Noninsulin agents Flashcards
Oral agents
-metformin
-SGLT-2
-GLP-1
-DPP-4
-Sulfonylureas
-TZDs
Injectable agents
-GLP-1
-GIP and GLP-1
Person centered approach
-glycemic goals
-weight goals
-hypoglycemic risk (older peep)
-history of CVD/KD
-med cost
Metformin (Glucophage) MOA
-dec hepatic glucose production
-inc intestinal glucose utilization
-can inc GLP-1 secretion
-modest effect on inc tissue uptake and use by muscle
Metformin clinical applications
-adjunct to diet in t2dm
-combo
-consider for use in all t2dm
Why metformin recommended in t2dm
-reduce CVD rrisk
-extensive experience
-efficacious w minimal hypoglycemia
-positive/weight neutral effects
-cost effective
Off label indications metformin
-t1dm who are overweight w low ketoacidosis risk
-PCOS to lower androgen/inc ovulation
Overall efficacy metformin
-A1c 1.5-2%
-FBG: 60-80mg dec
Metformin excretion
-urine
-kidney function
Metformin advantages
-low hypoglycemia risk
-low lipids (LDL, TG)
-inc fibrinolysis = CV protection
-dec macrovasc probs
-dec stroke risk
-dec diabetic deaths
metformin disadvantages
-risk factor for fatal lactic acidosis (rare)
-GI side effects
-Vit B13 deficiency
-dementia risk
Risk factors of lactic acidosis in metformin use
-renal dysfunction (use eGFR not SCr)
-HF
-alcoholics
-shock
-COPD
-hepatic failure
-surgery/contrast dye
metformin and surgery
-hold metformin 1-2 days before and then around 2 days after depending upon pt status
Metformin GI effects
-30-50% pt
-diarrhea/flatulence
-N/V
-take w largest meal of the day
-titrate dosage
Vit B12 deficiency + metformin
-can worsen neuropathy
-monitor/provide supplementation
-check annually esp in pt w anemias and/or neuropathy
Risk of dementia w metformin
-controversial
-some say it does some say it doesn’t
Metformin dosing
-initial 500mg BID or 850mg qd wf
-titrate weekly and inc dose by 250-500mg
max dose of metformin
-2g/day actual
-2.5g/day according to package inserts
Metformin dosage forms
-500mg, 850mg, 1000mg
-SustainedActing formulation back (less GI effects) (recalled in 2020 bc NDMA levels that inc cancer and liver damage)
metformin and eGFR > 60
-no contraindication
-monitor SCr annually
metformin and 45 < eGFR < 60
-dafe
-continue use
-monitor SCr 3-6 month
metfromin and 30 < eGFR < 45
-not recommended
-recude dose by 50% if already taking
-monitor SCr q3months
metformin and eGFR < 3o
-do NOT start
-STOP if taking
SGLT2
-major transporter of renal glucose
-inhibition allows renal glucose excretion
-pissing sugar
SGLT-2 uses
-adjuct to diet/exercise t2dm
-recommended +/- metformin as initial therapy
SGLT-2 also good for pt w
-ASCVD or high risk
-HF
-CKD
SGLT efficacy
-A1c: 0.5-1%
-FBG: 25-35mg
-PPG: 40-60
-weight: 1-5kg
-x: dec
SGLT adverse effects
-UTI
-genital micotic infections
-inc urination
UTI from SGLT
-53% inc risk of UTI in t2dm in general
-not contraindicated in asx bacteruria
-pt w lots of UTIs should be seen for risk factors
-consider SLGT if pt UTI free for year
Genital mycotic infections (SGLT)
-already 81% inc risk in t2dm
-counsel on s/s and hygiene
-d/c in life threatening infections
FDA warning for serious genital infections
-necrotizinf faciitis of perimeum (Fournier’s gangrene)
-need abx and surgery
-seek med attention (tenderness, swelling, fever)
SLGT2 and urination
