Diabetes / insulin therapy

list regular insulins available

• Humulin R (U-100 and U-500)

• Novolin R (U-100)

characteristics of 100% regular insulin

• soluble

• zinc stabilized

• hypoglycemic effect 30 mins after SQ inj

• peak effects at 2 hrs

• short acting

which regular insulin is intermediate-acting

Humulin R (U-500) → reserved for insulin resistant pts

<15 min onset; 24 hr duration

describe the pharmacokinetics of U-500 insulin

in hexamer formation when injected → slower release; absorption is more like basal rate or delivery

NPH insulins that are available

• Humulin 70/30

• Novolin 70/30

• **intermediate acting

characteristics of NPH insulin

• mixture that contains some regular insulin

• cloudy suspension

• after SQ inj, proteolytic enzymes degrade protamine = insulin is released

pharmacokinetics of NPH insulin

onset = 2-4 hr

peak = 4-12 hr

duration = 13-15hr

list the rapid acting insulins

• lispro (Humalog, Lyumjev-aabc, Admelog)

• aspart (Novolog, Fiasp)

• glulisine (Apridra)

pharmacokinetics and properties of lispro

• contains Zn and phenol to stabilize

• amino acid changes favor monomer form upon inj

• onset = 15 mins

• peak = 30-90 mins

• duration = 3-4 hrs

what makes Lyumjev-aabc different from the other forms of lispro insulin

classified as ultra-rapid; contains treprostinil (vasodilator) causing 10min onset

pharmacokinetics and properties of aspart

• contains Zn and phenol to stabilize hexamer in formulation

• amino acid changes favor monomer upon inj

Novolog specific kinetics

• onset = 15mins

• duration = 3.5 hr

Fiasp specific kinetics and properties

contains niacinamide (vasodilator) → ultra rapid

onset = 10mins

glulisine kinetics

onset = 20 mins

duration = 3.5 hr

technosphere (Afrezza) kinetics and formulation

inhaled dry powder formulated as monomers

onset = 15 mins

peak = 1hr

duration = 2-3 hr

list the long-acting insulins

• glargine (Basaglar, Lantus, Toujeo, Besvoglar, Semglee)

• degludec (Tresiba)

what are the pharmacokinetics and properties of glargine

• amino acid changes the pI to 7 = precipates after SQ inj and causes slow release of insulin with no peak

• onset = 30-60 mins

• duration = 24 hr

what are the pharmacokinetics and properties of degludec

• replaces amino acids with fatty acid = dihexamer

• contains Zn, m-cresol, and phenol

• classified as ultra-long acting

• onset = 30-90mins

• duration = 40 hr

hexamer insulin structure characteristics

primary form in the pancreas and in many insulin formulations; serves as a storage mechanism

dimer insulin structure characteristics

principle circulating form of insulin and some rapid-acting insulins

monomer insulin structure characteristics

lowest circulating levels; can distribute to cells and is the active form of insulin

describe the MOA of metformin

inhibits liver gluconeogenesis by blocking mitochondrial glycerol-3-phosphat3e dehydrogenase (GPD2)

• enters thru OCT 1/2 and OCT3 transporters

• causes increased lactate = decreased pyruvate = decreased DHAP and glucose

describe the MOA of 2nd gen sulfonylureas

increase insulin release from pancreas → binds to Katp channels preventing K efflux → activates voltage gated Ca channel = insulin release from islet cells

list the 2nd gen sulfonylureas

• glyburide

• glipizide

• glimeperide

describe the MOA of Katp channel modulators (non-sulfonylureas)

increase insulin release from pancreas → binds to Katp to prevent K efflux and activates Ca channel for insulin release

list the non-sulfonylurea agents

repaglinide and nateglinide

describe the MOA of thiazolidinediones (TZDs)

PPAR-X activators (increases insulin sensitivity)

