DM Flashcards
how does the body increase blood glucose levels
1) absorption of glucose from GIT
2) glycogenolysis in muscle & liver
3) gluconeogenesis in liver
how does body decrease blood glucose levels
1) uptake & utilisation of glucose by tissues
2) glycogen synthesis in muscle & liver
pre-DM - general
- can be asymptomatic
- predispose individuals to T2DM & cardiovascular disease
pre-DM components
1) impaired fasting glucose (IFT)
2) impaired glucose tolerance (IGT)
nonpharmaco for pre DM
1) lifestyle intervention to prevent/delay progression
- healthy diet
- increase physical activity (150 min moderate or 75 mins vigorous)
pharamco for pre DM
metformin
- only used when:
1) glycaemic status X improve despite lifestyle intervention
2) X to do lifestyle intervention esp if BMI ≥ 23 kg/m^2, younger than 60, women w history of gestational DM
what is type 1 DM associated with
insufficient secretion of insulin
pathogenesis for type 1 DM
absolute deficiency of pancreatic beta cell function due to immune mediated destruction or positive antibodies
staging for type 1 DM
1) type 1, type 2
- +ve antibodies, asymptomatic
2) type 3
- +Ve antibodies, symptomatic
what is type 2 DM associated with
body resistant to insulin
pathogenesis for type 2 DM
- progressive loss of adequate beta-cell insulin secretion on the background of insulin resistance
- insulin resistance:
1) glucose utilisation impaired
2) hepatic glucose output increased
how is the levels of insulin and glucose like at the early stage of type 2 DM
high levels
Type 1 vs Type 2 DM
1) primary cause
- type 1: autoimmune-mediated pancreatic beta cell destruction, +ve antibodies
- type 2: insulin resistance, impaired insulin secretion, negative antibodies
2) insulin production
- type 1: absent, type 2: normal/abnormal
3) age of onset
- type 1: < 30 yo, type 2: often > 40 yo but increasing prevalent in obese children/younger adult
4) onset of clinical presentation
- type 1 abrupt, type 2 gradual
5) physical appearance
- type 1 thin, type 2 overweight
6) proneness to ketosis
- type 1 frequent, type 2 uncommon
signs and symptoms of hyperglycaemia
1) polydipsia, polyuria, polyphagia
2) decreased healing, dry skin
3) drowsiness, blur vision
signs and symptoms of hypoglycaemia
1) fast heartbeat, shaking
2) Sweating, dizziness
3) hungry, impaired vision
DM measuring parameters
1) fasting plasma glucose (FPG)
- X calorie intake for ≥ 8 hrs
2) random/casual plasma glucose
3) postprandial plasma glucose (PPG)
- glucose level after meal, usually after 2 hrs (time taken for glucose to be stable)
- 75g oral glucose tolerance test (OGTT)
4) HbA1c
- average amt of glucose over 3 months (glucose stay attached to haemoglobin over lifespan of RBC
- 3 month average of FPG + PPG
diagnosis of DM (MOH guidelines)
- 2 abnormal test results required to diagnose DM
- HbA1c values
1) ≥ 7%: X further test, confirm DM
2) 6.1% - 6.9%: take second test
** FPG values: > 7 confirm DM | 6.1 - 6.9 pre DM | < 6 no DM
** OGTT: > 11.1 confirm DM | 7.8 - 11.0 pre DM | < 7.8 no DM
3) < 6% no further test, no possibility of DM
complications of DM
1) microvascular
- retinopathy, blindness
- nephropathy, kidney failure
- neuropathy, amputation
2) macrovascular
- increase cardiovascular disease
3) others
- decrease life expectancy for 5-10 yrs
screening tests before confirming DM
- recommended for asymptomatic individuals ≥ 40 yo +/- risk factors
- FPG, HbA1c
what are the 4 screening tests to do after confirming DM
1) Retinal fundal photography
2) urine microalbumin/creatinine ratio
3) diabetic foot screening
4) diabetic nephropathy test
screening test after confirmed DM - retinal fundal photography
- test for diabetic retinopathy
- within 5 yrs of onset for adults w T1DM
- at time of diagnosis for T2DM
- every 1-2 yrs if X evidence of retinopathy & well controlled hyperglycaemia
- annual if any level of diabetic retinopathy present
- pregnant ladies w DM: before pregnant/1st trimester, followed up to 1 year after giving birth
screening test after confirming DM - urine microalbumin/creatinine ratio
