DM-2 Flashcards
Decreased insulin secretion __________ beta cells sensitivity to glucose
decreased
What is the drug of choice for type 2 diabetes
metformin
Metformin is transported into the cells by organic _______ transporters
cation
Metformin is excreted into urine by what
MATE 1 and 2
OCT-1 and OCT-3 are in _______ for activity in the liver
hepatocytes
OCT-2 are in ____ cells for excretion
renal
Metformin has a slow onset and a long duration of action meaning it is what kind of coverage
basal
Effects of metformin in liver
decrease gluconeogenesis
decrease lipogenesis and increase fatty acid oxidation
Effects of metformin in muscle
increase glucose uptake
increase glycogen storage
decrease lipogenesis
Effects of metformin in intestine
decrease intestinal glucose absorption
MOA of metformin (biguanides)
-decrease cellular respiration by inhibiting mitochondrial respiratory chain complex 1
-decrease ATP by inhibiting fructose 1,6 bisphosphate
-activate AMPK causing protein phosphorylation and decrease gluconeogenesis and lipogenesis gene expression
-antagonizes the action of glucagon by inhibiting adenylate cyclase
Adverse effects of metformin
GI upset
Metallic taste
decrease Vit B12
Rare: lactic acidosis
Metformin drug interaction with inhibitors of _____ transporters
OCT
Metformin drug interactions with drugs that increase plasma glucose can _________ the effects
antagonize (corticosteroids, estrogens)
Cimetidine _______ renal elimination of metformin
decreases
Ranolazine ___________ metformin serum levels
increase
Iodinated contrast media can enhance _______ adverse effecrs and renal failure
metformin
Insulin secretagogues are effective in patients with functional ______ cells
beta
Sulfonylureas cover _____ insulin levels and ________ insulin
basal
mealtime
MOA of sulfonylureas
-Bind to SUR 1 complex in Katp channel
-activate exocytosis and release endogenous insulin independent of plasma glucose
-increase tissue sensitivity to insulin (improved metabolic control)
-decreased hepatic glucose production and increase glucose uptake
Sulfonylureas adverse effects
hypoglycemia
weight gain
(GI, hematological rxn, hypersensitivity rxns, SIADH)
Aspirin, sulfonamides, chlorofibrates cause increased hypoglycemic effect in which drug class
Sulfonylureas
Miconazole, chloramphenicol, warfarin decrease __________ metabolism
Sulfonylureas
Ethanol increase action of _____________
Sulfonylureas
_________ are two hormones secreted from enteroendocrine cells in the intestine in response to food intake
incretins
______ is secreted from L-cells
GLP-1
_____ is secreted from K-cells
GIP
Incretins are metabolized by
DPP-4
_______ activate insulin secretion from the pancreas in response to food intake
incretins
GLP-1 MOA
-insulin secretion by activation of GLP-1 GPCR on beta cells
-receptor also in other cells
-PKA phosphorylates the channel (closes it)
-increase calcium from intracellular store -> exocytosis -> insulin secretion
GLP-1 is secreted into circulation from endocrine L cells in ______ __________ after a meal
small intestine
GLP-1 Effects in brain, stomach, liver, pancreas
brain: decrease appetite
stomach: decrease gastric empty
liver: decrease glucose production
pancreas: increase insulin secretion, decrease glucagon secretion
What two classes of drugs can restore GLP-1 activity from decreased GLP-1 postprandial, inadequate glucagon suppression, increase glucose output
GLP-1 analogs
DPP-4 inhibitors
Short-acting GLP-1 receptor agonists (exenatide, lixisenatide) cause what
postprandial hyperglycemia
Long-acting GLP-1 receptor agonists (exenatide, dulaglutide, liraglutide, semaglutide) cause what
basal glycemia
Metabolism of GLP-1 RA
proteolytic degradation and beta oxidation of FA
Adverse effects of GLP-1 RA
nausea, vomiting, diarrhea
weight loss
(hypersensitivity, hypoglycemia, altered kidney function, thyroid cancer, pancreatitis)
Contraindications of GLP-1 RAs
hypersensitivity rxns
GI problems or moderate to severe kidney disease
FH of medullary thyroid cancer
pregnancy
breast-feeding
Drugs that affect gastric emptying and drug absorption from GI tract cause a drug interaction with what class of drugs
GLP-1 RAs
Increased risk of hypoglycemia when used with other antidiabetic drugs cause a drug interaction with what class of drugs
