DM Flashcards
insulin effect
- Increase uptake of glucose, translocate GLUT 4
- GLUT 4: muscle, adipose tissue
- GLUT2: kidney, liver, pancreatic b cell
- GLUT3: neurons
- Glycogenesis
- Glucose –> glycogen (storage in liver muscle)
- Also causes:
○ lipogenesis (FFA–> TG in adipose tissue)
Proteogenesis (aa –> proteins in muscle)
glucagon effect
- Glycogenolysis
- Glycogen –> glucose
- Lipolysis
- TGL –> FFA –> glycerol + ketones
- Proteolysis
- Protein –> aa
- Gluconeogenesis
- Aa –> glucose
Glycerol –> glucose
- Aa –> glucose
DM acute consequences
*Polyuria (excess urine production)
*Polydipsia (extreme thirst)
1) Excess BGL & urine
2) Osmotic diuresis
3) More urine produced
4) Dehydration
a) Decr blood vol –> peripheral circ failure –> renal failure –> death
b) Polydipsia –> cell shrink –> nervous system malfunction
*Polyphagia (appetite)
1) Incr glucose uptake
2) But still poor intake of glucose intracellularly
*Ketosis – rapid breathing
1) Use up other sources for energy
2) Decr TG synthesis & Incr lipolysis
3) Incr blood FA
4) Alternative energy source
5) Ketosis –> metabolic acidosis
a) Incr ventilation
b) Diabetic coma
i) Death (acidosis depress brain)
**fruity breath [acetone as by-product of fat metabolism]
*death
*weightloss
1) Decr aa uptake by cells + incr prot degradation
2) Muscle waste –> weight loss
3) Incr blood aa –> incr gluconeogenesis
4) Aggravates hyperglycemia (body has glucose but cannot use)
Degenerative blood vessels
□ Microvascular: retinopathy, nerve damage, kidney failure
□ Macrovascular: stroke, heart attack, reduce blood circ
Degenerative blood vessels
□ Microvascular: retinopathy, nerve damage, kidney failure
□ Macrovascular: stroke, heart attack, reduce blood circ
sx diabetes
Symptoms:
1) Tired
2) Weight loss
3) Slow wound healing
4) Sexual problems
5) Vaginal infections
6) Numb, tingling in feet
7) Blurry vision
8) Polydipsia,
9) polyphagia, polyuria
Incretins
Grp of metabolic hormones: released after eating
GIP (DPP4i)
GLP-1 (GLP1 Receptor agonist)
function of incretins
Augment secretory insulin released from pancreatic B cells of islets of Langerhans
Glucose-dependent manner – only when hyperglycemia
1) Gastric emptying in stomach
2) Glucose dependent insulin biosynthesis and secretion
i. Decr glucagon
ii. Improve b-cell function
3) Decr food intake (brain signal)
i. NV (common ADR)
Glucose-dependent insulinotropic polypeptide (GIP)
a. Insulin secretion
b. Expansion of pancreatic B cell
Glucagon-like peptide 1 (GLP-1)
a. Satiety
b. Gastric emptying decr
- Decr weight gain
METFORMIN MOA
- Incr glucose uptake into tissues
- Inhibit gluconeogenesis in liver
* Incr AMP-activated protein kinase - Enhance tissue sensitivity to insulin
* Uptake more glucose - Useful for obese pts
Weight loss and improve lipid levels
function of metformin
- Does not cause hyperinsulinemia
- No hypoglycemia
- Weight loss
- T2DM
- Alone/ other oral hypoglycemic agents
PK of metformins
A: PO, (duration 8-12hr)
D: rapidly distributed, minimal plasma protein binding
(T1/2 ~ 3hr)
M: NA
E: excreted unchanged in urine
- avoid in pt w/ renal insuff
- titrate
ADR of metformin
- Anorexia (LOA –> weight loss)
- GI disturbances
- Diarrhea, vomit indigestion, weight loss
- Take with/ after meal
- risk of Vit B12 def
- Malabsorption, more in LDC
CI of metformin
- Renal problems
- Lactic acidosis (hepatic, CVS problem)
Sulphonylurea MOA
- Glipizide
- Insulin secretagogues (2nd gen)
