Type-2 Diabetes Management Flashcards
How should therapy be chosen for T2DM?
Study Flow Chart
What is important for pharmacists and pt’s to know about Type-2 diabetes?
T2DM is a progressive disease – where you start is rarely where you will end
What is an example of a biguanides?
Metformin (Glucophage)
How does metformin work?
↓’s hepatic glucose production
Can also enhance sensitivity to insulin
Increases glucose utilization via action in the gut (interaction with incretins)
Has effects on the gut microbiome which may explain some anti-inflammatory effects
What is the dose for metformin? Does it require titration?
Start slow: Initiate at 250mg - 500mg od
Titrate up by 500mg weekly if no GI side effects
What is the desired usual dose of metformin?
Desired usual dose: 850 - 1000mg bid. Max dose of 850mg TID
- ADJUST in RENAL FAILURE
What is the efficacy of metformin?
- Decrease A1C by 1 to 1.5%
- Decreases TG and LDL, and slightly increases HDL
↓ MI & mortality in T2 patients with obesity (No definite evidence that metformin is cardio protective)
What are some drug interactions of metformin?
Cimetidine: competes for renal tubular secretion; ↑’s metformin levels by 60%
Dolutegravir: can increase metformin concentration
Alcohol: potentiates metformin’s effect on lactate metabolism; enhanced hypoglycemic effect
Contrast media: hold for 48hrs after imaging
Adverse Effects of Metformin. Common and Less Common
GI*: (up to 30% will experience, and about 5% will d/c)
Diarrhea, nausea, abdominal discomfort
Less common:
Metallic taste: if occurs, generally only lasts a few weeks
Vitamin B12 deficiency with long-term use (>5yrs)
Metformin Weight Loss?
Weight neutral to modest weight loss
Precaution of Metformin
Lactic acidosis: A ↓ in arterial pH & an accumulation of serum lactate (medical emergency)
Sx’s: weakness, malaise, myalgias, heavy laboured breathing
Metformin, in part, inhibits the conversion of lactate into glucose in the liver
Since it is eliminated unchanged by the kidneys, those with reduced eGFR will have reduced elimination. The concern is an accumulation of lactate
- Rare
Does metformin dose need to be educed in renal impairement?
Yes
Decrease dose if Clcr <60ml/min
eGFR 45-59: 1500mg/d (divided doses)
eGFR 30-44: 1000mg/d (divided doses) – check eGFR q3mos
CI when eGFR<30ml/min (majority of cases)
What are some risk factors for lactic acidosis?
- Effects on Kidney or Liver Function
History of lactic acidosis
Severe liver disease
Alcohol abuse
Radiologic procedures (iodinated contrast)
Acute illness (severe infection, trauma)
Severe dehydration
Why is metformin used first line?
Efficacy
Mild side effect profile
Long-term safety
Neutral effect on weight
Low hypoglycemia
Cost
Cardiac outcomes in overweight
Sulfonureas MOA
they enhance the secretion of insulin by beta-cells by binding to SU receptors on the beta cells of the pancreas
This leads to closing of K+ channels and opening of calcium channels which stimulates insulin secretion
they stimulate both basal and meal-stimulated insulin release
Sulfonureas are also known as
Insulin Secretagoues
What are examples of sulfonureas?
2nd generation: glyburide, gliclazide, glimepiride
Glyburide Dose? GFR?
Glyburide: 5mg–20mg/d (once or twice daily)
Usual dose is 5mg BID; may ↑ to 10mg BID
CI in eGFR<60ml/min
Gliclazide Dose. GFR?
Gliclazide: 80mg-160mg (80mg od or 80mg BID)
Gliclazide MR 30mg -120mg od
Caution in eGFR 30-60ml/min. CI in eGFR<30ml/min
Glimepiride Dose GFR?
Glimepiride: 1mg - 8mg/d
Caution in eGFR 30-60ml/min. CI in eGFR<30ml/min
Sulfonurea Taking Med Info
Take with food
Take in am
Start at lower doses and increase prn
Sulfonurea Efficacy. Better Response? renal Impairement?