GLP-1 RAs
Drugs that elevate plasma glucose and antagonize effect cause drug interaction with what class of drugs
GLP-1 RAs
What class of drug is Tirzepatide and what does it treat
GIP/GLP-1 RA
diabetes and obesity
Effects of Tirzepatide
significantly lower blood glucose levels
improve insulin sensitivity
reduce weight
amend dyslipidemia
When to take DPP-4 drugs
mealtime
DPP-4 MOA
-inhibit DPP-4 enzyme found on cell membrane
-serine protease cleaves N-t aa to inactivate incretins
-inhibit degradation of GLP-1 and GIP increasing levels of endogenous incretins and increase insulin secretion in a glucose independent manner
Effects of DPP-4 I
increase cellular glucose uptake
decrease hepatic glucose output
Adverse effects of DPP-4
pharyngitis/upper respiratory tract infections
hypoglycemia w/ other antidiabetic agents
(pancreatitis, hypersensitivity rxn, hepatotoxicity)
Drugs that inhibit CYP3A4/5 will elevate plasma levels in which class of drugs
DPP-4
Corticosteroids decrease effects of which class of drugs
DPP-4
All metabolites of SGLT-2s are _______
inactive
Filtered glucose is returned to the circulation by the action what
SGLT 1 and 2
_________ is in the s1/s2 segments and is a low affinity and high capacity transporter
SGLT-2
________ is in s3 segment of the proximal convoluted tubule and has high affinity and is a low capacity transporter
SGLT-1
SGLT2 Inhibitors MOA
-suppress of glucose reabsorption
-insulin-dependent
-decrease hyperglycemia by increasing urinary clearance of glucose to improve glycemic control and decrease toxicity
-do not confer a risk of hypoglycemia
-efficacy is reduced in renal impaired function
What SGLT-2 drug is the only inhibitor that also inhibits SGLT-1
Invokana
Side effects of SGLT2
-genital fungal and urinary infection
-GI, nausea, constipation
-hypotension and hypovolemia
-hypersensitivity
-not used in pregnancy
Side effects of metformin
diarrhea
stomach upset
nausea
vit B12 deficiency
Renal considerations in metformin
GFR <30 Cl contraindication
GFR <45 no new start, cut dose by 50%
What are these other considerations drug class apart of: weight neutral and insulin sensitizer
Metformin
GLP-1 agonists and GLP/G1P agonist side effects
nausea
vomiting
Other consideration in GLP-1 agonists and GLP/G1P agonists
injection
weight loss
reverse/improve insulin deficiency
global shortages
GLP-1 RAs risk and reduction
benefit: CKD and ASCVD
used: clinical ASCVD and high risk, albuminuria (>300mg/g)
SGLT-2 Inhibitors side effects
genital infections (yeast and UTI)
Other considerations in SGLT-2 inhibitors
weight loss
diuresis (BP lowering)
SGLT-2’s risk and reduction
Benefits: CKD, ASCVD, heart failure
Used: clinical and high-risk ASCVD, albuminuria (>300mg/g +eGFR >25), HF
Sulfonylureas side effects
weight gain
hypoglycemia
Sulfonylureas other considerations
pancreas burn out
renal adjustment needed
mechanistically unfavorable
DPP-IV inhibitors side effects
infectious complications (URIs)
usually very well tolerated
Other consideration in DPP-IV Inhibitors
renal adjustment (except tradjenta)
weight neutral
What are the 5 steps in diabetes management
glucose control
cardiorenal risk (anti-clotting, statin, ACE, GLP-1, SGLT-2)
DRP
Monitor
Follow-up
What are the fasting and post-pranial goals for diabetes
fasting: <130
post-prandial: <180
Statin use in diabetes
40-75 and low risk = moderate intensity
ASCVD or high risk = high intensity
Anti-clotting drugs in diabetes
ASCVD
-ASA
-low dose rivaroxaban if low bleeding risk
ACE/ARB in diabetes
UACR >30 +/- HTN
Drug-related problems in diabetes patients
drugs that interfere w/ glucose control
smoking
duplicate therapy
sulfonylureas + mealtime insulin
DPP-IV plus GLP-1s
Drugs that require renal adjustment
Monitoring of non-insulin diabetes medications
blood sugar checks
-bid to qid -> unstable hypoglycemia, MDI insulin
A1C
-every 3 months if not at goal, every 6 months if at goal
What is the pharmacophore in sulfonylureas
benzenesulfonylurea (weak acids)
First generation sulfonylureas have small __________ substituent on phenyl ring of _____
lipophilic
R1
First generation sulfonylureas have lipophilic ____ or _______ substituent on non-sulfonyl-attached urea nitrogen on R2
alkyl
cycloalkyl
Second-generation sulfonylureas are more _____ than first generation
