DM - overview/ oral agents

Question 1

What is Pre-DM and what is clinically significant for a patient with pre-dm?

Answer 1

Pre-DM: ASYMPTOMATIC (predisposes individuals to T2DM & CARDIOVASCULAR DISEASE)

Entities of pre-DM: Impaired fasting glucose (IFG) & Impaired glucose tolerance (IGT)

Question 2

Who & what should be screened for DM?

Answer 2

Who: Individuals (Asymptomatic) =/>40y/o with or without risk factors for diabetes

What: Fasting blood glucose (FBG), HbA1c

*individuals who are asymptomatic with result suggestive of DM should have a REPEAT test on a subsequent day
**individuals between 18-39y/o can consider doing the Diabetes Risk Assessment Tool (DRAT) to assess their risk of having DM

Question 3

Prevention/ Delaying progression of DM

Answer 3

LIFESTYLE INTERVENTION
- Healthy diet
- Increased physical activity (at least 150mins of MODERATE intensity exercise) every week
*individualised enables sustained behavioural changes

Consider metformin for persons with pre-diabetes when:
- glycemic status does not improve despite lifestyle intervention OR
- they are unable to adopt lifestyle interventions
*esp if BMI =/>23kg/m2, <60y/o, women with gestational diabetes

Question 4

Diabetes definition & types

Answer 4

Metabolic disorder characterised by resistance to the action of insulin, insufficient insulin secretion or both

Types: type 1/2, gestation, others (infection/drugs/ monogenic diabetes syndrome, endocrinopathies, pancreatic destruction, type 3)

Question 5

T1DM pathogenesis

Answer 5

Absolute deficiency of pancreatic beta-cell function
- Immune mediated destruction
- Positive antibodies

Stage 1
Autoimmunity (+ve antibodies)
Normoglycemia
Presymptomatic

Stage 2
Autoimmunity (+ve antibodies)
DYSglycemia
PREsymptomatic

Stage 3
Autoimmunity (+ve antibodies)
HYPERglycemia (NEW ONSET)
SYMPTOMATIC

Question 6

T2DM pathogenesis

Answer 6

Progressive lose of beta-cell insulin secretion on the background of INSULIN RESISTANCE (in the presence of insulin, glucose utilisation is impaired & HEPATIC glucose output INCREASED)

Question 7

T1 vs T2DM

Answer 7

Primary Cause: T1 (autoimmune-mediated pancreatic beta-cell destruction; +ve antibodies) vs T2 (insulin resistance; impaired insulin secretion, -ve antibodies)

Insulin production (C-peptide levels): T1 (absent) vs T2 (normal or abnormal)

Age of onset: T1 (usually <30y) vs T2 (often >40y, although increasing prevelant in disease in obese children/ younger adults)

Onset of clinical presentation: T1 (ABRUPT) vs T2 (gradual)

Physical appearance: T1 (often thin) vs T2 (often overweight)

Proneness to ketosis: T1 (frequent) vs T2 (uncommon)

Question 8

Signs & symptoms of DM

Answer 8

*3Ps: Polyphagia (hunger), Polydipsia (thirst), Polyuria (freq urination)

Hyperglycemia: 3Ps, dry skin, blurred vision, drowsiness, impaired healing

Hypoglycemia: shaking, fast HR, sweating, dizziness, anxious, hunger, impaired vision, weakness/fatigue, headache, irritable

Question 9

Parameters used to measure DM

Answer 9

1. Fasting Blood Glucose: NO CALORIE INTAKE for >/=8h
2. Random or casual plasma glucose: glucose @ any time of the day, regardless of meals
3. Post Prandial Glucose (PPG): glucose level 2h after meal
   *can also be measured by using a standard 75g oral glucose tolerance test (OGTT)
4. HbA1c: average amount of glucose in one’s blood over the past 3 months (glucose attached to hemoglobin for lifespan of RBC ~3months)

Question 10

HbA1c definition & contribution

Answer 10

HbA1c = 3 months average of (FBG + PPG)

as HbA1c increases:
- Increasingly due to FAST/ basal hyperglycemia (FBG)

Question 11

Criteria for diagnosis of DM

Answer 11

*in general: requires at least 2 different readings to diagnose DM (if first test is NOT HbA1c); if HbA1c measured sufficient to diagnose DM