-pt w bladder probs not gonna want it
-AM dosing
other adverse effects SGLT2
-hypotension due to osmotic diuresis (worse on diuretics)
-hyperkalemia (rare)
-inc cholesterol
-DKA FDA warning
DKA risk and SGLT
-t2dm w mild elevated BG
-euglycemic
-illness, dec food/water intake, dec insulin dose, alcohol
-dont give to t1dm
DKA recommendations w SGLT
-hold 3 days before surgery (4 if ertugliflozin)
-restart once oral intake back to baseline
-wait until risk factors resolve
-discuss sick day rules
SGLT FDA warning
-DKA
-bone fracures + dec BMD
-AKI
-amputation risk
SGLT and bone fractures (canagliflozin)
-canagliflozin
-loss of BMD at spine and hip
-other flozins fine
-caution hypotension as fall risk
SGLT and AKI (canagliflozin and dapagliflozin)
-50% cases start within one month of starting tx
-pt improve after d/c
-volume depletion and hypotension likely causes
SGLT cautions
-dehydration or hypotension risk (diuretics, NSAIDs, ACEI/ARBs)
SGLT and amputation
-canagliflozin
-toes
-weigh risk v benefits
-monitor pain sores
-risk factors: amputations, PVD, neuropathy, foot ulcers
SGLT drugs
-Canagliflozin
-Dapagliflozin
-Empagliflozin
-Ertugliflozin
Canagliflozin dosing
-100mg qd
-max 300mg
-max 100mg if eGFR 30-60 and no signs of albuminuria
-or <30 may use if albuminuria >300 but don’t start
SGLT2 contraindication
-end stage renal failure on HD
-not gonna d/c until they are on dialysis tho
-use in pt w eGFR>20
Dapagliflozin dosing
-5mg
-10 max
Empagliflozin dosing
-10mg
-max25
Ertugliflozin dosing
-5mg qd
-max 15
SGLT2 counseling
-stay hydrated
-monitor renal function
-suspend use during acute illlness or planned surgery (3days (4 on ertugliglozin))
SGLT2 CV benefits
-better on outcome, hospitilizations
-good for renal protection
-starting to be used outside of diabetes (HF and CKD)
GLP-1 drugs
-Liraglutide
-Dulaglutide
-Semaglutide
-Exenatide
-Lixisenatide
GLP1s
-stimulate B-cell growth
-inhibit B-cell death
-short acting
-inhibit glucagon
-delays emptying (slow absorption)
-dec appetite
-highly resistant to DPP-IV
-inc first and second-phase insulin secretion
-GLUCOSE DEPENDENT (insulin only released w BG) less risk of hypoglycemia
Clinical applications of GLP-1
-intial therapy +/- metformin
-preferred to insulin in t2dm
-if insulin used, combo w GLP1 for better efficacy
GLP1 efficacy
-A1c more effective than SGLT2
-short-acting = PPG control
-long-acting = FBG control
-weight loss UP
GLP1 excretion
-short acting GLP-1 eliminated by kidneyss
GLP-1 contraindication
-severe renal disease
-pancreatitis (TG>300)
-thyroid cancer
GLP1 adverse effects
-dose dependent nausea
-V/D
-dose titration dec sx and will improve over couple weeks
-acute pancreatitis
-inc risk of thyroid tumors
-gall bladder disease
-Gastroparesis (avoid)
-Retinopathy
gall bladder disease from GLP-1
-esp high dose and long term use
-inc risk of gallstones, inflammation, biliary sludge
-use caution/avoid in preexisting gallbladder disease
-consider d/c if gallbladder probs
-prevent w low fat diet, hydration, activity
Gallstones (cholelithiasis)
-cholestero or bilirubin stones
-can block flow of bile = pain, infection, inflammation
-may alter bile composition
-rapid weight loss = rapid mobilization of cholesterol from adipose tissue during weight loss into bile