↓ A1C 1 to 1.5% (up to 2% in drug naïve and elevated A1C)
May get a better response if initiated early in diagnosis; long-term durability is poor
Must dose adjust in renal impairment
Sulfonurea Onset of Action. Titration?
Work quickly: can start titrating dose after 2 weeks based on fasting BG, then can titrate every 1-2 weeks
Get bang for buck at lower doses (effective at ½ max dose and max effective dose is about 60-75% of the max dose)
Are sulfon ureas cardio-protective?
neutral CV outcomes –> No harm, no benefit
Adverse Effects of sulfonureas
Hypoglycemia (2-30%)
–> glyburide > glimepiride > gliclazide
Weight Gain
Less Frequent:
Less frequent (<2%):
nausea, skin reaction: rash, photosensitivity
Cross-sensitivity with those with a sulfa allergy is very rare (no C.I. with sulfa antibiotics, but cation with severe anaphylaxis)
Sulfonurea Precautions and C.I.’s
Pregnancy/breast-feeding (all cross placenta except glyburide)
Metabolized in the liver and excreted through kidneys. CI in severe hepatic and renal impairment
Hold in acute illness
Drug Interactions of Sulfonureas
When these drugs are used along with SU’s, there may be an increased risk of hypoglycemia:
Sulfonamides, salicylates, warfarin (via displacement from albumin binding sites)
Alcohol
Cimetidine, clarithromycin, fluconazole, NSAIDs, beta-blockers, MAOIs
Some drugs when combined may lead to lessened effects and increased blood sugar:
Phenytoin
Rifampin
Colesevelam (binding, separate by 4hrs)
Bosentan: glyburide can enhance its hepatoxic effects
Meglitinide Example and MOA
Repaglinide
Binds to a site adjacent to the SU receptor, resulting in stimulation of the secretion of insulin from the pancreas
Difference between meglinides and SU’s
Similar to SUs but have a faster onset and shorter D of A
Peak levels within 1 hour and half-life is 1 hour
Efficacy of Meglinides. Works primarily to….
↓ A1C 1 to 1.5% (similar to SUs)
Works primarily to decrease PPG: Is intended to be taken before meals to improve early phase meal-induced insulin secretion
Dosing of Repaglinide. Titration?
A1C <8%: initiate at 0.5mg (lower dose) before each meal + titrate up
A1C >8%. Initiate at 1-2mg (higher dose) before each meal + titrate up Max dose: 4mg before each meal (max dose 16mg/d)
Start at a low dose and titrate up every 1-2 weeks until target BG achieved
When does repalginlide need to be adminstered?
Due to its short D of A, it needs to be administered right before a meal (within 30 minutes)
Provides some flexibility:
skip a meal, skip a dose, add a meal, add a dose
repaglinide GFR
Use with caution if eGFR <30ml/min
Adverse Effects of repaglinide
Hypoglycemia (more so when combined with other agents)
Weight gain (~0.3 to 1kg)
Similar to SUs, but to a lesser extent
Precautions and C.I.’s of Repaglinide
Metabolized in the liver: CYP 450. Clearance significantly reduced in hepatic impairment. Hence, precaution with moderate hepatic impairment and CI with severe liver disease
Increased repaglinide with:
3A4 inhibitors (cyclosporine, clarithromycin, grapefruit, azoles
2C8 ( gemfibrozil, clopidogrel; these are CI)
Decreased repaglinide with 3A4 inducers (e.g. carbamazepine, rifampin) HIV medications
Alpha-Glucosidase Inhibitor Example and MAO. Net result?
Acarbose
α-Glucosidase enzymes in the small intestine are responsible for the breakdown of polysaccharides into absorbable glucose
Acarbose inhibits these enzymes, hence there is a delay in the rate of digestion of CHO’s and glucose absorption
Net effect is reduction in PPG levels
Efficacy of Acarbose. Effect other things?
A1C: ↓ 0.5-0.8%
Does not affect body weight or lipids
Dose of Acarbose. When is it adminstered?
Initial: 25-50mg od. Titrate up every couple of weeks to 50mg tid
Assess for efficacy q 4-8 weeks to a max dose of 100mg tid
Take with the first bite of each main meal
Acarbose Adverse Effects. Effect on weight? How should hypo be tx?