test for diabetic nephropathy/albuminuria
screening test after confirming DM - diabetic foot screening
- reduce risk of diabetic foot ulcer
- at least once a year
- process: inspection of skin, assess foot deformities, neurological assessment, vascular assessment
- non pharmacotherapy for this (glycaemic control, quit smoking, good foot care)
screening test after confirming DM - diabetic nephropathy test
- T1DM within 5 yrs of onset
- T2DM upon diagnosis
- components
1) serum Cr +/- eGFR
2) urine albumin/creatinine ratio or protein-creatinine ratio if albuminuria heavy (≥ 300mg/g)
monitoring cardiovascular risk factors for DM
- macrovascular
1) HbA1c: X well controlled every 3 months, controlled every 6 month
2) lipid panel: X well controlled every 3-6 month, controlled annually
3) BP: Every visit
treatment goals for DM - HbA1c
1) less stringent: 7.5 - 8.0%
- history of severe hypoglycaemia
- limited life expectancy
- advanced complications
- extensive comorbid conditions
- target hard to attain despite intensive SMBG, repeated counselling, effective pharmacotherapy
2) normal: < 7.0%
3) more stringent: 6.0 - 6.5%
- short disease duration
- long life expectancy
- X significant cardiovascular disease
target for FBG & PPG
- mmol/L X 18 = mg/dL
- FBG: 4.4 - 7.2 mmol/L
- PPG: < 10 mmol/L
metformin - change in lab values
- 1.5 - 2.0% reduction in HbA1c
- marked reduction FBG
- mild reduce PPG
metformin - non DM uses
- polycystic ovarian syndrome (POS)
- weight loss
- improve lipid levels
metformin formulations
- immediate release: 250, 500, 850, 1000mg
- extended release: 500, 750,1000mg (BD)
metformin dosing
1) immediate release
- start 500 - 850 mg OD
- titrate 500 - 850mg every 1 - 2 wks in divided doses (OD - TDS)
- max 2550mg per day
2) extended release
- 500mg OD
- increase 500mg weekly
- max 2000mg OD, can divide into 1000mg BD
MOA of metformin
1) primary
- lower hepatic glucose production (gluconeogenesis)
2) Secondary
- enhance tissue sensitivity to insulin
- enhance peripheral glucose uptake & utilisation
- increase AMP activated protein kinase
PD for metformin
- onset within days
- duration of action 8-12 hrs
- max effect 2 wks
metformin PK
- absorption: oral
- elimination: renal, excreted unchanged in urine
metformin AE
1) common: GI disturbances (V/D/indigestion), metallic taste
- transient
- take w food/increase dose gradually
- diarrhoea -> weight loss
2) long term
- increase risk of Vit B12 malabsorption -> deficiency
3) rare but fatal
- lactic acidosis (block gluconeogenesis -> prevent lactic broken down to glucose -> increase lactate concentration -> lactic acidosis)
metformin special population
can use for pregnant & > 10 yo
metformin CI
- severe renal impairment (GFR < 30ml/min, worse than stage 4)
- hypoxic state/risk of hypovolemia (HF, sepsis, respi failure, liver impairment)
metformin drug interactions
1) alcohol: increase risk for lactic acidosis
2) iodinated contrast material
- radiologic procedure
- temporarily withhold metformin for 48 hrs after iodinated contrast administration
- restart when renal function stable & acceptable post procedure
3) inhibitor/inducer of organic cationic transporter (OCT)
- OCT 2 inhibitor: cimetidine, dolutegravir, ranolazine
- increase metformin by reducing renal elimination
Thiazolidinediones (TZD) indication
1) combination to reduce HbA1c when X tolerate metformin
2) change in lab values
- 0.5-.14% reduction HbA1c
- moderate reduction FBG & PPG
3) good for fatty liver disease
4) CV effect: reduce stroke risk, increase HF risk
thiazolidinediones (TZD) - formulation
15, 30mg tablets
thiazolidinediones (TZD) - MOA
PPARgamma agonist -> promote glucose uptake into target cells (skeletal/adipose), decrease insulin resistance & increase insulin sensitivity
thiazolidinediones (TZD) - PDPK
- 1 month max effect
- liver elimination
thiazolidinediones (TZD) - adverse effect
1) hepatotox
- monitor LFT prior initiation & after
- X use if ALT > 3x ULN
- if > 1.5x ULN then repeat tests
- discontinue if sign of hepatic dysfunction
2) fluid retention (monitor HF)