- Pancreatic b cells secrete insulin
1) SU bind to SU receptor proteins (subunit of K ATP channels)
2) Drug binding inhibits K ATP channel mediated K+ efflux
3) Depolarisation, Ca2+ influx
4) Trigger Ca dependent exocytosis of insulin granules
- from pancreatic B cells
glipizide function
Lowers BGL acutely
* Activate release of insulin from pancreas
* Depends on functioning B cells in pancreas islets
K ATP channel:
b cell ATP-sensitive K channel
- major role in control B cell mem potential
Glipizide: 2nd gen lower risk of hypoglycemia than other SU
PK of glipizide
A: PO
- F>95%, delayed with food intake
- (onset 0.5hr)
- (duration 12-24hr)
D: binds extensively 99% to plasma proteins (albumin)
(T1/2 ~ 4hr)
M: liver (90%)
E: <10% excreted unchanged in urine, feces
Metabolites: urine, feces
- avoid in renal insuff
- titrate
glipizide metabolism
- P1: hydroxylation
- liver disease, titrate
ADR of glipizide
- Hypoglycemia
- Elderly (poorer liver, kidney function)
*Weight gain
Sitagliptin
DPP-4i MOA
1) Binds, inhibit DPP4
2) Decr enzymatic degradation of GLP-1
3) Prolong action of endogenous insulin (by body)
* Stimulate B cells Release insulin (as if there is presence of glucose)
4) Suppress a- cell mediated glucagon release & hepatic glucose production
* Decr BGL (less glucagon)
DPP-4i function
- Incretin-based therapy
- Dipeptidyl peptidase-1 inhibitor
- less break down incretin
Mono: when MET not suitable/ no response
Combi: MET/ SU/ TZD + DPP4i
Triple:
Insulin+MET/
MET+SU/
MET+TZD
DPP4i PK
A: PO
- F ~ 87%
D: (T1/2 ~ 10-12hr)
M: low liver metabolism
E: 80% excreted in urine
- avoid in renal insuff
- titrate
DPP4i ADR
- GI disturbances
- Flu-like symptoms
- Headache, running nose, sore throat
- Skin reactions
DPP4i CI
- Pt with history of pancreatitis
GLP1 inhibited, incr B cell secretion —> Over stimulate pancreas
Liraglutide MOA
GLP-1 agonist
- Activate GLP-1 receptor
- Mem GPCR on Pancreatic B cells (conformational change)
- Activate adenylate cyclase
- Incr cAMP
- Incr PKA
a. Downstream activation - Incr insulin release and Decr glucagon release
- Insulin secretion subsides as blood glucose conc decr
- Approach euglycemia
structure of GLP-1 agonist
LA peptide (DPP-4 resistant form of GLP-1*)
- C16 FA prevents cleavage breakdown, incr t1/2
function of GLP1 agonist (pros and cons)
- Initial rapid release of endogenous insulin
- Suppress glucagon release
- Delay gastric emptying
- Reduce appetite (weight loss) – Manage obese pt
- Reduce risk of CVS death, non-fatal MI, HF among T2DM pt
Adjunct: for pt not achieve glycemic control w/ oral (first-line) anti-hyperglycemic agent - Expensive $$$ ($700/mnth)
PK of GLP1 agonist
A: SC, (OD dose –> 3mg maintenance dose)
F = 55%
D: C16 FA binds to plasma proteins (albumin)
(T1/2 ~ extend to 13hr)
M: endogenous metabolised in similar manner to large proteins w/o specific organ (non-specific catabolism)
E: 60% renal, 5% feces
Empagliflozin
SGLT2i MOA
- Inhibit sodium-glucose co-transporter-2 (SGLT2)
-Decr reabsorption of filtered glucose in Proximal tubules- Decr renal threshold for glucose
- Incr urinary glucose excretion
-Glucosuria
- DM pts have too high BGL, kidney unable to reabsorb , over saturated
*SGLT2i: stop reabsorption all tgt, just excrete as much glucose as possible
SGLT2i function
- Reduced risk of major cardiac event (11% in pt with asCVD)
- Reduce risk of composite endpt
- Worsening renal function
- Renal failure
- Renal death