GI: flatulence (40-80%), diarrhea (30%) –> bloating, abdominal pain
May elevate ALT: monitor LFT’s first 6-12 months
Hypoglycemia: only negligible risk; may be ↑ with concomitant use of SU’s
Weight neutral
→ the digestion of sucrose is impaired by acarbose, hence hypo should be treated with glucose rather than sucrose
Acarbose D.I’s
Digestive enzyme preparations
May decrease digoxin effect
Cautions of Acarbose
Those with IBD or GI conditions
CI: eGFR<25ml/min and severe liver disease
Thiazolidines Examples
Rosiglitazone
Pioglitazone
Thiazolidines MOA
Bind to PPAR-γ receptors which are primarily found in adipose tissue. Activation alters genes that influence glucose and lipid metabolism
Enhance insulin sensitivity at muscle, liver, and fat tissues
They ↓ insulin resistance
↓ hepatic glucose production
Convert small, dense LDL particles to large, fluffy LDL’s that are less dense and less atherogenic
Efficacy of Thiazolidines –> A1C, TG, LDL, HDL?
↓ A1C 1 – 1.5%
Effects on TG: PIO ↓’s by 10-20%, Rosi neutral
Effects on LDL: Rosi ↑’s LDL 5-15%, Pio is neutral
Effects on HDL: Both may ↑ HDL to some degree
Thiazolidines Rosi Dose
Rosi: initiate at 2-4mg od; may ↑ to 4mg bid or 8mg od (greater effects seen bid)
Thiazolidine Pio Dose
initiate at 15mg od; titrate up to 30 - 45mg od
Thiazolidines Onset of Action
Have a delayed onset: wait 4-8 weeks for dose adjustments (max effects 3mos)
Larger people will generally require a larger dose
A to Z –> Long time
Thiazolidines GFR
Caution in eGFR <60ml/min (no dose adjustment required)
Thiazolidne Cautions
Mainly metabolized by liver: use with caution or use an alternative in severe liver disease (monitor LFT at baseline and periodically)
D.I.’s of Thiazolidines
Metabolized by CYP 2C8:
↑ effects with inhibitors (e.g. gemfibrizol, TMP)
↓ effects with inducers (rifampicin)
A/E of Thiazolidines
Peripheral edema(~5%); combined with insulin (~15%)
Hence, do not use with insulin
New-onset / worsening of HF
Weight gain (2.5 to 4.8kg; dose related)
↑ distal fractures in postmenopausal women
Caution in those at risk of fracture /elderly
Rare:
Macular edema: report any blurred vision, loss of sight
Anemia: not very common; long-term side effect
Pio Caution?
Bladder Cancer
Rosi caution?
Possible MI
Thiazolidines and HF
Heart failure: Both rosiglitazone and pioglitazone can promote fluid retention and edema & increase risk of HF → both are CI in heart failure
What are the two types of incretin based tx?
1) GLP-1 receptor Agonists (glucagon-lik peptide)
2) DPP-4 (dipeptidyl peptidase) inhibitors
GLP-1 receptor Agonists (glucagon-lik peptide) Examples
Exenatide
Liraglutide
Dulaglutide
Exenatide weekly
Lixisenatide
Semaglutide
“TIDES”
DPP-4 Inhibitor Examples
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
“LIPTINS”
What are incretin hormones? Type-2?
Are secreted from the gut in response to ingestion of nutrients
Main role is to augment (increase) insulin secretion
People with T2 have a reduced incretin effect
Activation of GLP-1 receptor results in:
Potent inhibition of gastric emptying
Potent inhibition of glucagon secretion
Reduction of food intake and body weight
What is the role of GLP-1? How does it breakdown?
Decreased gastric emptying, food intake and glucagon secretion
- Enzyme DPP-4 breaks it down
How do DPP4-i work?
Efficacy?
Onset of Action?