gallbladder disease
-ab pain (right upper quadrant)
-N/V
-fever
-use GLP w ca
Retinopathy in GLP-1
-caused by rapid drop in A1c
-CAUTION pt w nonproliferative retinopathy
-AVOID in proliferative diabetic retinopathy
Dulaglutide (trulicity) dosing
-0.75-4.5mg
-qweek
-do NOT use in ESRD
-needles included
Semaglutide (Ozempic) dosing
-0.25 x 4 weeks then 0.5mg-2mg
-qweek
-needles included
Liraglutide (victoza) dosing
-0.6mg x 7 days the 1.2-1.8mg
-qd
Exenatide (Byetta) dosing
-5mcg x month then 10 mcg
-BID
-avoid if CrCl<30
Lixisenatide (Adylyxin) dosing
-10mcg x 14 fays then 20mcg
-avoid eGFR< 15
-qd
Dulaglutide (trulicity) counseling
-admin in thigh, ab, arm
-single dose pens
-remove cap, press pen aginst skin and press button
-good for needlephobes
Semaglutide (ozempic) counseling
-admin thigh, ab, arm
-store pens in fridge
-can store 56 days at room temp
-check flow every pen
Liraglutide (victoza) counseling
-give any time of day independent of meals
-admin in thigh, ab, arm
-pre-filled pens
Oral semaglutide (rybelsus)
-3mg PO x 30 days then inc 7mg qd
-inc 14mg if needed
-can change to 7mg if on 0.5mg SQ
-take 30 min before first food or other oral meds with no more than 4 oz water (vomiting)
GLP1 benefits
-CVD and renal
dual GIP/GLP1
-Tirzepatide (Mounjaro)
Tirzapatide (mounjaro)
-enhance both phase insulin secretion
-reduce glucagon levels in glucose-dependent manner
-delay gastric emptying
-inc satiety
Tirzepatide (Mounjaro) efficacy
-A1c: 1.5-2.3 close to metformin
-FBG: 40-60
-weight loss 6-11kg
tirzepatide adverse effects
-similar to GLPs
-N/V/D
-pancreatitis, thyroid tumors, gallbladder disease
-tachycardia
Tirzepatide dosing
-2.5mg SQ weekly
-adjust qmonth by 2.5mg/week
-up to 15mg weekly
DPP-4 inhibitors
-Sitagliptin (Januvia)
-Saxagliptin (Onglyza)
-Linagliptin (Tradjenta)
-Alogliptin (Nesina)
-not as strong efficacy
-weight neutral
-renal dosing
DPP-4 adverse effects
-nasopharygitis
-upper RTI
-headaches
-pancreatitis
-joint pain
-HF risk (sitagliptin fine tho)
which DPP-4 for HF
-sitagliptin
Whidh DPP-4 not renally eliminated
-linagliptin
-no dose adjustment required
Sitagliptin dosing
-100mg CrCl >50
-50 mg CrCl 30-50
-25mg for CrCl <30 or HD
Saxagliptin dosing
-2.5-5mg qd
-2.5mg for CrCl <50
Linagliptin
-5 mg qd
-no renal dose adjustment
Alogliptin
-25mg qd CrCl > 50
-12.5mg CrCl 30-50
-6.25mg CrCl < 30 or HD
Sulfonylureas moa
-stimulate insulin release from B cells
-may inc binding between insulin and receptors or inc amt of receptors
-glucose independent tho (hypoglycemia)
Sulfonylurea clinical application
-adjuct diet/exercise t2dm
-combo w insulin and non insulin
-CHEAP
Sulfonylurea efficacy
-A1c: dec 1-2%
-FBG dec 60-70
2nd gen sulfonylureas
-Glipizide*
-Glyburide
-Glimepiride
-we dont use 1st gen
Sulfoynlurea kinetics
-glyburide and glipizide more effective when taken 30 min BEFORE meal
-metabolized by liver
-excreted in urine
-glipizide metabolized w/o formation of active metabolites = better in renal disease
sulfonylurea preferred in renal disease
-glipizide
-no formation of active metabolites
-good for elderly too
Sulfonylureas adverse effects
-hypoglycemia
-weight gain
-hematologic
-allergy (steven johnsons)(sulfa)
hypoglycemia + sulfonylurea risk
-renal/hepatic probs
-elderly or malnourished