- Similar benefit in those with OR w/o asth CVD
Dual: MET
Dual: SU
Triple: MET + SF
SGLT2i PK
A: PO
- F~ 60-80%
- Cmax 1-2h
D: (T1/2 ~ 12h) so only OD
- 90% plasma protein binding
M: meta in liver – Phase 2: glucuronidation (incr solubility)
E: 40% feces, 55% urine
SGLT2i ADR
- UTI
- Incr urination
- Female genital mycotic (fungal) infection
- Diabetic ketoacidosis
diabetes classification
metabolic disorder characterised by resistance to action of insulin, insuff insulin secretion or both
- clinical manifestation = HYEPRGLYCEMIA
types of DM
type 1
type 2
gestation DM
others (infection, monogenic DM syndrome, endocrinopathies, pancreatic destruction)
drug – steroids, HIV, immunosupp, Ab
removal of pancreas
T1 definition
Absolute deficiency of pancreatic b-cell function
- Immune mediated destruction
- Positive Ab
○ Islet cells
○ GAD
○ Insulin
○ Tyrosine phosphatases IA-2, 2b, zinc transporters 8 (ZnT8)
Autoimmune disease
T1 staging
1) Autoimmune (Ab+ve)
-Normoglycemia
- Presymp
2) Autoimmune (Ab+ve)
- Dysglycemia
- Presymp
3) New onset hyperglycemia
- Symptomatic
- (Ab+ve)
(onset is rapid)
NO C-peptide level, no insulin production
presentation in type 1
Young onset, <30yrs
Abrupt clinical presentation (when reach metabolic ketosis – high BGL)
Often thin appearance
type 1 DKA
Diabetic ketosis
* High risk
* Emergency as when BGL too high, insulin too low
* Body breaks down muscle –> ketones produced
* H+: acidity
T2 pathogenesis
- Progressive loss of adequate b-cell insulin secretion (background of insulin resistance)
- Insulin resistance
* Presence of insulin but glucose ultilisation (unable to ab from blood) is impaired* Hepatic glucose output incrs -- not respond to high BGL * Early stage: elevation in both glucose and blood insulin lvls
type 2 onset
(slow onset)
1) Normal insulin release
2) Reduced insulin release
- C-peptide present, remission
- Glucose abnormal –> Overt DM
3) Absent insulin release
- C-peptide absent
C peptide (insulin production)
short aa chain, by-product of insulin
Released into blood when insulin produced by pancreas
clinical presentation of type2
Often >40yrs, incr prevalent in obese children, younger adults
Gradual, still have insulin production
Often overweight appearance (metabolic syndromes)
type 2 metabolic syndrome
Risk of:
- DM, polycystic ovary syndrome, fatty liver
abdominal obesity + 2/4 of factors
- Abdominal obesity (waist circum)
○ M: >90cm
○ F: > 80cm
- TG > 1.7mmol/L , on meds (150mg/dL)
- HDL
- M: <1mmol/L (40mg/dL)
- W: <13 mmol/L (50mg/dL) - BP
- >130/85 mmHg, or on meds - Fasting glucose
- >5.6mmol/L (100mg/dL)
screening for Asx adults
screening at ANY age if risk factors
- metabolic syndrome, obese, gestational, HTN, HDLc/TG, PCOS, CVD
no risk factors = >40yo
- every 3 yrs for annual glucose tolerance
annual for IFG, IGT
hyperglycemia sx
Polydipsia
Polyuria
Polyphagia
Dry skin
Drowsy
Blurred vision
Decr healing
hypoglycemia sx
Shaking
Fast HR
Sweat
Dizzy
Anxious
Hunger
Impaired vision
Weakness, fatigue
Headache
Irritable
shared sx in both HYPER, HYPO
shake
dizzy
drowsy
hungry
fatigue
Parameters to measure DM control
1) Fasting plasma glucose (FPG)
2) Random, casual plasma glucose
3) Postprandial plasma glucose (PPG)
4) Hemoglobin A1c (HbA1c/ A1C)
Fasting plasma glucose (FPG)
No calorie intake for >8hrs
Random, casual plasma glucose
a. Glucose level at any time of the day
Regardless of meals
Postprandial plasma glucose
a. Glucose level measured after meal – 2hrs
