lecture 4 & 5: drugs to treat type 2 diabetes

incretins

a group of hormones produced by the gastrointestinal system that stimulate the release of insulin from the pancreas and help preserve the beta cells

-ex: GLP-1 and GIP

•Increase in insulin only 50% of that seen in nondiabetic patients following ingestion of meal

•GLP-1 levels decline as hyperglycemia increases

incretin effect in pts with type 2 diabetes

GLP-1

•Secreted from L-cells in the distal intestinal mucosa

•Rises within minutes of food ingestion

•Stimulates insulin secretion, increases satiety, suppressess glucagon, slows gastric emptying

GIP

•Secreted by K-cells in the intestine

•Increases insulin secretion

dipeptidyl peptidase 4

incretins are rapidly inactivated by

-increased hepatic glucose production, decreased glucose uptake, increased lipolysis

how does insulin resistance manifest in liver, muscle, and adipose tissue?

SGLT-2

transporter responsible for 90% of filtered glucose reabsorption

sulfonylureas, meglitinides

name the insulin secretagogues

DPP-IV inhibitors, GLP-1 agonists

name the incretin mimetics

metformin

preferred initial pharm agent for type 2 DM, given alongside lifestyle changes

metformin

MOA: decreases hepatic glucose production; activation of AMP-activated protein kinase in hepatocytes

lowers A1C and has potential macrovascular benefits

-neutral on weight loss

-no hypoglycemia

efficacy of metformin

severe renal impairment (eGFR <30), bc it is excreted in kidney

contraindication of metformin

metformin

BW!: Drug accumulation can lead to lactic acidosis

Risk is increased in moderate-to-severe renal disease or hypoperfusion (hepatic impairment, CHF, sepsis, dehydration, excessive alcohol consumption)

metformin

adverse effects: diarrhea, vitamin B12 deficiency, metallic taste

metformin

discontinue ________ on day of procedure due to drug interaction of radiocontrast dye---> kidney injury

metformin

•Typically, safe to co-administer with other agents used to lower blood glucose due to low risk of hypoglycemia (continue with insulin initiation)

the --tides

name of the GLP-1 receptor agonists

GLP-1 receptor agonists

reduces major adverse CV events in adults with type 2 DM with established CV disease

GLP-1 agonists

preferred secondn line add on to metformin

-lowers A1C

-macrovascular benefit

-weight loss

-no hypoglycemia

efficacy of GLP-1 agonists

liraglutide

GLP agonist with an effect on reducing CKD pprogression

exenatide

renal inssufficicency prolongs the half life of thiss GLP-1 RA

GLP-1 RA

CI: •Hypersensitivity, history of or family history of medullary thyroid carcinoma (MTC) or in patients with multiple endocrine neoplasia syndrome type 2 (MENS2)

GI intolerance, delayed gastric emptying, weight loss, acute renal failure

main adverse effects of GLP-1 RA

risk of thyroid C Cell tumors (medullary thyroid cancer)

BBW of GLP-1 RA

Tirzepatide

agonist for GL-1 and GIP, sronger effects on weight loss and A1C

--flozin

name the SGLT2 inhibitors

Inhibition of SGLT-2 in the proximal renal tubules, to block glucose reabsorption

•Enhance renal excretion of glucose

MOA of SGLT-2 inhibitors

moderate A1C lowering, macrovascular benefit

-weight loss

-no hypoglycemia

efficacy of SGLT-2 inhibitors

eGFR <30, hemodialysis

contraindication of SGLT-2 inhibitor

-•Genital mycotic infections (vaginal yeast infections in females), UTIs

•Osmotic diuresis, hypotension, hypovolemia

-expensive!

adverse effects of SGLT-2 inhibitors

rifampin

interacts with SGLT2 inhibitors, need to increase dose

canagliflozin

_______ + digoxin---> increases digoxin exposure

•GLP-1 receptor agonist or a SGLT2-inhibitor independent of A1C baseline or target

If patient has established ASCVD or is at high risk of developing ASCVD, has established CKD, or established HF, add on these treatments