-other hypoglycemic drugs
sulfonylurea hematologic adverse effects
-leukopenia
-thrombocytopenia
-aplastic anemia
-sulfa component
sulfonylurea dosing
-start low and slow esp in old ppl
-inc dose every 1-2 weeks until max
-max dose inc side effects w no benefit
sulfonylurea max dosing
-about 60-75% of current max dose listed
-glipizide might actually be 20mg
Glipizide dose
-start 2.5-5mg qd
-max 40mg (20mg for XL)
Glyburide dose
-start 1.25-5mg qd
-max 20mg
Glyburide micronized dose
-start 1.5-3mg qd
-max 12mg
Sulfonylurea population cautions
-elderly
-renal/hepatic disease
-irregular dietary intake
-alcoholics
-with hypoglycemic agents
-all inc risk of hypoglycemia
Sulfonylurea best candidates
-type 2 only
-short duration of diabetes (newly diagnosed)
-FBS < 250mg/dL
-high fasting C-peptide levels
Sulfonylurea treatment failure
-25% primary failure
-after 5 years, 50-75% secondary failure
-common failure after 612 months
Thiazolidinediones (TZDs) MOA
-bind to peroxisome proliferator activator receptor y on fat cells and vascular cells (PPAR-y)
-improve cell response to insulin w/o inc secretion
-dec insulin resistance
-dec hepatic glucose production
other benefits of TZDs
-Pioglitazone can dec TG by 10-20%
-LDL unchanged w Pioglitazone but maybe inc w rosiglitazone (converts LDL to large fluffy ones?)
-inc HDL 3-9 mg/dL
-inc endothelial function
-slight dec in BP
TZD efficacy
-dec A1c 0.5-1.5%
-FBG dec 60-70
-dependent on insulinemia
TZD adverse effects
-Hepatotoxicity
-resume ovulation (good in PCOS tho)
-exacerbations of HF
-macular edema
-inc fracture risk 25%
TZD hepatotxicity
-check baseline LFTs
-do NOT start is LFTs > 2.5x nl
-check LFTs periodically
-d/c if LFTs > 3x normal
-monitor N/v, ab pain, fatigue, anorexia, urine
TZD monitoring
-LFTs > 3x = d/c
-N/V
-ab pain
-fatigue
-anorexia
-dark urine
TZD and HF
-caution in pt w NYHA class 3-4 HF
-inc edema
-inc weight
which TZD we using
-pioglitazone
Pioglitazone (TZD) dosing
-start 15-30mg qd
-max 30-45mg
-inc dose every 12 WEEKS
Tx principles for T2DM
-treat aggressively to achieve goals
-start diet/exercise
-consider metformin and combo therapy
-consider weight
considerations for T2DM tx
-disease states
-BG and A1c
-HYPOglycemia risk
-SE
-impact on weight
-cost and other pt factors
T2DM tx in ASCVD, HF, CKD
-SGLT2is and GLP1s
When to start dual therapy T2DM
-A1c > 1.5-2% above goal
-or A1c > 7.5-9%
-at least 8.5% get them on 2
Insulin tx for T2DM
-prefer GLP1 when possible
-use insulin if:
-weight loss
-hyperglycemia signs
-A1c > 10%
-BG> 300mg/dL
-recommend BASAL insulin combo therapy w GLP1
-go to basal-bolus insulin for tighter control if no GLP1
-be aware of overbasalization
-additional therapy if goals not reached after 3 months
Overbasalization
-if basal dose is 0.5units/kg/day or high variability in BG readings
-evaluate basal level and consider basal-bolus
1st line for T2DM w ASCVD
-GLP1 or SGLT2
1st line in pt w HF
-SGLT2
1st line in pt w CKD
-SGLT2
-GLP1 if not
Efficacy considerations
-Metformin
-consider combo
-avoid risk of HYPOglycemia when necessary
Tx for pt that need to minimize weight gain
-GLP1 or SGLT2
Rx to avoid in pt that need to minimize weight gain
-sulfonylureas
-meglitinides
-TZDs
Cost considerations
-cheaper: sulfonylureas and TZDs
drug chart
drug chart