b. Measured using standardised 75g oral glucose tolerance test (OGTT)
Hemoglobin A1c (HbA1c/ A1C)
a. Measure average amt of glucose in person’s blood over past 3mnths
b. Glucose stays attached to hemoglobin for lifespan of RBC ~120 days
HbA1c dependent on RBC count
RBC low = hbA1c low
RBC last longer than 120days, anemia = higher hbA1c
RBC shorter lfiespan = decr
vit B12 decr, less erythropoietin = incr
blood loss, incr erythropoietin = decr
blood transfusion (dilute) = decr
renal failure = decr
preg = decr
HbA1c = 3mnths average of _____
i. Fasting (FPG) + postprandial (PPG) combined
- Basal and postprandial contributes to hyperglycemia
- Basal hyperglycemia contributes more to high HbA1c
Use of glucometers
- Monitor hypo/hyperglycemia
○ Adjust meds, diet, exercise - Frequency varies
○ T1DM, preg women, insulin pump users
- >4 times daily
- Before meals/ snacks (3), bed time, 3am
T2DM freq of monitoring
> 3 times daily
-Often at practise setting: pt check before bfast & 2hrs after largest meal = 3times
□ Before fasting, after meal (2hrs after largest meal)
§ for pt: on multiple inj of insulin
§ For pt: less freq insulin inj/ noninsulin therapies/ medical nutrition therapy alone/ self monitor blood glucose (SMBG)
□ Guide for success of therapy
□ Monitor for glucometer use initially and at regular intervals
diagnose DM in SG
2 abnormal test results from same blood sample may be used to diagnose T2DM
- HbA1c >7
HbA1c 6.1-6.9%
+
FPG>7mmol/L
2hOGTT >11.1mmol/L
pre-dm
HbA1c 6.1-6.9%
+
FPG 6.1-6.9 mmol/L
2hOGTT 7.8 - 11mmol/L
How does culture/ race influence DM risk?
- Genetics/ fam history
○ Asians incr risk of developing T2DM, compared to Europeans
○ Asians, less muscle, more abdominal fat, incr insulin resistance - Environment
○ Stress levels — binge eating, fast food, less exercise time
○ Poor health literacy, misconceptions (more rice to keep u full)
○ Language barrier - Food
○ Asian diet carb heavy
○ Stir fry/ deep fry with oil
effects when fasting, RAMADAN
no food
= Hypogly
= hypergly (Lack exercise, Binge eat )
no water
* Risk dehydration, thrombosis
* Risk acute DM
DKA, HHS
no meds
= hypergly
= acute DM (DKA, HHS)
adjust for DM in fasting pt
○ TDS –> BD
○ Reduce meds with high HYPOGLY potential
○ Evening dose > morning dose (heavier meal)
- But adjust accordingly as pt will overall eat less during fasting period
DF/ wound care
○ Foot infections are common and serious complications of DM
○ Gram +ve cocci (staphylo, streptococci) —> mild-moderate infections
○MIXED +ve cocci, -ve bacilli, anaerobic org —> CHRONIC/ severe infections
wound care for DF
(TIME)
○ TISSUE: assess for non-viable/ necrotic tissue (debride)
○ INFECTION: chronic wounds stuck in INFLAMMATION (bacterial) – Need remove bact, infection
○ MOISTURE: assess, manage wound EXUDATE
○ EDGE OF WOUND: non advancing wound edge and conditions of periwound
DF risk factors for wound
○ Poor glycemic control
○ Peripheral artery disease (poor blood supply)
○ Peripheral neuropathy (tingling/ no feeling)
○ Visual impairment (unable to see wounds on the foot)
○ Smoking (incr risk of inflam, clot, damage to vascular tissue, decr artery thickness)
Foot care education:
Maximise BGL control, reduce risk factors
Self examine foot
§ Every night
Foot protection
§ Socks, fitted shoes
§ No bare foot
Nail, foot care, hygiene
§ 1-2 mins soak with soap, between toes
□ Too moist, weakens skin
□ Moisturize to prevent dry skin, cracking
§ NAILS:
□ Sharp edge to prevent ingrown
Annual foot examination
§ Visual / vascular assessment of foot pulses / neuropathy monofilament test
□ Pulse: popliteal art, dorsalis pedis art, posterior tibial art
HbA1c and microvascular complications
effectively delays ONSET, SLOW progression of DM (MICRO complications)
retinopathy, nephropathy, neuropathy in T2DM
1% Decr HbA1c ~ reduce risk of 35% MICRO
HbA1c and macrovascular complication
CV outcome improve as HbA1c decr
WORSENS as HbA1c decr
HYPOGLY –> contribute to CVS mortality
DM goals in sg
HbA1cL <7 (7-8.5% for vulnerable)
FBG 5-7mmol/dL
PPG <10 mmol/dL
stringent goal
6-6.5%
□ Shorter disease duration
□ Long life expectancy
□ No significant CVS disease
Less stringent goal
7.5-8%
□ History of severe hypoglycemia
□ Limited life expectancy
□ Advanced complications
□ Extensive comorbid conditions
□ Unable to attain target even when:
-Intensive SMBG
- Repeated counselling
-Effective pharmacotherapy
monitor parameters for DM
HbA1c Every 3mn –> 6mn (stable)
lipid (3-6mn –> annual (stable)
BP (every visit)
eye (6mn –> annual (stable)
Albuminuria/ renal function (6mn –> stable) depends in protein/ albumin present in urine
foot (everyday, annual by podiatrist)
DM Nonpharmacologic therapy:
Therapeutic lifestyle change (TLC) — 1st line
1) Quit smoking (5A: Ask, Assess, Advice, Assist, Arrange)
2) Weight reduction
-Achieve, maintain 7% loss of initial body weight
- Beneficial for pt newly diagnosed, reduce risk of resistance to insulin
3) Exercise
-150min/ week. Moderate intensity
- Muscle strengthening activity
- >55yr: balance, functional training
4) Diet modification
- Fruit, vege, grains, cereals, legumes
- Skinless poultry, fish, lean meat
- Low fat dairy products
- Restrict alcohol, simple carbs (lower TG)
PO PHARMACOLOGICAL DM
metformin
Sulfonylureas (SU)
Thiazolidinediones (TZDs)
a-glucosidase inhibitors
GLP-1 receptor agonists
DPP4i
SGLT2i
metformin benefits
- Decr HbA1c 1.5% ~2%
- Negligible weight gain, hypoglycemia
- 1st choice in T2DM , Gestational DM
○ If no CI - Low SE risk
- Positive effect on lipids
○ TG -0.13mmol/L
○ TC: - 0.26
○ LDL: -0.22 - May reduce CVS events
- Delay T2DM (for preDM)
○ BMI > 35
○ Age > 60yrs
○ Women w/ prior gestational DM
metformin MOA
1) Decr hepatic glucose production
2) Incr peripheral, muscle glucose uptake and ultilisation
- Insulin sensitivity
metformin PK and dose
Regular: 850mg tab TDS
Extended release: 1g tab TDS
*max dose at 2.5-2.55g per day
* Onset (within days). Max effect in 2wks
Elimination: RENAL. 90% unchanged in urine
ADR of metformin
Common: GI, anorexia, metallic taste (w/ food)
LT: decr B12 serum conc
- monitor anemia, peripheral neuropathy
- megaloblastic anemia (decr RBC, but incr size)
- Rare, fatal: lactic acidosis
lactic acidosis
Nausea, shallow/ laboured breathing, mental confusion
glucose –> pyruvate (when O2)
glucose –> lactate (when lack O2, anaerobic resp)
Incr lactate = lactate acidosis
○ Metformin decr metabolism of pyruvate. Inhibits enzyme for metabolism
= hypoxic state
CI for metformin
- Severe renal impairment
○ Renally cleared
GFR: 30-45: use half dose
<30: STOP, do not start, do not continue - Hypoxic state/ risk hypoxemia –> lactate acidosis
○ HF
○ Sepsis (infection in body, hypotension. Insuff O2)
○ Liver impairment (cannot clear pyruvate)
○ Alcoholism (malnutrition)
○ >80yrs (unless hypoxic)
DDI for metformin
- EtOH: incr risk for lactic acidosis
- Iodinated contrast material/ radiologic procedure