•Initiate GLP-1 RA with proven CVD benefit or SGLT2i with proven CVD benefit (if eGFR adequate)

in diabetic pt with ASCVD, add on this therapy

preferred: SGLT2 inhibitor

in diabetic pt with HF or CKD, add on thhihs therapy

canagliflozin

empagliflozinn

SGLT-2 inhibitors with proven CVD benefit

dapagliflozin, empagliflozin

SGLT-2 inhibitors with proven HF benefit

canagliflozin, dapagliflozin, empagliflozin

SGLT2-I with proven renal benefit

dulaglutide, liraglutide, semaglutide

GLP1 RAs with proven CVD and CKD benefit

NONE

GLP RAs with proven HF benefit

DPP-4i, GLP-1, SGLT2, Thiazolidineddione

add on agents when you need to minimize hypoglycemia

•GLP-1 RA with good efficacy for weight loss

•SGLT2-I

add on agents when you need to minimize weight gain or promote weight loss

•Sulfonylurea (SU)

•TZD

add on agents with low cossts

the gliptins

name the DPP-4 inhibitors

-moderate, lowers A1C, neutral CV benefit

-neutral weight gainn, no hypoglycemia

efficacy of DPP-4 inhibitors

DPP-4 inhibitors (Saxa, alo)

add on agent associated with increased heart failure hospitalizations

•Nasopharyngitis, upper respiratory tract infections

most common adverse effect of DPP-4 inhibitorrs

the -zones

name the thiazoliddinediones

Binds to the peroxisome proliferator activator receptor-gamma (PPAR- g), located on fat and vascular cells, which leads to transcription of several genes involved in glucose and lipid metabolism

•Enhances insulin sensitivity at muscle, fat, and liver to directly reduce insulin resistance

MOA of TZDs

HIGH; decreases A1C, increasses HDL, decreases TGs, increases LDLs

-weight gain

-no hypoglycemia

efficacy of TZDs

pioglitazone

TZD with macrovasccuarl benefit

TZDs

hepatic metabolism, slow onset of action (3 months)

TZD

CI in pts with NYHA class III/IV heart failure

BBW: HF exacerbations

•Fluid retention and edema

•Macular edema

•Weight gain (5 kg)

•BBW: HF – may exacerbate or cause HF

adverse effects of TZDs

glipizide, glimepiride, glyburide

name the sulfonyllureas

Bind to sulfonylurea receptor (SUR1) to close ATP-sensitive K+ channels in the β-cell membrane leading to an influx of calcium ions and exocytosis of insulin containing granules eventually ↑ pancreatic secretion of insulin

MOA of sulfonylureas

high! A1C lowering, but lacks durability

-weight gain

-hypoglycemia present

efficacy of sulfonylurea

sulfonylureas

add on agent associated with microvascular complication reductio

-associated with higher rates of CAD

hypoglycemia, weight gain

most common side effect of sulfonylurea

insulin in T2DM

1st line therapy if symptomatic or persistent elevated HbA1C (>7-8%) despite maximum tolerated doses of oral agents

insulin use in T2DM

•AE: weight gain; highest risk of hypoglycemia

•CV Data: CV neutral

•Cost: High

long acting insulin once daily; 10 units once daily or 0.1-0.2 units/kg/day

-increase units if FBG remains above 130

starting insulin regimen of type 2 pt

meglitinidess/glinides

•MOA: bind to site adjacent to the sulfonylurea receptor to stimulate insulin secretion from the β-cells of the pancreas in the presence of glucose

-not included in the ADA guidelines

glinides

lower hypoglycemic effect than sulfonylureas, may cause wight gain

acarbose, miglitol

name the alpha-glucccosidase inhibitors

•competitively inhibits intestinal α-glucosidase enzymes that line the brush border of the small intestine (maltase, isomaltase, sucrase, glucoamylase)

-reduces rise in post prandial glucose

MOA of alpha glucosidase inhibitors

undigested carbohydrates leads to gas production due to their fermentation in the colon

Flatulence, bloating, abdominal pain, diarrhea

adverse effectss of alpha-glucosdidase inhibitors

alpha-glucosiddase inhibitor

Must be taken 3x/day with first bite of each meal

Decrease prandial insulin dose if initiated together

pramlintide

amylin analog that decreases glucagon secretion, promoting satiety an delaying gastric emptying

Hypoglycemia: Yes, when added to insulin

Weight: Loss

adverse effects of pramlintide

insulin

preferred management of type 1, type 2 DM, and gestational diabetes in pregnancy