potent (rapid onset and longer duration of action)
The enhancement of glyburide activity is attributed to the strong binding affinity of that what group
p-beta-arylcarboxyamidoethyl
Metformin is the only biguanides derivative and is considered to be the _____ ______ therapy for treatment of type 2 DM
first line (basic drug with 2 guanidine groups)
Metformin in high doses can increase what
lactic acidosis
Thiazolidenediones (TZD) are classic examples of PPAR gamma agonists and are commonly referred to as the ___________
glitazones (increased sensitization of cells to insulin)
What is the pharmacophore of TZDs
thiazolidinedione moiety
The ______ ring attached to the TZD ring via methylene group is essential for activity
phenyl
A ___________ linker is found to be more potent than the ___________ counterpart of TZD
saturated
unsaturated
__________ at either carbon adjacent to the pyridine ring leads to metabolites which appear to contribute to the biological activity of pioglitazone
oxidation
GLP-1 exists in two equipotent forms of GLP-1 (__-__)-NH2 and GLP-1 (__-__)
2-36
7-37
GLP-1 is rapidly metabolized by an aminopeptidase enzyme which is called what
DPP-IV
One of the reasons that GLP-1 is susceptible to DPP-IV is because it contains an ____ in the penultimate N-terminal position
Ala
Exenatide is a GLP-1 analogue that has a modification at position 8 of what
Gly instead of Ala
Liraglutide is a GLP-1 analogue that has a modification of what
Lys 26
Arg 34
(best combination for albumin binding)
Dulaglutide is a GLP-1 analogue that has a modification of what
fusion protein that is prepared by fusing two identical GLP-1 analogs protecting it from inactivation
Lixisenatide is a GLP-1 analogue that has a modification of what
Gly at position 8
ser and lys tail
extends half-life
Semaglutide is a GLP-1 analogue that has a modification of what
amino-terminal sequence on ala 8
lys 26
(fatty acid chain enhances affinity for albumin)
The fatty-diacid section of tirzepatide is linked via a _________ acid and two acetic acids units to the side chain of the lysine residue
glutamic
(once weekly dosing)
DPP-IV are peptide derivatives of alpha-aminoacyl pyrrolidines or alpha-aminoacyl thiazolidines which also take advantage of the enzyme’s high preference for ____ binding
Pro
DPP-IV have an electrophilic group in the 2-position of the pyrrolidine or thiazolidine ring where ______ is the most common group present
cyano (Vildagliptin, Saxagliptin, and Alogliptin)
DPP-IV have ______ _______ group in the position equivalent to the penultimate amino acid (Ala) in GLP-1 which also is important for binding through ionic interaction with Glu205 and Glu206 of DDP-IV.
basic amino
The aminopiperidine’s primary amino group occupies the recognition site for the amino terminus of GLP-1, and hydrogen and ionic bonds with Glu residues. What drug class does this belong to
DPP-IV
SGLT2 is expressed in the epithelial cells of the brush border of S1 and S2 segments of the proximal convoluted of renal tubule and reabsorbs ___ to ____% of filtered glucose.
80-90%
Changing the O-glycoside linkage to a C-glycoside linkage has led to the development of __________ structures that are resistant to hydrolysis by b-glucosidases in the gut.
“Gliflozin”
UGT -> uridine glucuronyltransferases
(have an aryl moiety linked to a benzyl group pharmacophore)
Macrovascular DM indications
CVD and PVD
Microvascular DM indications
retinopathy
nephropathy
neuropathy
-peripheral
-autonomic
There are slight differences between how and when complications may develop in type 1 versus type 2 diabetes
Most mechanisms, screening, and treatment recommendations remain the same for both
Glycemic control is the primary prevention and treatment for all _____________ complications
microvascular
Relationship between _____________ complications and glycemic control: Its complicated
macrovascular
Unifying Mechanism
-Hyperglycemia leads to increased production of reactive oxygen species which may activate all of these pathways
-Some pathways may predominate in certain organs/areas
Medications emphasized under CV Risk
statins
ASA
rivaroxaban
icosapent ethyl
ezetimbie
PCSK-9I
SGLT-2I
GLP-1
ACE/ARB
Bempidoic Acid
How do you identify cardiovascular disease?