• moves balance of lipogenesis away from skeletal muscle and liver and encourages transition of glucose to TGs

list the TZD agents

pioglitazone and rosiglitazone

describe the MOA of incretin mimetics

mimics GLP-1 and GIP via GPCR-Gs pathway that stimulates adenylyl cyclase activity and Ca-channels = insulin release

describe the MOA specific to GLP-1 agonists

activate adenylate cyclase → PKA activation → enhance pancreas insulin production and release → delays gastric emptying → inhibit glucagon release from pancreatic alpha cells

list the GLP-1 agonist agents

• exenatide

• dulaglutide

• liraglutide

• semaglutide

describe the MOA of DPP-4 inhibitors

inhibit the deactivation/metabolism of endogenous GLP-1 and GIP

list the DPP-4 inhibitor agents

• saxagliptin

• sitagliptin

• linagliptin

• alogliptin

describe the MOA of SGLT2 inhibitors

blocks 85% of glucose reabsorption back into the bloodstream; instead continues thru proximal tubule and is excreted in urine

list SGLT2 inhibitors

• canagliflozin

• dapagliflozin

• empagliflozin

• ertugliflozin

DM screening criteria for asymptomatic adults >35

test q 3 years

DM screening criteria for adults <35

• if BMI >25 (23 if asian american)

• and at least one of the following:

  • 1st degree relative with DM

  • high risk ethinicity

  • hx of CVD/HTN/HDL<35 and or TG >25

  • PCOS

  • sedentary life style

  • clinical condition associated with insulin resistance

clinical presentation of DM

• polyuria

• polydipsia

• polyphagia

• wt loss

• dry skin

• weakness

• nocturia

• blurred vision

• fatigue

• persistent recurrent infections

• DKA

• HHS

diagnostic criteria for DM

any of the following:

• A1C > 6.5%

• fasting BG > 126 mg/dL

• 2 hr post load BG > 200mg/dL during oral glucose test

• classic symptoms of hyperglycemia/crisis with random glucose test >200 mg/dL

appropriate DM treatment plan if pt has ASCVD/high risk

start: GLP-1 RA or SGLT2i with ASCVD benefit

• if not at goal: add the other agent that wasn’t used before

• add TZD (low dose) or metformin

• use other agents based on pt characteristics

appropriate DM treatment plan if pt has HF

start: SGLT2i with HF benefit

• if contraindicated or inadequate eGFR: use other agents based on pt characteristics

appropriate DM treatment plan for pt with CKD or albuminuria pathway

**ensure pt is on maximally tolerated ACE/ARB

start: SGLT2i or GLP-1 RA with CKD benefit

• if not at goal: add or start GLP-1 RA with CV benefit

• other agents based on pt characteristics

**do not use TZDs here!!

appropriate DM treatment plan for very high glycemic efficacy

dulaglutide/ semaglutide/ tirzepatide + insulin combo therapy

appropriate DM treatment plan for high glycemic efficacy

liraglutide, exenatide, metformin, SGLT2i or sulfonylureas

appropriate DM treatment plan for intermediate glycemic efficacy

DPP-4 inhibitors

appropriate DM treatment plan for very high wt loss

semaglutide or tirzepatide

appropriate DM treatment plan for high wt loss

dulaglutide or liraglutide

appropriate DM treatment plan for intermediate wt loss

exenatide or SGLT2 inhibitors

appropriate DM treatment plan for neutral wt loss

DPP-4 inhibitors or metformin

what are the exceptions to monotherapy

• A1C >1.5% above target = add another agent

• A1C >10% and s/s of catabolism = add basal insulin

pre-prandial goals

80-130 mg/dL

post-prandial goals

<180 mg/dL

when to give a pt an A1c goal <6.5%

• pts without CVD

• shorter duration of DM

• treated with metformin or lifestyle only

• long life expectancy

• must be willing and able

when to give a pt an A1C goal <8%

• pts with severe hypoglycemia

• limited life expectancy

• extensive comorbidities