FPG or OGTT:
1. FPG </= 6.9mmol/L OR 2hOGTT <11.0mmol/L: PRE-DM (if HbA1c measure between 6.0- 6.9%, measure FPG/ 2hOGTT)
2. HbA1c >/= 7.0% OR FPG >/=7.0mmol/L OR 2hOGTT >/= 11.1mmol/L: DIABETES

Question 12

Complications of DM & relevant monitoring tests

Answer 12

1. Retinopathy (micro)
   -> Retinal Fundal Photography (all DM pts, T1DM within 5 years of onset, T2DM at time of diagnosis)
   * if no evidence for retinopathy, glucose well-controlled: screen annually (6mths if unstable)
   ** women with diabetes: conduct eye exam before pregnancy/ during 1st trimester of pregnancy (pregnancy can cause retinopathy/ worsen it)
2. Nephropathy (micro)
   -> Urine microalbumin/ creatinine ratio (all DM pts, T1DM within 5y of onset, T2DM at time of diagnosis)
   Measure:
   - Serum CR &/ eGFR
   AND
   - Urine Albumin/ Creatinine ratio (uACR) OR Protein-Creatinine ratio (uPCR) *if significant levels of proteinuria
   ** 6mth/ annual screening
3. Neuropathy (micro)
   -> Diabetic Foot Screening (annually, daily by pt)
   *encourage smokers to quit, educate on proper foot care & footwear
4. CVD (MACRO) [or metabolic syndrome]
   Measure:
   - HbA1c
   - Lipid panel (annually, 3-6mth if not controlled)
   - BP (every visit)

Question 13

Treatment goals for DM (target values)

Answer 13

HbA1c <7%
- more strict: 6-6.5% (younger pt/ no sig. CVD)
- less strict: 7.5-8% (older pts w comorbidites)
FBG 4-7mmol/L
PPG < 10mmol/L

*HbA1c & FBG more impt

Question 14

Does improvement in HbA1c decrease complications of DM?

Answer 14

Microvascular only; no correlation with macrovascular

Question 15

Metformin indication, MOA, PK, dose, pregnancy use, ADR, DDI

Answer 15

• 1st line therapy for all T2DM patients
  (reduces HbA1c by 1.5%; UP 2.0%)
• Negligible weight gain & hypoglycemia
• Possibly reduces CV events in T2DM patients
• Helps prevent/ delay T2DM
  *REDUCES FASTING BLOOD GLUCOSE
• MOA: reduces hepatic glucose production (primary); increases peripheral/ muscle glucose uptake & utilisation [increase insulin sensitivity] (secondary)
• PK: onset within days, max effect takes up to 2 weeks
  Mainly cleared renally (90% in urine as unchanged drug)
• Dose:
  [Regular/ immediate release)
  Initial: 500mg- 850mg OD
  Titration: EVERY 1-2 weeks increase by 500-850mg OD in divided dose (OD -> BD)
  MAX: 2500-2550mg daily

[Extended release]
Initial: 500mg OD
Titration: EVERY week increase by 500mg
MAX: 2000 mg (may divide into 1000mg BD if glycemic control not achieved with OD dosing)

Special population indication: can be used in pregnancy (BUT drug of choice is insulin)

ADR:
GI (N/V/D), metallic taste
*transient, take w food & increase dose gradually to minimise (GI disturbances)
Long-term use -> decrease in serum B12 conc
(RARE but FATAL) LACTIC ACIDOSIS [N/V, SHARP abdominal pain, shallow/laboured breathing, mental confusion] (accumulation of lactate as pyruvate cannot be broken down to ATP)

CI: Severe renal impairment, hypoxic states/ risk of hypoxemia (heart failure, liver impairment, respi failure, sepsis, alcoholism, >/= 80yo)

DDI:
Alcohol (increased risk of lactic acidosis)
Iodinated radio contrast material (WITHHOLD metformin for AT LEAST 48h after iodine administration, restart when renal fxn stable POST-procedure)
Inhibitors/ inducers of Organic Cationic Transporters (OCT) eg. cimetidine, dolutegravir, ranolazine -> affects elimination of metformin