○ Temp hold metfomin for 48hrs after admin
○ Continue when renal function normal - Cationic drugs
○ Dofetilide, cimetidine, digoxin
○ Compete for renal tubular transport (metformin incr)
SU indications
- Manage T2DM when cannot manage with Exercise, diet
- Use w/ other agents/ insulin
Generation:
1) Rarely used as incr likelihood for ADR – Tolbutamide
2) Glipizide, gliclazide, gilbenclamide
3) Glimepiride
benefits of SU
- Decr HbA1c by 1.5% (presence of functioning B cells)
- Cost effective therapy
- For renal pts (glipizide CL Hepatically)
risk for SU
- Need functional b cells
- No other apparent benefits other than lower BGL
- Caution for pt with irregular meals (hypogly)
- Weight gain risk
MOA of SU
1) Stimulate insulin secretion
* Block K+ channel of B cell
* Need functional B cells
* Lose effectiveness over time, when gain insulin resistance
2) Decr hepatic glucose output
* Incr insulin sensitivity
dose of glipizide (SU)
- DF: 5,10mg
- Given: 5mg BD (max 40mg /day)
- Inactive metabolites
- Elimination: 90% H,R
- Prevent accumulate in body, hypogly risk
15-30mins before meals
* If skip meal, don’t take med –no food, no need for insulin
*Mostly for postprandial glucose (post meal insulin)
ADR of SU
- Hypoglycemia (esp in elderly)
- Weight gain (2-5kg)
- Blood dyscrasias (rare)
DDI fo SU
- Mask hypogly symptoms (prevents tremors, rise in HR)
○ Except sweating - Disulfiram-like rxn
○ When take alcohol
○ 1st > 2nd/ 3rd
adverse reaction to alcohol leading to NV, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. - CYP2C9i – Amiodarone, 5FU, fluoxetine
○ incr glipizide, glimepiride
TZD indications
rosiglitazone
pioglitazone
- Manage T2DM as mono/ combi (other anti DM)
- Only pioglitazone can be used in combi w/ insulin
- Others will have strong hypogly effect
benefits of TZD
Benefits:
* Decr HbA1c by 0.5 - 1.4%
* Benefit pt with FATTY LIVER DISEASE
- NAFLD, NASH
risk of TZD
Risks:
* HF stage 3,4
* LT use, incr risk of fractures
* Weight gain
* Liver toxicity
- Takes mnth to work
- Eliminated by liver
TZD MOA
- Peroxisome proliferator activated receptors agonist
- Promote glucose uptake into target cells (skeletal muscle/ adipose)
- Decr insulin resistance
- Incr insulin sensitive
dose for TZD
rosiglitazone 4mg OD (max 8mg)
pioglitazone 15mg OD (max 45mg)
Monitor for LFT (bimonthly –> annually)
ADR of TZD
- Incr risk of CONGESTIVE HF
- If HF signs, sx develop
- Hepatotoxicity
- Oedema (HF?) — weight gain
- Fracture (F > M)
- Bladder cancer (piog)
- Elevated LDL (ros)
Hepatotoxicity when to start TZD
- Hepatotoxicity
- NOT start if
○ ALT >3XUNL - DISCONTINUE
○ ALT > 3X UNL
○ If hepatic dysfunction sx start - > 1.5 UNL during therapy (repeat LFT wkly until normal)
- NOT start if
CI for TZD
- NYHA class III, IV HF
○ BLACK BOX WARNING- Need observe for signs, sx
○ After initiate/ dose incr - If HF signs, sx develop
○ Appropriate HF management needed
○Discontinue/ dose reduction
- Need observe for signs, sx
- Active liver disease
a-glucosidase inhibitors indication
Management of T2DM when hypergly cannot be managed by diet alone
- not used as mono
(off-label) treat T1DM on insulin therapy, but need additional PPG control
a-glucosidase inhibitors risk and benefits
benefits:
* Decr HbA1c by 0.5-0.8%
* Control postprandial blood glucose
* Carb-rich diet
○ Can take with largest meal of day
○ With meal that consists most carbs
* onset is rapid with each meal
