DM - overview/ oral agents Flashcards
What is Pre-DM and what is clinically significant for a patient with pre-dm?
Pre-DM: ASYMPTOMATIC (predisposes individuals to T2DM & CARDIOVASCULAR DISEASE)
Entities of pre-DM: Impaired fasting glucose (IFG) & Impaired glucose tolerance (IGT)
Who & what should be screened for DM?
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
Prevention/ Delaying progression of DM
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
Diabetes definition & types
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)
T1DM pathogenesis
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
T2DM pathogenesis
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)
T1 vs T2DM
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)
Signs & symptoms of DM
*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
Parameters used to measure DM
- Fasting Blood Glucose: NO CALORIE INTAKE for >/=8h
- Random or casual plasma glucose: glucose @ any time of the day, regardless of meals
- Post Prandial Glucose (PPG): glucose level 2h after meal
*can also be measured by using a standard 75g oral glucose tolerance test (OGTT) - HbA1c: average amount of glucose in one’s blood over the past 3 months (glucose attached to hemoglobin for lifespan of RBC ~3months)
HbA1c definition & contribution
HbA1c = 3 months average of (FBG + PPG)
as HbA1c increases:
- Increasingly due to FAST/ basal hyperglycemia (FBG)
Criteria for diagnosis of DM
*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
Complications of DM & relevant monitoring tests
- 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) - 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 - Neuropathy (micro)
-> Diabetic Foot Screening (annually, daily by pt)
*encourage smokers to quit, educate on proper foot care & footwear - CVD (MACRO) [or metabolic syndrome]
Measure:
- HbA1c
- Lipid panel (annually, 3-6mth if not controlled)
- BP (every visit)
Treatment goals for DM (target values)
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
Does improvement in HbA1c decrease complications of DM?
Microvascular only; no correlation with macrovascular
Metformin indication, MOA, PK, dose, pregnancy use, ADR, DDI
- 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
Thiazolidinediones indication, MOA, PK, dose, pregnancy use, ADR, DDI
- 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
Sulfonylurea indication, MOA, dose, pregnancy use, ADR, DDI
*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
DPP-4i indication, MOA, dose, pregnancy use, ADR, DDI
*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
SGLT2i indication, MOA, dose, pregnancy use, ADR, CI
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
alpha-glucosidase inhibitors indication, MOA, PK, dose, pregnancy use, ADR, DDI
*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
What type of agent is GLP-1 Receptor AGONISTS?
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
Overview of GLP-1 RA agents available (dosing, AE)
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
Effects of GLP-1 RA
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)
Choice of injectables (GLP-1RA VS insulin)
GLP-1 RA as CHOICE of first-line injectable (over insulin) when GREATER GLUCOSE LOWERING is needed
Gestational DM frequency of blood glucose monitoring
7x a day:
before + after each meal
+
before bedtime
Management of patient newly diagnosed with T2DM (choice of pharmacologic agents, consideration of ASCVD/HF/CKD)
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
Consideration for add-ons (on top of metformin)
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
What is diabetic ketoacidosis? + how it arises
DIABETIC KETOACIDOSIS (DKA)
*ketones: byproducts of fat metabolism
MORE common in type 1»_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)
describe Somogyi effect & dawn phenomenon
*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
diabetic emergencies in T1DM & T2DM, common underlying cause(s)
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
Limitations of using HbA1c for monitoring
- 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)