MI, PVD, CHF, CAD, angina, stroke, PCI, Stent, ACS, USA, CABG
Additional major risk factors for CVD according to the ADA
Hypertension
Hyperlipidemia
Smoking
Family History
Albuminurea
Obesity
CKD
Preventing Cardiovascular Disease
Glycemic Control
Weight Loss in overweight and obese patients
HTN management
Lipid management
Anti-clotting agents
Drug classes with evidence in reducing CV events in DM patients: (HTN)
Beta-blockers (mask sign of hypoglycemia)
Give one antihypertensive at bedtime
ACE/ARB with albuminuria or CAD
Primary goal of hyperlipidemia
LDL <70 mg/dl, <55 mg/dl if ASCVD
Secondary Goals of hyperlipidemia
HDL>40 mg/dL
TG<150 mg/dL
at >500 mg/dl TG become primary target
Screening recommendations of hyperlipdemia
Check lipid panel every 5 years if not on statin, yearly if on statin
Primary Prevention (no ASCVD) 40-75 years old
moderate intensity statin
Primary Prevention (no ASCVD) multiple risk factors
high intensity statin
Primary Prevention (no ASCVD) ASCVD Risk >20%
High Intensity +/- ezetimibe to lower LDL by 50%
Secondary Prevention (ASCVD)
High intensity statin for all
Secondary Prevention (ASCVD) If LDL >70 with statin
consider addition of ezetimibe (cheaper) or PCSK9 inhibitor (more effective)
Secondary Prevention (ASCVD) If 75-year-old and already on statin vs not on a statin
on statin: keep it
not on statin: consider risk/benefit
DM + ASCVD + elevated TG
may add icosapent ethyl
Statin + Fibrate or Niacin
generally not recommended
Statins and DM Risk
benefit of statins outweigh the risk of use
Statins and Cognitive Function decline
evidence points against this association
If TG>500, target TG lowering to prevent what
pancreatitis
Antiplatelet agents: Low-dose aspirin (ASA) therapy should be considered in what groups of patients
CVD
increased risk -> risk benefit discussion
Antiplatelet agents when to use clopidogrel
ASA allergy
Antiplatelet agents Add low dose rivaroxaban if what
CAD/PAD and low bleeding risk
Other ASCVD Considerations: ASCVD or high risk add what two things
SGLT and/or GLP
Smoking considerations in DM
-Nicotine increases insulin resistance
-Smokers=greater risk of CVD, microvascular complications and premature death
-Smoking may have a role in DM2 development
PVD lead to what
May lead to skin ulcers, intermittent claudication and foot infections or gangrene
PVD symptoms
Leg pain, especially at night
Cold feet
Decreased or absent radial or pedal pulses
PVD treatment
Smoking cessation
Control blood pressure
Antiplatelet agents
Pentoxyphylline or cilostazol for symptoms
Medications Emphasized for CKD/DKD
ACE/ARB
Finerenone
SGLT-2
GLP-1
Nephropathy occurs in how many DM patients and leads to what
Occurs within 20-40% of DM patients and is the leading cause of end-stage renal disease (ESRD)
Nephropathy monitoring
Urine albumin excretion should be measured at least annually with a Urine Albumin-creatinine ratio (Alb/Cr ratio or UACR)
SCr checked annually
Difference between Micro-albuminurea and albuminuria
Micro-albuminurea 30-299 mg/g creatinine
Albuminuria is defined as >300 mg/g creatinine
DKD vs CKD
DKD is CKD where DM is the cause of the CKD
Finerenone (Kerendia®)
-non-steroidal mineralocorticoid receptor antagonist
-used in patients with DKD
-shows positive outcomes with DKD progression, reduce CV events and HF hospitalizations
-it increases K+
Nephropathy - Treatment in UACR, CKD/DKD
UACR >30 add ACE/ARB (maxed out add finerenone)
CKD/DKD - eGFR >25 SGLT-2I
Optimize BP control
Main risk factors neuropathy
Longer duration of diabetes
Poor diabetes control
Increased BMI
Smoking
(other include CVD, increase TG, HTN)
Sensory (peripheral) Neuropathy sensory loss (feet/lower legs or hands)
Usually presents as numbness, tingling, sharpness or burning
Generally present at rest and worsens at night
Can be very painful but usually progresses to be complete loss of feeling over time
Screening - yearly through physical exam and diabetic foot exam
Testing for loss of protective sensation
-Monofilament test
-Pinprick sensation
-Vibration perception
Treatment of neuropathy
Specific treatment for underlying nerve damage not available