risk: Flatulence #1 cause for drug discontinuation
a-glucosidase inhibutor MOA
1) Delay glucose absorption and lowers PPG by completely inhibit brush border a-glucosidase enzyme
2) Required for breakdown of complex carbs
Acts LOCALLY
a-glucosidase dose
- ACARBOSE
- 25, 50, 100mg
- Start: 25mg TDS with each meal
○ Incr by 25mg/day every 2-4 wks - Max dose:
○ 150mg/day (<60kg)
○ 300mg/day (>60kg)
Decr of PPG is dose dependent
a-glucosidase PKPD
PD: rapid onset with each meal
PK: elimination, 50% via feces
a-glucosidase ADR
- GI
- Flatulence **
- Abdominal pain
- Diarrhea (common cause for drug discontinuation)
○ Osmotic diarrhea
§ Draws fluid into gut due to cards, complex in gut
- Incr LFT
- For ACARBOSE
- Incr dose > 100mg TDS
*Hepatotoxic
CI for a-glucosidase
- Breast feed
*GI diseases (obstruct, irritable bowel disease)
DDI for a-glucosidase
Intestinal adsorbents, digestive enzyme prep
May decr effects
GLP-1 receptor agonists
Liraglutide indication
§ GLP-1 receptor agonist
□ Binds to b-cell
□ Same effect as endogenous GLP1
1) Gastric emptying in stomach
2) Glucose dependent insulin biosynthesis and secretion
i. Decr glucagon
ii. Improve b-cell function
3) Decr food intake (brain signal)
i. NV (common ADR)
benefits of GLP1 agonist
Decr HbA1c by 0.7-1.5%
Weight loss
□ Overweight pts (NV, diarrhea)
1st line injectable > insulin
other benefits
□ ASCVD (benefits)
□ HF (neutral)
□CKD (minimal benefit)
Liraglutide dose
- Sc inj OD regardless of meals
- Initiate:
○ 0.6mg - Titrate
○ 1.2mg after 1 week
○ Max 1.8mg
NIL renal adjustment needed
liraglutide ADR
- GI effects: NV, diarrhea
- Acute pancreatitis
*Dyspepsia - Black box warning: thyroid c-cell tumours
- In animals, counsel risk for pt
Medullary thyroid carcinoma
- In animals, counsel risk for pt
DPP4i indication
Sitagliptin
Linagliptin
Inhibit DPP-4 enzyme and incr conc of endogenous incretins
same function, MOA as GLP1 agonist
DDP4i benefit
- Decr HbA1c by 0.5-0.9% (monotherapy)
- Very mild ADR
- Usually 2/3rd line
Combi therapy
DPP4i vs GLP1 agonist
ADV: ROA is PO
DISADV:
weight neutral, smaller HbA1c reduction
no big 3 benefits
sita pancreatitis
sita vs lina dose
- Sitagliptin
- 100mg OD
○ CrCl 30-50m/min = 50mg OD
○ Severe renal impairment, ESRD = 25mg OD
- 100mg OD
- Linagliptin
- 5mg OD
- No renal adjustment
sita vs lina ADR
- Sitagliptin
- Acute pancreatitis
- HA
- NV
- Ab pain
- Skin reaction
- Angioedema
- Linagliptin
- Naso pharyngitis
SEVERE JOINT PAIN
sita vs lina DDI
- Sitagliptin
- Incr Digoxin
- Linagliptin
* CYP3A4 inducers will decr linagliptin action
SGLT2i MOA
Empagliflozin
Canagliflozin
Dapagliflozin
- SGLT2 glucose transporters located in proximal tubule (of kidney)
- Inhibited:
○ Incr renal glucose excretion
○ Decr blood glucose
SGLT2i benefits
- HbA1c: 0.8-1%
- Slight weight loss benefits
- Other benefits:
○ Glucosuria
○ ASCVD: benefits if use CANA, EMPA
○ HF: benefits if DAPA, EMPA
○CKD: benefits (mostly DAPA)
dose for SGLT2i
Canagliflozin
* 100mg, 300mg PO
* Taken before 1st meal
Empagliflozin
* 10, 25mg PO
* Taken with or without food
Dapagliflozin
* 5, 10mg PO
* Taken with or without food
SGLT2i ADR
- Hypotension
- Hypoglycemia
- Renal impairment
- Incr LDL
- Urinary urgency
- Genital mycotic infection, UTI >5%
- Incr risk of diabetic ketoacidosis
- Euglycemic DKA
- Fournier’s gangrene
- Canagliflozin:
* Amputations, hyperkalemia, fractures
SGLT2i CI
ESRD
dialysis
- require kidney function for drug to exert effect
SGLT2i in renal pts