MOA: block the enzyme DPP4 (dipeptidyl peptidase-4) which rapidly hydrolyzes incretins, thus enhancing the action of endogenous incretins
As a result, they increase insulin release and decrease glucagon in a dose-dependant manner
Efficacy: A1C ↓ ~ 0.7 (ranges, but typically < 1%)
Work quickly – can see effects within a couple of weeks
Sitagliptin Dose. Renal Impairement?
100 mg po od
Decrease dose
Saxagliptin Dose. Renal?
5 mg po od
Decrese Dose
Linagliptin Dose. Renal?
5 mg po od
No dose adjustment for renal impairement
Alogliptin dose Renal?
25 mg po od
Dose adjustment
Is titration required for dpp4-i?
No
A/e of dpp4-i
Overall, well tolerated medications
No hypo on their own
Weight neutral
More common: headache, nasopharyngitis, URTI
Less common/Rare:
Hypersensitivity reactions
Bullous pemphigoid: An autoimmune disease presenting with urticarial plaques, subepidermal bullae, and pruritis. D/c if any new-onset diffuse itchiness, lesions/blisters
Joint Pain: case reports. If symptoms appear, contact HCP
Pancreatitis: case reports, but no causal relationships
Caution in those with a history of pancreatitis; report signs of acute pancreatitis to physician
Dpp4-i D.I.
When combined with a SU or insulin, may increase the risk of hypoglycemia (rates are still low)
Saxagliptin: clearance is reduced / enhanced with strong CYP 3A4 inhibitors and inducers
Linagliptin: clearance is enhanced with strong 3A4 inducers
All: avoid with GLP1RA: similar MOA and increased risk of pancreatitis (similar MOA)
GLP-1 receptor agonist MOA
stimulate insulin secretion in a glucose-dependent manner; ↓ glucagon, slow gastric emptying, increase satiety
- work all over the body
Where are GLP-1 recptor agonists stored? Exception?
At the pharmacy or at home and not in-use: in the fridge
Semaglutide oral (Rybelsus): room temp always
GLP-RA’s Short Acting
Exenatide
Lixsenatide
- Take with meals
Long-acting GLP-1 RA’s
Liraglutide
Exenatide
Dulaglutide
Semaglutide
Can take any time of day, irrespective of meals
Oral semaglutide Dose and Administration
- Low dose and titrate up 3–> 7–> 14 mg
empty stomach upon waking - take tab with sip of water
- wait 30 mins before eating, drinking, or taking other oral meds
GLP1RA’s Efficacy A1C Other Effects
↓ A1C by about 1 - 1.5%
Long-acting GLP’s more potent on A1C than short-acting
Work on both FPG and PPG, however, short-acting GLP’s have more effect on PPG, & long-acting have more effect on FPG
Modest decrease in blood pressure (within 3 weeks)
A/E’s of GLP1RA’s
Nauseau, vomitting, diarhhea
- Particularily Nauseau
GLP-1’s may increase the risk of retinopathy –> rapid glucose lowering can increase retinopathy
CI in personal/family history of MTC (medullary thyroid cancer) or MEN2 (multiple endocrine neoplasia syndrome type 2) –> Rare –> Never shown in humans; rat studies
GLP1RA’s Weight
GLP1RAs cause weight loss
Amount varies across clinical trials, but on average it is ~3kg weight loss
Weight loss is not due to N/V/D
GLP1RAs slow gastric emptying and cause a sense of satiety – leading to reduced food intake and weight loss
GLP1RA’s Hypo?
Low risk of hypoglycemia
When initiate a GLP1RA, depending on baseline BG, may either stop or decrease dose of SU, and perhaps ↓ insulin dose
D.I. GLP1RA’s
If a drug requires rapid GI absorption, space these oral agents out (≥ 1hr before the GLP1RA)
Oral contraceptives
Antibiotics
Narrow TI drugs
↑ levothyroxine by 33%
GLP1RA’s are _____ and ______ because
Have effects on CVD parameters such as BP, LDL/TG (although modest)
Have effects on weight (on average – modest reduction)
Have effects on BG, but ACCORD, VADT, ADVANCE only show modest decrease in non-fatal MI, not all-cause mortality
May help modulate vascular inflammation (inhibit atherogenesis)
Most likely due to a combination of metabolic, CV, and anti-inflammatory effects
Examples of SGLT2 Inhibitors
Dapaglifozin
Canaglifozin
Empaglifozin
SGLT2 Ihibitor MOA. Hypoglycemia?