Duloxetine, pregabalin and gabapentin are recommended first line
Autonomic Neuropathy
vary in type, severity, onset
full history and physical exam should be performed at each diabetes follow-up to screen
Individual symptoms should be treated as necessary
Symptoms of autonomic neuropathy
Resting tachycardia
Exercise intolerance
Orthostatic hypotension
Constipation
Gastroparesis
Erectile dysfunction
Genitourinary tract disturbances
Retinopathy
Optimize glycemic and blood pressure control
Annual dilated eye exams
Treatment
-Laser photocoagulation therapy
-Intra-corneal injections - VEGF Inhibitors
What is diabetic ketoacidosis (DKA)
life-threatening state resulting from a relative or absolute deficiency of insulin (mainly Type 1)
What is the triad in DKA
hyperglycemia
anion gap metabolic acidosis
ketosis
Pathophysiology of DKA
Insulin deficit with increased levels of stress hormones and a precipitating factor
-Stress hormones: glucagon, cortisol, epi, growth
-Precipitating factors: insulin deficiency, undiagnosed DM1, non-compliances, stress
What are the 5 results of insulin deficiency
hyperglycemia
glycogen catabolism
glycogen depletion
lipolyis
ketosis
What is the main result of hyperglycemia
polydipsia*
polyuria*
weight loss*
volume depletion
electrolyte depletion
renal hypoperfusion
hypotension
What are the 4 ketosis results
anion gap metabolic acidosis
compensatory alkalosis
hypotension
shock
What are the diabetic ketoacidosis clinical course effects
hyperglycemia
polydipsia, polyuria dehydration
anorexia, ab pain, acidosis
Kussmaul breathing
altered consciousness
coma, death
Diagnostic criteria for DKA
BS > 250
pH <7.3
Bicarb <15
Ketonuria or ketonemia
Treatment of DKA
-IV Regular Insulin 0.1 u/k bolus or 0.1 u/kg/hr infusion (MONITOR potassium before starting)
-IV fluids 0.9% NS if corrected NA+ <135 or 0.45% NS if corrected NA >135
-IV potassium supplementation: K+ will be elevated then when IV given K+ returns to intracellular space and serum K+ will be low
Before IV regular insulin is given for DKA what level does the serum K+ have to be
> 3.3
When to give dextrose in DKA treatment
blood glucose falls <250 replace dextrose but continue IV insulin until ketones are undetectable
When to use bicarb in DKA treatment
not recommended
could use when pH <6.9
What is hyperglycemia hyperosmolar syndrome (HHS)
life-threatening emergency resulting from severe dehydration and hyperglycemia in Type 2 DM
-serum osmol elevates and severe dehydration occurs as result of osmotic diuresis
HHS diagnostic criteria
BG: >600 mg/dl
pH >7.3
Bicarb >18 mEq/l
Serum Osmol: >320 mOsmo/L
Treatment for HHS
IV fluids ~9L
IV regular insulin infusion
Electrolytes (K+, Mg)
Treat precipitating event
DKA:
age
duration of symptoms
glucose level
potassium conc
bicab conc
ketone bodies
pH
serum osmolarity
prognosis
age: <40
duration of symptoms: <2 days
glucose level: <600
potassium conc: low
bicab conc: <18
ketone bodies: yes
pH: <7.3
serum osmolarity: <350
prognosis: 3-10% mortality
HHS:
age
duration of symptoms
glucose level
potassium conc
bicab conc
ketone bodies
pH
serum osmolarity
prognosis
age: >60
duration of symptoms: >5 days
glucose level: >800
potassium conc: variable
bicab conc: normal
ketone bodies: no
pH: normal
serum osmolarity: >350
prognosis: 1-20% mortality
Primary problems in DKA and HHS
DKA: acidosis
HHS: dehydration
Key things to look for in DKA and HHS
DKA: acidosis, ketones
HHS: glucose, no ketones, no acidosis, high osmols
Primary treatment strategies for DKA and HHS
IV fluids, IV insulin, IV potassium
Monitoring for DKA and HHS
DKA: glucose, pH, ketones, e-lytes
HHS: glucose, osmol, e-lytes, fluid/urine output
What is the correct sodium equation
measured Na + [(glucose level - 100) x 0.016]
Daily patient responsibilities for DM
check feet daily
check blood sugars as recommended
medication compliance
What should you check at each DM follow-up
blood sugar
blood pressure
weight
visual foot exam
physical exam and history screening for neuropathy
Other screening tests that are needed every 3-6 months, 6 months, and annually
3-6: HgbA1c
6: dental
year: comprehensive foot exam, urine albumin/cr ratio, SCr, dilated eye exam