3) increase fracture risk (esp women)
4) weight gain (dose-related)
5) risk of bladder cancer
6) increased risk of hypoglycaemia w insulin therapy
thiazolidinediones (TZD) - CI
1) acute liver disease
2) symptomatic/history of HF
3) active/history of bladder cancer
thiazolidinediones (TZD) - drug interaction
- coadministered w CYP inhibitor/inducer
sulfonylureas (SU) - change in lab values
- 1.5% reduction HbA1c
- mild reduction FBG
- marked reduction PPG
types of sulfonylureas (SU)
1) 1st gen: tolbutamide
2) 2nd gen: glipizide, gliclazide, glibenclamide
3) 3rd gen: glimepiride
sulfonylureas dosage
- OD dosage improve adherence but $$
- take immediately after meal, X miss/delay meal
- caution if irregular meal schedule
sulfonylureas MOA
1) primary
- bind to SU receptor proteins of ATP sensitive potassium channels -> inhibit channel mediated K+ efflux -> trigger calcium dependent exocytosis of insulin granules from pancreatic beta cells
2) Secondary
- decrease hepatic glucose output & increase insulin sensitivity
sulfonylureas PD
onset 30 mins, duration of action 12-24 hrs
sulfonylureas PK
- oral absorption
- highly plasma protein bound, t1/2 4h
- hydroxylation in liver
- < 10% excreted unchanged in urine & faeces
AE sulfonylureas
hypoglycaemia (Esp elderly), weight gain
drug interaction sulfonylureas
- BB mask signs of hyperglycaemia
- disulfiram-like reaction w alcohol (more common w 1st gen)
- CYP2C9 inhibitor increase glimepiride & glipizide
DPP-4i - incretin
- released after eating
- augment secretion of insulin from pancreatic beta cells in glucose-dependent manner (presence of hyperglycaemia)
DPP-4i change in lab values
- 0.5 - 0.8% decrease HbA1c
- mild reduction FBG
- moderate reduction PPG
DPP-4i types
1) sitagliptin
- eGFR < 30 -> 25 mg OD
- eGFR 30 - 45 -> 50 mg OD
2) vildagliptin
- CrCl < 50 -> 50mg daily
- CrCl >50 -> 50mg BD
3) linagliptin
- X dose adjustment
DPP-4i MOA
- GLP-1 make you full by
1) decrease gastric emptying
2) improve beta cell function -> increase more insulin, reduce glucagon
3) decrease food intake
- DPP-4 inactivate GLP-1 so DPP-4i extends GLP-1 action
DDP-4i PK
- oral absorption
- t1/2 10-12h
- low liver metabolism
- 80% unchanged urine, rest shit
DDP-4i AE
- severe joint pain
- skin reaction (Rash, itch)
- hypersensitivity
- flu like symptoms
- GI
- rare: acute pancreatitis, bullous pemphigod (blister on skin)
DDP-4i drug interaction
CYP3A4 inhibitor
SGLT2-i cariorenal beneift
- cana & empa
- HF & CKD
- discontinue when start dialysis
SGLT2-i change in lab values
- reduce HbA1c by 0.8-1%
- moderate reduction FBG
- mild reduction PPG
types of SGLT2-i
1) Canagliflozin
- 100, 300mg
- X initiate if eGFR < 30ml/min
2) empagliflozin
- 10, 25mg
- X initiate if eGFR < 45ml/min
3) dapagliflozin
- 5, 10 mg
- X initiate if eGFR < 45 ml/min
SGLT2-i MOA
- inhibit SGLT2
- reduce absorption of filtered glucose
- reduce renal threshold for glucose & increase urinary glucose excretion
SGLT2-i PK
1) absorption
- oral, Cmax 1-2 hr
2) distribution
- highly plasma protein bound
- t1/2 12 hr, OD
3) minimal liver metabolism (glucuronidation)
4) excreted unchanged pee/shit
SGLT2-i AE
1) hypotension (titrate anti HTN)
2) hypoglycaemia
3) increase urination
4) genital mycotic infection/UTI
- more for female
- check UTI/history of fungal infection in vagina
- good toilet hygiene, drink more water
5) euglycemia diabetic ketoacidosis (DKA)
- more common if undergoing severe stress (dehydrated, alcohol abuse, X eating well, poor oral intake)
- hold of SGLT2-i until recover from stress
6) fournier’s gangrene
- more for males
- necrotising fascitis of perineum
- good toilet hygiene, drink more water
7) canagliflozin: lower limb amputation, hyperkalaemia, fracture
SGLT2-i CI
X dialysis
MOA of insulin - liver
1) decrease gluconeogenesis (make glucose
2) increase glycogenesis (convert to glycogen for storage)
3) decrease glycogenolysis (reduce breakdown of glycogen to glucose)
MOA of insulin - pancreas
increase insulin secretion
MOA of insulin - muscle
1) increase glucose transport