Question 16

Thiazolidinediones indication, MOA, PK, dose, pregnancy use, ADR, DDI

Answer 16

• Used as alternative MONOTHERAPY when metformin cannot be used/ in combination with other antidiabetic agents
• Reduces HbA1c by 0.5-1.4%
• Beneficial for patients with Fatty Liver Disease (NAFLD/NASH)
• Potential reduction in stroke (BUT increased risk of heart failure)
• neutral progression of Diabetes Kidney Disease

MOA: PPARgamma AGONIST -> promotes glucose uptake in target cells (skeletal muscle/ adipose tissue); increases insulin sensitivity

PK: takes up to a month for maximal effect; LIVER elimination

*limited human data for pregnancy -> avoid

Dose:
Pioglitazone 15/30mg OD initially; uptitrate 15mg; MAX 45mg OD
*DDI: CYP3A4/ 2C8 inhibitors/inducers

ADR: hepatotoxicity, fluid retention, fracture (increased risk), weight gain (dose dpdnt), risk of bladder cancer, increased risk of hypoglycemia(if on insulin)

CI: HEART FAILURE, active liver failure, active/history of bladder cancer

Question 17

Sulfonylurea indication, MOA, dose, pregnancy use, ADR, DDI

Answer 17

*HELPS TARGET POST PRANDIAL GLUCOSE (PPG)
** REQUIRES FUNCTIONAL BETA CELLS
- Management of T2DM when hyperglycemia cannot be controlled through diet & exercise alone (can be used concomitantly with other oral agents &/ insulin)
*no other apparent benefits other than blood glucose lowering effects
**to be taken IMMEDIATELY before meal, do not miss/ delay meals (hypoglycemia risk)

MOA: stimulates insulin secretion (blocks K+ channel of beta cell) (primary); reduces hepatic glucose output (increase insulin sensitivity) (secondary)

Dose:
Glipizide 5mg BD (MAX: 40mg daily)
(PK: 90% hepatic, duration of action 12-24h)
*TAKE 15-30MINS BEFORE MEAL
Newer gens - gliclazide MR, glimepiride (OD dosing improves adherence, but higher cost)

ADR:
Weight gain (dose dependent)
Hypoglycemia *esp elderly

CI: hypersensitivity

DDI:
Beta-blockers (masks symptoms of hypoglycemia like tachycardia)
Alcohol -> disulfiram-like reactions (1st gen most)
CYP2C9 inhibitors eg. amiodarone, 5-FU, fluoxetine INCREASES glipizide & glimerpiride

Question 18

DPP-4i indication, MOA, dose, pregnancy use, ADR, DDI

Answer 18

*usually OD dosing
reduces HbA1c by 0.5-0.8% (as monotherapy) - 2nd/ 3rd line agents (usually as dual/ triple combination)
generally very mild in A/E
*NOT recommended for patients with acute pancreatitis
(vs GLP-1RA: more convenient route of administration, lower incidence of GI AE, cheaper BUT does not help with weight management, smaller HbA1c reduction, no effect on ‘big 3’/ ASCVD HF and CKD

MOA: increases concentration of endogenous incretins (decreses gastric emptying, increases insulin synthesis/secretion + decreases glucagon secretion -> improves beta-cell function, stimulates brain to reduce food intake)

Dose:
Linagliptin: 5mg OD (no need for renal adjustment)
Sitagliptin: 100mg OD (CrCl <45: 50mg OD // CrCl <30: 25mg OD)
Vidagliptin: 50mg BD (if with metformin/ TZD), OD (if with SU) (CrCl <50: 50mg daily)

Pregnancy use: avoid

ADR: severe joint pain that can be disabling
acute pancreatitis
headache
hypersensitivity
bullous pemphigoid, skin rash

DDI:
Linagliptin: CYP3A4 inducer (decreases conc)
Sitagliptin: increases digoxin (minimal)
Vitagliptin: not reported

Question 19

SGLT2i indication, MOA, dose, pregnancy use, ADR, CI

Answer 19

Reduces HbA1c by 0.8-1%
Neutral for hypoglycemia
Slight weight loss benefits
Glucosuria benefits
Big 3 effects: canag/empag improves ASCVD, all for HF (less hosp stay), CKD (less macroalbuminuria)

