Diabetic drugs

What are the __rapid-acting__ Insulins?

* Lispro
* Aspart
* Glulisine

What delays rapid-acting Insuins’s?

NPH - Neutral protamine hagedorn

What are the __long-acting__ Insulins?

* Glargine
* Detemir
* Degludec

MOA of Insulins?

Activates receptors & reduce circulating glucose

Adverse effects of Insulin?

* Hypoglycemia
* Weight gain
* Lipodystrophy

Insulin allergy involves which immunoglobulin?

IgE

Immune insulin resistance involves which immunoglobulin?

IgG

What are the 1st generation Sulfonylureas?

Tolbutamide

What are the 2nd generation sulfonylureas?

• Glyburide

• Glipizide

• Glimepiride

MOA of sulfonylureas?

Inhibit K+ efflux through the channel = depolarization → voltage-gated calcium channel opens, calcium influx, & release of insulin + increase number of insulin receptors

Which Sulfonylureas give more hypoglycemia?

Glyburide > Tolbutamide > Glipizide

Who shouldn’t use Glyburide?

Liver failure, chronic kidney disease patients, & obese patients

Which sulfonylurea binds to the receptor & becomes sequestered within the B cell?

Glyburide

Which Sulfonylurea, because of its shorter duration of action, is prefered in elderly & those with renal impairment & non-obese patients?

Glipizide

What can inhibit tolbutamide’s metabolism resulting in prolonged hypoglycemia?

Some sulfonamides (sulfisoxazole) & oral azole

What are contraindicatiions of sulfonylurea?

Pregnant & breast feeding mothers

Duration of Sulfonylureas?

10-24hrs

Duration of non-Sulfonylureas?

5-8hrs

What are the non-sulfonylureas?

Meglitinide analogs

• Repaglinide

• Nateglinide

What is a Meglitinide & its MOA?

Regulates K+-ATP channels in pancreatic beta cells

What are indications of meglitinide?

• Best to control postprandial glucose bc of its rapid onset to avoid hypoglycemia

• Patients with renal failure &/or the elderly

• Monotherapy or with biguanides

MOA of nateglinide?

Stimulates rapid & transient release of insulin through closure of ATP-sensitive K+ channels

Why should repaglinide & nateglinide be taken with a meal specifically one with adequate carbs?

To reduce the chance of hypoglycemia - reduce postprandial rise in blood glucose

What is the T2D drug of choice?

Biguanides - metformin

MOA of Biguanides?

Reduces hepatic & renal gluconeogenesis (glucose production) & increases glucose uptake & utilization in skeletal muscle

Adverse effects of Biguanides?

• GI effects - anorexia, nausea, vomiting, etc

• Interferes with absorption of B12

• Lactic acidosis (alcoholics)

• Patients with renal or hepatic disease; alcohol (contra)

What are the thiazolidinediones?

• Pioglitazone

• Rosiglitazone

MOA of thiazolidinediones?

Regulate gene expression by binding to PPAR-y & PPAR-a

What drugs will cause no hypoglycemia?

Thiazolidinedione + Metformin

What can improve nonalcoholic fatty liver disease?

Thiazolidinediones

What drug:

• Lowers TG & increases HDL without effecting total cholesterol & LDL

• Reduces risk of stroke or MI in non-diabetic insulin-resistant patients

• PPAR-a & PPAR-y activity

Pioglitazone

What drug:

• Increases total cholesterol, HDL, & LDL without affecting TGs

• Improves nonalcoholic fatty liver disease

Rosiglitazone

Adverse effects of Thiazolidindediones?

• Fluid retention (insulin therapy patients)

• HF

• Macular edema

• Loss of bone mineral densitiy - fracture

Contraindications of Thiazolidindediones?

* HF
* Pregnant & breastfeeding women
* Active liver disease or pretreatment elevation of ALT

What are the a-Glucosidase inhibitors?

• Acarbose

• Miglitol

MOA of a-Glucosidase?

Competitively inhibits intestinal a-glucosidase enzymes which convert starch & disaccharides into monosaccharides in SI

Adverse effects of a-Glucosidase inhibitors?