2) increase glycogenesis
3) inhibit proteolysis
MOA of insulin - adipocyte
1) increase glucose transport
2) increase protein synthesis
3) increase lipogenesis (make more fat cell)
4) decrease lipolysis & FFA oxidation (reduce breakdown of fat tissue)
metabolism of insulin
- exogenous: kidney
- endogenous: liver
insulin needle length
- pen needle: 4mm - 12.7mm
- syringe needle: 6mm - 12.7mm
insulin gauge size (needle thickness)
- 28, 29, 30, 31
- higher gauge = finer needle - lesser pain but increase needle weakness & decrease speed of injection
insulin syringe size
- 100 IU/ml
- 1cc: max dose 100, increment 2
- 1/2 cc: max dose 50, increment 1
- 3/10 cc: max dose 30, increment 1
insulin vial size
- U-100 (100 units/1mL of solution)
stability of insulin
1) unopened: good till expiration if store in fridge
2) opened: good for 28 days regardless of fridge
3) insulin containing device: product insert
4) detemir: opened good for 42 days
insulin administration sites
- outer upper arms: fatty tissue area
- abdomen: 2 inch circle around navel
- top & outer thigh: avoid bony area above knees
- rotate sites to prevent lipohypertrophy
- speed of absorption: abdomen > outer upper arm > top & outer thigh > buttock
factors that increase insulin absorption
1) heat
2) massage
3) exercise
4) lipoatrophy (concavity/pitting of adipose tissue)
5) IM administration
factors that decrease insulin absorption
1) cold
2) lipohypertrophy (bulging of adipose tissue)
indication for basal-prandial (basal/bolus)
- T1DM w severe insulin deficiency
- insulin deficiency - longer duration of T2DM
- tighter glucose control (coronary artery bypass grafting, gestational DM)
ultra short acting insulin
- added excipients to increase rate of absorption & stabilise
rapid acting insulin
- e.g. aspart (novorapid), lispro (humalog)
- target PPG (shjort action)
- 5 mins before meals
short acting/regular insulin
- e.g. actrapid
- target PPG, 30 mins before meals
intermediate acting insulin
- e.g. NPH (insulatard)
- target FPG, 16 hrs (inject 2x for 24 hrs coverage)
long acting insulin
- glargine (lantus), detemir (levemir)
- target FBG
what insulins cannot be mixed with others (pre/self mix)
1) glargine (incompatible pH)
2) glulisine (only can w NPH)
3) detemir
stable mixes for insulin
regular/rapid insulin + NPH
examples of compatible insulin mixtures
1) Novomix 30
- 30% short, 70% long, within 15 mins meal
2) humalog 75/25
- 25% short, 75% long, within 15 mins meal
3) humalog 50/50
- 50% short, 50% long, within 15 mins meal
4) mixtard 70/30
- 30% regular, 70% intermediate, within 30 mins meal
insulin + concurrent oral therapy
1) continue metformin
2) discontinue TZD or reduce dose when initiating
3) sulfonylureas
- discontinue/reduce dose by 50% when initiate basal
- discontinue if initiate prandial/premix
- effectiveness decrease over time
4) continue SGLT2-i
5) discontinue DPP-4i if initiate GLP-1
insulin dose conversion
- most 1:1 (basically same AM & PM doses)
- reduce by 10-20% if high risk of hypoglycaemia
- if switch from BD NPH (intermediate) -> OD glargine/detemir (long acting) -> decrease by 20%
- if switch from ultra long acting to other -> decrease by 20%
insulin AE
1) hypoglycaemia (BG < 4 mmol/L)
- S&S: blur vision, sweat, tremor, hunger, confuse, anxiety, shake, rapid heart beat, dizzy, headache, weakness & fatigue, irritability
- management: 15-15-15 (15g fast acting carbs, 15 mins waiting time, another 15g if still BG < 4.0 mmol/L)
2) weight gain
- dose dependent
- management: diet, exercise, lose weight
3) lipodystrophy
4) local allergic reaction
5) rare: systemic allergy, insulin resistance
types of GLP-1 agonist - liraglutide
- SC OD regardless of meals
- initiate 0.6 mg -> titrate 1.2 mg after 1 wk
- max 1.8 mg
types of GLP-1 agonist - Dulaglutide
- SC injection once weekly regardless of meals
- initiate 0.75mg -> titrate 1.5mg after 4 wks
- max 3/4.5mg
types of GLP-1 agonist - semaglutide (Ozempic)
- SC injection once wkly regardless of meals
- initiate 0.25 mg -> titrate to 0.5mg after 4 wks
- max 1mg