MOA: reduces reabsorption of glucose/ increases renal excretion of glucose

Dose:
Canag: 100mg OD (before 1st meal of the day), MAX 300mg OD *DO NOT INITIATE/STOP IF CrCl <30 (30 < CrCl <60: 100mg OD) unless albuminuria >300mg/day (benefit vs risk)
Dapag: 10mg OM (with/ without food), MAX 25mg OD
Empag: 5mg OM (with/ without food), MAX 10mg OD
*dapag/empag: DO NOT INITIATE/STOP if CrCl <45

Pregnancy use: avoid (limited data)

ADR:
Hypotension, hypoglycemia, renal impairment, increased LDL, urinary frequency
Genital mycotic infection/ UTI
increased risk of diabetic ketoacidosis (esp euglycemic DKA)
Fournier’s gangrene
*Canag: lower limb amputation, hyperkalemia, fractures

CI: ESRD/ dialysis
*if goal is glycemic control, do not initiate if eGFR <45/ discontinue if persistently <45
if goal is cardiorenal benefit: do not initiate when GFR <25 (Dapag)/ <20 (empag)/ discontinue when dialysis initiated

Question 20

alpha-glucosidase inhibitors indication, MOA, PK, dose, pregnancy use, ADR, DDI

Answer 20

*MAINLY CONTROLS PPG (dose-dependent)
Reduces HbA1c by 0.5-0.8%
Management of T2DM when diet & exercise insufficient to control hyperglycemia (usually NOT monotherapy)
Acts locally
Beneficial in carb-rich diet
*flatulence no.1 cause of drug discontinuation

MOA: delays glucose absorption by inhibiting the alpha-glucosidase at the brush border competitively

PK: onset is RAPID with each meal, eliminated 50% via faeces as unabsorbed drug

Pregnancy use: avoid (limited data)

Dose:
Acarbose: initial 25mg BD-TDS with each meal, titrate every 2-4weeks: increase 25mg each day, Max dose: 150mg daily (pts </= 60kg) OR 300mg daily (pts >60kg)

ADR: GI (FLATULENCE, abdominal pain, diarrhea)
INCREASES LFTs (increased risk with doses >100mg TDS)

CI: severe renal impairment (CrCl <25)
GI diseases (obstruction, IBD)
Liver cirrhosis

DDI: intestinal adsorbents & digestive enzymes preparation may reduce effects

Question 21

What type of agent is GLP-1 Receptor AGONISTS?

Answer 21

injectable (non-insulin) agent
[MOA] acts like endogenous GLP-1 and binds to receptors on beta-cells

*incretins: naturally occurring hormones released from GIT
-> GLP-1: type of incretin

effects of GLP-1:
decreases gastric emptying
stimulates brain to decrease food intake
increases glucose-dependent insulin biosynthesis & secretion
decreases glucagon secretion
-> IMPROVES BETA CELL FUNCTION

Question 22

Overview of GLP-1 RA agents available (dosing, AE)

Answer 22

Liraglutide, Dulaglutide, Semaglutide (ozempic) - SC injection
Semaglutide (rybelsus) - ORAL

L: once DAILY regardless OF MEALS
initiate @ 0.6mg, titrate to 1.2mg after ONE WEEK (MAX: 1.8mg)
D/S: once WEEKLY regardless of meals
initiate @ 0.75mg (D)/ 0.25mg (S), titrate to 1.5mg (D)/ 0.5mg(S) after FOUR WEEKS (MAX: 3/4.5mg (D)/ 1mg (S))

S (PO): 1x daily 30 MINUTES BEFORE 1st meal of day
**on empty stomach; at least 1/2h before OTHER MEDS/ FOOD/ DRINK + NO MORE THAN 120ML
initiate @ 3mg, titrate to 7mg after 30 DAYS (MAX: 14mg)

*all: no renal dose adjustment

AE: N/V (common *dose dpdt), headache, acute pancreatitis, acute cholecystitis, injection site reactions
**BLACK BOX WARNING: THYROID C-CELL TUMORS (in animals); counsel on risk of medullary thyroid carcinoma + symptoms of thyroid cancers

Question 23

Effects of GLP-1 RA

Answer 23

Lowers HbA1c by 1-2%
causes WEIGHT LOSS *N/V S/E- suitable for overweight pts
does not cause hypoglycemia BUT costly