SGLT2 is a high capacity transporter that is responsible for glucose reabsorption (90%) from the glomerular filtrate, & is overexpressed in those with T2DM
These drugs inhibit SGLT2, thereby decreasing the reabsorption of glucose, and ↑’ing urinary glucose excretion
They have insulin-independent action
There is no insulin stimulation, hence no hypoglycemia
SGLT-2 Efficacy. Work when?
↓ A1C 0.5-0.8% in clinical trials as add-on agent (same as acarbose)
Works on both FPG and PPG
Begin working quickly (FPG ↓ within 2 weeks)
What do SGLT-2 require to work?
hey require functioning nephrons to work; hence blood glucose lowering ability declines with ↓ renal function
Do SGLT-2 cause wght loss?
YES
Dose of SGLT-2
Are oral, once daily medications
Start at low dose; effects on A1C, cardio / renal outcomes are not dose-dependant
Do SGLT-2 require renal dose adjustments?
At eGFR<45, no longer effective for BG lowering (but beneficial for cardio renal protection)
What occurs when first starting an SGLT-2?
When initiating, they cause a very early decrease in kidney function – about 5ml/min in eGFR
This is not kidney damage – it is a hemodynamic effect that is reversed upon d/c
a/e of sglt-2
↑ urination, ↑thirst
mycotic genital infections
females (~8%) > males; usually 1 time only and rarely leads to d/c (once and done, happens once, get tx)
SGLT-2 Cardio Effects
Mild ↑ in LDL & HDL, and ↓ in TGs (all about 5%)
Mild ↓ in SBP and DBP (3-5mmHg and 2mmHG) – hence maybe some postural hypotension
C.I. of SGLT-2
Dehydration potential: use cautiously in patients at risk for volume depletion effects
Elderly, loop diuretics, low SBP, CKD, ACEi/ARBs
DKA risk: rare, but severe if it occurs
DKA and SGLT-2
withhold SGLT2i and check ketones regardless of BG value (as it can occur at normal BG) Notify physician if symptoms are occurring
Drug Interactions of SGLT-2
Concomitant use with diuretics may increase risk of hypovolemia and hypotension
SGLT2is cause diuresis and small ↓ in BP
If hypovolemia present, address before adding SGLT2i
If adding to someone on a diuretic, consider adjusting diuretic first
How are SGLT-2 cardio-renal protetctive?
They cause natriuesis and glucosuria – lowers cardiac pre-load and reduces pulmonary congestion and systemic edema
Decrease BP
Sodium depletion may improve ejection fraction
Stimulates renal erythropoietin secretion leading to new RBC formation and increased hematocrit – improved oxygen delivery
Decreases oxidative stress, local inflammation
Dose for Cardio-renal benefit
The dose of the SGLT2i doesn’t seem to matter (most of the time just use the lower dose
Insulin in Type-2
- Basal Insulin + antihyperglycemic medications
Usually initiated as 10 Units at bedtime - Basal and bolus insulin
- Biphasic (premixed) insulin
Why is basal insulin to start preferred?
Simplicity
Minimization of weight gain and hypoglycemia
Keeping oral meds on board helps with insulin sensitization (use lower amounts of insulin to achieve BG lowering)
What is overbasilization? When does it occur?
Basal insulin has a ceiling effect of about 0.5U/kg/d
If requiring >0.5U/kg/d, consider other options rather than continuing to increase the basal insulin dose –> Conversations about adding on naother insulin
Basal-Bolus Insulin Type-2
If patients are only willing to do 2 injections per day, BID split-mixed insulin is an option
If patients are willing to do MDI, start by introducing 1 prandial insulin at a time
Start with largest meal; 2-4U (most folks: supper time)
Titrate by 1-2U/week until FPG and PPG at target
As insulin gets added, consider removing secretagogues
Monitor for effectiveness (BG targets) as well as hypoglycemia