types of GLP-1 agonist - semaglutide (Rybelsus)
- PO OD 30 mins before first meal of day
** empty stomach (30 mins before meal, med, drink)
** X more than 120ml water - initiate 3mg -> titrate to 7mg after 30 days
- max 14mg
MOA of GLP-1 agonist
- activate GLP-1 receptor (GPCR) on pancreatic beta cell -> activate adenylate cyclase -> increase cAMP -> activate PKA -> phosphorylate all downstream proteins -> increase insulin secretion & decrease glucagon release
what extra thing does liraglutide & semaglutide have
- C-16 fatty acid on Lys -> Delay degradation & bind to plasma protein -> longer acting
GLP-1 agonist PK
- endogenously metabolised in similar manner to polypeptides wo specific major route of elimination
- little/non excreted unchanged
AE of GLP-1 agonist
headache, N/V, acute pancreatitis, acute cholecystitis, injection site reaction
special precaution for GLP-1 agonist
- X pregnant
- black box warning: thyroid C-cell tumour in animals -> counsel on risk of medullary thyroid carcinoma & symptoms of thyroid cancer
insulin dosing
1) initiation: basal control (FPG)
- bedtime NPH 10 units or 0.2/kg/day
- bedtime/morning glargine/detemir/degludex but $$
2) still controlled
- increase insulin 2 units every 3 days until FPG at goal
- increase insulin 4 units every 3 days if FPG consistently > 10 mmol/L
- decrease insulin by 10-0% if X clear reason for hypoglycaemia
3) uncontrolled after basal dose > 0.5 units/kg (ceiling effective dose or FPG at goal)
- prandial dose (rapid/regular)
** 1 dose (4 units/10% basal) w largest meal
** reduce basal by 4 units/10% if A1c < 8% - if bedtime NPH: split dose into 2 (2/3 morn, 1/3 evening)
treatment algorithm for DM from start to end
1) metformin 1st line if no CI
2) if A1c still elevated
- history of ASCVD/HD/CKD regardless of A1c
** ASCVD: GLP-1 agonist or SGLT-2i
** HF: SGLT2i
** CKD: SGLT2i then GLP-1 agonist - other combinations
** glucose lowering: insulin, GLP-1
** minimise hypoglycaemia: avoid SU, insulin
** promote weight loss: GLP-1, SGLT-2
when to initiate insulin?
1) ongoing catabolism (weight loss)
2) symptoms of hyperglycaemia
3) A1c > 10%
4) BG > 16.7 mmol/L
diabetic emergency - how is ketones formed
- break down fats -> produce fatty acids -> travel back to liver + glucagon -> change fatty acid into ketone (beta hydroxybutyrate measured in hospital)
diabetic emergency - diabetic ketoacidosis (DKA)
- more for type 1
- ketones formed
- testing: blood & urine, fruity breath, acidosis
- usually still alert
- BG > 14 mmol/L
diabetic emergency - hyperglycaemic hyperosmolar state (HHS)
- more for type 2
- residual insulin so X ketones & acidosis
- extremely dehydrated so BG can > 33
- stupor
why early morning blood sugar high but bedtime low?
1) Dawn phenomenon
- release of cortisol in waking hours -> BG rise sharply
2) Somogyi effect
- BG levels drop sharply at night (X eat + meds) -> body respond by releasing glucagon -> rebound increase BG
differentiate Somogyi effect & Dawn phenomenon
- consistently low sugar -> somogyi effect
BP management for DM
- target: BP < 130/80
- 1st line: ACEi/ARB w/wo kidney disease
lipid management in DM - primary prevention
- X cardiovascular disease but T2DM + risk factors
- 45-70 yo: moderate intensity statin
- additional ASCVD: high intensity
- goal: reduce LDL 50% baseline, < 70 mg/dL
lipid management in DM - secondary prevention
- already have cardiovascular disease
- target: LDL reduction 50% from baseline, < 55 mg/dL
- ASCVD: high intensity
- if X achieved then + ezetimibe/PCSK9i
CKD management in DM - primary prevention
- blood glucose, BP control
CKD management in DM - secondary prevention
1) ACEi/ARB for micro/macroalbuminuria
2) finerenone
- non steroidal MRA
- eGFR > 25
- SE: hyperkalaemia, hypotension, lesser risk of gynaecomastia
3) SGLT-2i
- T2DM + DKD + eGFR > 20
- ACEi/ARB
use of aspirin w insulin
- primary preventive measure for DM + increased CV risk + counsel on benefit vs risk of bleeding
- secondary preventive measure for DM + history of ASCVD
** use clopidogrel if allergic to aspirin - X for > 60 yo & low ASCVD risk
