Exam 2 - Non-insulin Therapies, Hospital Management, Adherence

functions of GLUTs

membrane proteins containing 12 helices that transport glucose either outside OR inside of the cell; glucose binds and causes a conformational change that releases glucose to the other side of the membrane

there are ____ known GLUT isoforms

14

GLUT family is divided into ___ subclasses

3

GLUT-1 function

responsible for the basal glucose uptake required to sustain respiration in ALL cells

- increased expression when REDUCED glucose

- decreased expression when INCREASED glucose

where is GLUT-1 expressed?

mostly in erythrocytes but also in barrier tissues such as the blood-brain barrier

GLUT-2 function

transfer of glucose between the liver and the blood; also has a role in renal glucose reabsorption

- increased expression during the FED state

where is GLUT-2 expressed?

liver, pancreatic beta cells, small intestine, renal tubular cells

GLUT-2 has a high capacity for _______

glucose!...but low affinity functions as a part of the glucose sensor in the pancreatic beta cells

GLUT-3 function

transports glucose into neurons (BBB and astrocytes)

where is GLUT-3 expressed?

mostly in the brain

GLUT-4 function

insulin-regulated glucose transporter; during low insulin, GLUT-4 is sequestered in intracellular vesicles of muscle and fat, but in response to insulin signaling, the vesicles are transported to the membrane and GLUT-4 transporters become available for transporting glucose INTO the cell (increased glucose absorption); glucose is then rapidly stored as glycogen

where is GLUT-4 expressed?

mostly in adipose tissues and striated muscle

GLUT-5 function

fructose transporter

where is GLUT-5 expressed?

apical border of enterocytes, skeletal muscle, testis, kidneys, adipocytes, brain

HbA1c and glucose equilibrium

glucose is in equilibrium with a hexose ring-close and ring-open form, which possesses an aldehyde at C6 that undergoes a glycation reaction with hemoglobin in a red blood cell with the C1 on glucose reacting with the N-terminal valine on hemoglobin

- gives a "history" of serum glucose concentrations over 8-12 weeks (2-3 months)

- normal is 4-6%,

- <7% is good maintenance in diabetics

diagnostic criteria for diabetes (4)

- FPG ≥126 mg/dL

- 2-hours post 75g-oGTT ≥200 mg/dL

- random PG of ≥200 mg/dL

- A1c ≥6.5%

which therapies cause weight GAIN?

- insulin

- sulfonylureas

- meglitinides

- TZDs

which therapies cause weight LOSS?

- GLP-1 RAs

- SGLT2 inhibitors

which therapies are weight NEUTRAL?

- metformin

- DPP-4 inhibitors

- colesevelam

- α-glucosidase inhibitors

- pramlintide

- bromocriptine

therapies that act in the small intestine?

- metformin

- DPP-4 inhibitors

- α-glucosidase inhibitors

therapies that act in the pancreas?

- GLP-1 agonists

- sulfonylureas

- meglitinides

therapies that act in adipose tissue?

TZDs

therapies that act in the kidneys?

SGLT2 inhibitors

therapies that act in the liver?

metformin

name the 3 sulfonylureas

glipizide, glyburide, glimepiride

name the biguanide

metformin

name the 2 glycosidase inhibitors

acarbose, miglitol

name the 2 meglitinides

natelinide, repaglinide

name the 2 TZDs

pioglitazone, rosiglitazone

MoA of sulfonylureas

increase glucose uptake in muscle by stimulating insulin release from pancreatic beta cells by binding to the SUR1 channel to artificially inhibit KATP channels (keeping them closed)

concerns with sulfonylureas

- will not work in type 1 diabetics or type 2 diabetics whose beta cells no longer produce insulin

- weight gain

- hypoglycemia

- DDIs since they bind to albumin

DDIs with sulfonylureas

- NSAIDs (salicylates)

- sulfonamides (chloramphenicol)

- coumadin

- probenecid

- thiazides

- phothiazides

- thyroid products

- oral contraceptives

- phenytoin

sulfonylurea structure

2nd generation sulfonylureas

glipizide and glyburide

MoA of meglitinides

bind to SUR1-KATP channels at sites that differ from sulfonylureas (but otherwise share the same mechanism) and are metabolized by CYP450/2C8/3A4

solubility of metformin

very soluble

permeability of metformin

poor

charge of metformin at physiological pH

cation (ionized form)

LogP of metformin

negative (more molecules in the water phase)

elimination/half-life of metformin

fast elimination, short half-life

metformin structure

solubility of glipizide

poor

permeability of glipizide

medium

charge of glipizide at physiological pH

neutral (unionized)

metformin: basic/acidic/neutral?

strong base

glipizide: basic/acidic/neutral?

slightly weak acid

LogP of glipizide

positive (more molecules in the oily phase)

glipizide structure

elimination/half-life of glipizide

higher protein binding so longer half-life

solubility of empagliflozin

high (despite the molecule itself being insoluble, it is high due to the dose being so small)

permeability of empagliflozin

poor

empagliflozin: basic/acidic/neutral?

neutral

charge of empagliflozin at physiological pH

neutral

LogP of empagliflozin

positive (more molecules in the oily phase)

empagliflozin structure

gastro-retention

delivery strategy used to retain drugs in the stomach and let them slowly move into the upper GI tract (avoids gastric emptying)

5 ways to accomplish gastro-retention in formulation of tablets

1) high-density systems that withstand peristalsis

2) swelling/expansion forms to prevent passage

3) adhesion to the stomach lining

4) superporous hydrogels

5) floating drug delivery

Glumetza formulation

metformin HCl extended release that is formulated with hypromellose (rate-controlling polymer layer) and polyethylene oxide (swelling agent)

