lipohypertrophy: bulging of adipose tissue due to not rotating injection sites.

Local allergic reaction
➢ Redness, swelling and itching at injection site
➢ More common with beef or pork insulin (phasing out already)

Systemic allergic reaction: rare

Insulin resistance: rare
➢ Immune phenomenon

Question 35

What is the OTC hypoglycemia 15-15-15 rule?

Answer 35

The 15-15-15 rule
➢15g of fast acting carbohydrates
➢Wait for 15 minutes
➢Check BG, if still < 4.0 mmol/L then another 15g of fast acting carbohydrates