- GFR > 30ml/min can be treated with SGLT2i (esp if have T2DM, CKD)
- Continue even if <30ml/min
- Unless not tolerated/ kidney replacement therapy initiated
- Efficacy (not safety issue):
- SGLT2i requires kidney to have some function, and to be able to reach site of action at proximal tubule
> 1.5% reduction in HbA1c
metformin (1.5 - 2%) — fasting BG, weight loss
SU (1.5 - 2%) — Post-prandial BG, weight gain
moderate decr in HbA1c (<1.5)
GLP1 Receptor agonist (0.7-1.5%), weight loss, post-prandial
TZD 0.5-1.4%, weight gain, fast/ppg
low HbA1c reduction
SGLT2i (0.8-1%) weight loss, mod fasting bgl
DPP4i (0.5-0.9%) weight neut, mod PPG
a-glucosidase i (0.5-0.8%) neut weight, mod PPG
lipid profile in DM
decr HDL
incr LDL marginally, incr TG
higher risk of atherosclerosis
TLC for hyperlipidemia (LDL)
exercise, weight loss (10kg), unsat fat have a marginal decr in LDL
sat and trans FA have greatest incr LDL
target LDL for very high risk ASCVD
<2.1 mmol/L
DM complication: macroalbuminuria (irreversible kidney damage)
- but if CVD event then <1.8 mmol/L
peripheral disease (stroke, ACS, IHD)
target LDL for high risk ASCVD
<2.6 mmol/L
incldues DM pt – CVS risk equivalent!!!
target LDL for moderate risk ASCVD
<3.4 mmol/L
target LDL for low risk ASCVD
<4.1 (SG)
<3.0 (if can tolerate ESC)
agents for hyperlipidemia
statins: inhibit HMG-CoA reductase (-21-63%)
ezetimibe: inhibit NPC1L1 protein, inhibit chloesterol absorption in SI (-21-27% add on to statins)
statins potency
rosuvastatin > atorvastatin > simvastatin > lovastatin = pravastatin = fluvastatin
rosuvastatin 5mg = atorvastatin 20mg
40% lowering
double dose = 6-7% lowering
hypertriglyceridemia
statins first line
unless TG >4.5% (consider fibrates add-on)
- risk pancreatitis, need to reduce TG levels
lipid perturbation in DM
marginally raised LDL
high TG
low HDL
metabolic syndrome, may not be statins that caused risk of DM
HDL < 1mmol/L
exercise most effective
why SGLT2i impt
improve outcomes in HF, faster outcomes
TZD, DPP4i, insulin incr HF
mechanism of SGLT2i
improved myocardial energetics
improved myocardial ionic homeostasis
incr EPO, Hb conc
autophagy (weight loss)
altered adipokine regulation (RBC)
monitoring and counselling for sglt2i
infectious complications (UTI, mycotic genital infections)
diabetic ketoacidosis (DKA)
diuresis and naturesis
acute kidney injury
infectious complications (UTI, mycotic genital infections)
- glucosuria, incr risk for GMI
- common in 1st mnths after initiate. F>M
-maintain genital hygiene, dry
**fournier gangrene (males)
diabetic ketoacidosis
- esp in T1DM (no insulin production)
- > 20% insulin reduction, lean body, F, alcohol abuse, intercurrent illness, trauma
- monitor urine ketones.
- ACUTE ILLNESS (diarrhea, vomit, extended fasting/ fluid) discontinue SGLT2i resumed 24-48hr following recovery
- withheld 2-3days before surgery
DKA sx
vomit
ab pain
SOB
fruit smelling breath
diuresis and natriuresis
- osmotic diuresis effect of SGLT2i: risk vol depletion
* during acute illeness risk: NVD
2*: hemoconcentration
loop diuresis (hypoK, Mg)
thiazide (serum uric acid)
- sick day advice, hold SGLT2i until sx resolve
- HF fluid restrict less strict if they euvolemic, not fluid congested
AKI
AKI not incr by SGLT2i
fluid intake counselling (depends!)
renal effects of SGLT2i
initial dip in GFR (1-2 wks by 5ml.min)
slow return over 3-9mnths
rate of decline in GFR slower than untx (renal protective in LT)