- keeps the dosage form within the stomach

- slows release through the hydrophilic polymer

osmotic pump formulation

tablet formulation that allows for an extended-release profile

- core containing the osmotic agent

- rigid, semi-permeable membrane surrounding the core

- delivery orifice (laser-drilled) to release the drug

3 key principles that define drug release from an osmotic tablet

1) water influx

2) interior solution formation

3) drug release

water influx equation

Jw = A x P x (Δπ/h)

Jw = flux of water

A = tablet geometry

P = permeability

Δπ = osmotic gradient

h = thickness

Fortamet formulation

ER metformin formulated as a single-composition osmotic technology (SCOT)

SCOT formulation

ER tablet that contains an osmotically active core formulation surrounded by semipermeable membrane -> water diffuses past the membrane to dissolve the drug -> drug can't move past the membrane = osmotic pressure

push-pull osmotic technology

two compartment ER model that contains one compartment of drug and one compartment of osmotic agent; the osmotic agent pushes the drug outside of the membrane

requirements for a semipermeable membrane

- sufficient strength

- biocompatible

- rigid and non-swelling

common membrane excipients

ethyl cellulose, cellulose acetate

are Fortamet and Glumetza interchangeable?

NO

(although they are both ER formulations of metformin, they have different release mechanisms leading to different PK responses)

formulation of glipizide

low solubility, so requires a two-compartment push-pull osmotic delivery system requiring a separate osmotic agent and a physical moveable partition

- lower chamber swells and pushes the dissolved drug through the laser-drilled orifice at a controlled rate

formulation design of semaglutide

purpose is to keep the peptide stable and in solution, so is formulated with a disodium phosphate dihydrate buffer to maintain pH, phenol as an antioxidant, and propylene glycol as a co-solvent with water

primary structure of semaglutide at pH 7.4

net charge is -4; everything will be ionized

- 4 acidic residues

- 3 basic residues

- 2 additional carboxylic acids on the Lys26

formulation of rybelsus

very low bioavailability, so is formulated with SNAC to enhance GI permeation

SNAC

salcaprozate sodium

- GI permeation enhancer used in rybelsus

- critical for making an oral peptide work

mechanism of SNAC

mostly unclear mechanism

- absorption only in the stomach

- surrounds semaglutide and neutralizes gastric fluids and inactivates pepsin

- boosts local solubility to drive transcellular uptake

macrovascular complications of diabetes

ASCVD and heart failure

microvascular complications of diabetes

nephropathy/CKD, neuropathy, retinopathy

"high risk" of developing ASCVD

age ≥55 with 2+ risk factors:

- obesity

- HTN

- smoking

- dyslipidemia

- albuminuria

first-line diabetes treatment for ASCVD and high ASCVD risk

SGLT2i and/or GLP-1 RA

recommended SGLT2i for ASCVD + diabetes

empagliflozin

recommended GLP-1 RA for ASCVD + diabetes

semaglutide

HFrEF vs HFpEF LVEF %

HFrEF ≤40%

HFpEF ≥50%

first-line therapy for HF + diabetes

SGLT2i

GLP-1 RAs for HF + diabetes?

not guideline recommended since they do not have proven CV benefit in patients with HF... still waiting for more trial data to come out

pathophysiology of nephropathy/CKD and diabetes

hyperglycemia and insulin resistance -> increased oxidative stress, inflammation, and overactive RAAS -> glomerular HTN and renal fibrosis

nephropathy/CKD occurs in ______% of people with diabetes

20-40

when to screen diabetics for nephropathy/CKD?

at least annually...

T1D: 5 years after diagnosis

T2D: at diagnosis

CKD diagnostic criteria

eGFR <60 or albuminuria UACr ≥30

first-line therapy for CKD + diabetes

SGLT2i, semaglutide, or ACEi/ARB

when to consider nonsteroidal MRA in CKD + diabetes?

if albuminuria persists and pt has normal potassium after max tolerated ACEi/ARB

in CKD, decision to use a GLP-1 RA or SGLT2i with proven benefit should be made irrespective of...

background use of metformin or A1c

first-line therapy for MASLD/MASH + diabetes

GLP-1 RA, terzepatide, pioglitazone

MASLD

metabolic dysfunction associated steatotic liver disease

- hepatic steatosis in the presence of at least one metabolic risk factor with alcohol consumption below thresholds likely to cause liver injury

MASH

metabolic dysfunction associated steatohepatitis

- progressive, inflammatory form of MASLD

pathophysiology of neuropathy and diabetes

increased serum glucose -> insulin resistance, dyslipidemia, oxidative stress -> inflammation and cellular damage to nerve fibers

peripheral vs autonomic neuropathy

peripheral: screen with diabetic foot exam

- up to 50% may be asymptomatic

- burning, sharp pain

- cold sensation

- numbness

autonomic: screen for symptoms

- orthostatic hypotension

- resting tachycardia

- dry or cracked skin in the extremities

- constipation/diarrhea

- erectile dysfunction

when to screen diabetics for neuropathy?

at least annually...

T1D: 5 years after diagnosis

T2D: at diagnosis

pathophysiology of retinopathy and diabetes

hyperglycemia +/- uncontrolled blood pressure damages the blood vessels supplying blood to the retina of the eye

when to screen diabetics for retinopathy?

at least annually with dilated and comprehensive eye exams...

T1D: 5 years after diagnosis

T2D: at diagnosis

treatment of retinopathy

no specific pharmacotherapy recommended to treat or prevent progression, just need to adequately control glucose concentrations and blood presure

4 pillars of reducing complications in diabetes

- glycemic management

- blood pressure management

- lipid management

- agents with cardiovascular and kidney benefit

goal A1 range to reduce complications from diabetes

≤7