**NOT RECOMMENDED for pts with history of PANCREATITIS/ family history of THYROID CANCER

MAJOR 3 effects:
ASCVD: most agents HAVE BENEFIT (liraglutide, dulaglutide, SC semaglutide)
Heart failure: neutral
CKD: minimal benefits (benefit in reducing MACROalbuminuira: SC GLP-1RA)

Question 24

Choice of injectables (GLP-1RA VS insulin)

Answer 24

GLP-1 RA as CHOICE of first-line injectable (over insulin) when GREATER GLUCOSE LOWERING is needed

Question 25

Gestational DM frequency of blood glucose monitoring

Answer 25

7x a day:

before + after each meal
+
before bedtime

Question 26

Management of patient newly diagnosed with T2DM (choice of pharmacologic agents, consideration of ASCVD/HF/CKD)

Answer 26

Initial pharmacologic agent: METFORMIN
*should be continued as long as possible if no contraindication

Early combination therapy (eg. metformin + ___) can be considered is A1c is quite elevated
^no A1c cut-off specified; individualise for pt
- choice of other agents depends on goal of therapy (eg. target FBG/ PPG)

If history of ASCVD/HF/CKD, consider INDEPENDENTLY OF A1c to add:
- ASCVD: GLP-1 agonist OR SGLT-2i
- HF: SGLT-2i
- CKD: SGLT2i > GLP-1 agonist
*not commonly done due to cost despite strong evidence for additional benefits

Question 27

Consideration for add-ons (on top of metformin)

Answer 27

IF A1c STILL ABOVE TARGETED GOAL

-> need for glucose lowering efficacy: Insulin, certain GLP-1 & combination therapy highest
*greater glucose lowering effect in injectables (GLP-1 RA preferred over insulin; insulin considered when ongoing catabolism, symptomatic hyperglycemia, A1c >10%, BG >16.7mmol/L)

-> Need to minimise hypoglycemia (eg. elderly): AVOID SU, insulin

-> Need to promote weight loss - GLP-1, SGLT2i

Question 28

What is diabetic ketoacidosis? + how it arises

Answer 28

DIABETIC KETOACIDOSIS (DKA)
*ketones: byproducts of fat metabolism
MORE common in type 1&raquo_space;» type 2

MOA:
1. Absolute insulin deficiency -> lipolysis + metabolism of free fatty acids -> formation of beta-hydroxybutyrate + acetoacetic acid + acetone in liver
2. Stress -> stimulates insulin counter-regulatory hormone (glucagon, catecholamines, glucocorticoids, growth hormones)
*excess glucagon increases gluconeogenesis & DECREASES peripheral ketone utilisation

**type 2 usually has some residual insulin production -> protected against excessive lipolysis & ketone production

**DKA =/= lactic acidosis (associated with metformin)

Question 29

describe Somogyi effect & dawn phenomenon

Answer 29

*common to have high BG levels at dawn

Dawn phenomenon: release of cortisol in waking hours -> BG levels rise sharply

Somogyi effect: BG levels drop SHARPLY at night (missed bedtime snack/ too much insulin etc) -> body responds by releasing glucagon -> BG level shoots UP
*2am glucose always low
** reduce NIGHT dose glucose lowering agent/ basal insulin

Question 30

diabetic emergencies in T1DM & T2DM, common underlying cause(s)

Answer 30

T1DM: diabetic ketoacidosis (DKA)
-> formation of ketones: found in blood/urine; fruity breath odor; acidosis
*USUALLY STILL ALERT
-> BG > 14mmol/L

T2DM: Hyperglycemic Hyperosmolar State
residual insulin -> NO KETONES -> NO ACIDOSIS
-> usually EXTREMELY DEHYDRATED; BG can be >33mmol/L***
*USUALLY STUPOR (confused)
(serum osmolality can be >320mmol/kg)

Most common underlying cause of BOTH DKA/HHS: INFECTION; others: MI, stroke, inadequate insulin therapy, pancreatitis

Question 31

Limitations of using HbA1c for monitoring

Answer 31

• Does not correlate with macrovascular outcomes
• population A1c differs among racial & ethnic groups (south asians higher hemoglobin glycation index)
• does not reflect harms of hypoglycemia
• does not reflect glycemic variability
• represents a ‘target’ w/o providing guidance as to how to achieve it

*guidelines - no fixed A1c targets; more individualised targets -> switch to Time-In-Range (TIR)