• GI issues

• Hypoglycemia if used w/ secretagogues (sulfonylureas) (treat with glucose)

What are the amylin analogs?

Pramalintide

MOA of pramalintide?

Acts as a negative feedback on insulin secretion, & reduces glucagon secretion → slows gastric emptying & decreases appetite

What is pramlintide indicated for?

Patient with T1D presents with consistent postprandial hyperglycemia

Adverse effects of pramlintide include GI symptoms & hypoglycemia. How exactly does the drug cause hypoglycemia?

Slows gastric emptying so recovering can be problematic bc of the delay in absorption of fast-acting carbs

What are the bile acid sequestrants?

Colesvelam hydrochloride

MOA of colesevelam hydrochloride?

Lowers glucose through unknown mechs → may involve FXR (farnesoid X receptor) that has effects on cholesterol, glucose, & bile acid metabolism

Who is colesevelam hydrochloride indicated for?

Patients with T2D who have not achieved adequate control with diet & exercise or other glucose lowering medications

• Lowers LDL-C in adults with with hyperlipidemia & pediatric patients with heterozygous familial hypercholesterolemia

What are adverse effects of colesevelam hydrochlorid?

• GI issues

• Exacerbate hypertriglycerimidemia, common in T2D patients

What are the dopamine agonists?

Bromocriptine

MOA of bromocriptine?

D2 (dopamine) receptor agonist, lowers glucose through unknown mech

What drugs can be used in T1D & T2D?

Insulin & Pramalide

Oral glucose in the SI stimuate the release of hormones called incretins. What are these incretins?

• Glucagon-like peptide-1 (GLP-1)

• Glucose-dependent insulinotropic peptide (GIP)

What is the role of incretins?

Regulate postprandial glucose regulation, stimulating insulin secretion in response to food ingestion

What are the GLP-1 agonists?

* Exenatide
* Lixisenatide
* Liraglutide
* Dulaglutide
* Semaglutide

MOA of GLP-1s?

• Stimulate insulin release & lower glucose levels

• Glucose-dependent, so more glucose = more insulin

• Lower risk for hypoglycemia

• Suppresses glucagon secretion, delays gastric emptying, & decreases appetite

• Reduces postprandial hyperglycemia

What degrades GLP-1 agonists?

DPP-4

Adverse effects of GLP-1 agonists?

• Nausea, vomitting, diarrhea

• Renal injury (exenatide)

• Increased risk of pancreatitis

What shouldn’t be used in patient with a FH or PMH of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome type 2?

Exenatide & liraglutide

Which GLP-1 reduces A1C, causes weight loss, & has a low hypoglycemic risk?

Exenatide

Which GLP-1 has a half-life of 5 days & is indicated in to reduce major cardiovascular events?

Dulaglutide (trulicity)

Which GLP-1 is approved for weight loss in patients without T2D?

Liraglutide

Which GLP-1 has the longest half-life (1 week)?

Semaglutide (ozempic)

What are the DPP-4 inhibitors?

• Alogliptin

• Linagliptin

• Saxagliptin

• Sitagliptin

MOA of DPP-4 inhibitors?

Block degradation of GLP-1, increase insulin secretion, & suppress glucagon release

When alogliptin & linagliptin are added to _ it lowers A1C:

Metformin, sulfonylurea, or pioglitazone

Which DPP-4 inhibitors require a dosage adjustment in renal impaired patients?

Saxagliptin & sitagliptin

Adverse effects of DPP-4 inhibitors?

• Nasopharyngitis/upper resp. tract infections

• Anaphylaxis, angiodema, & skin conditions

• Pancreatitis/hepatic failure

• HF

• Joint pain (severe arthralgia)

What are the SGLT-2 inhibitors?

• Canagliflozin

• Dapagliflozin

• Empagliflozin

• Ertugliflozin

MOA of SGLT-2 inhibitors & what it causes?

Blocks renal glucose resorption which causes glycosuria & lowers blood glucose& A1C levels, & contributes to modest weight loss

Adverse effects of SGLT-2 inhibitors?

• Genital mycotic infections & UTI

• Pyelonephritis & septicemia

• Necrotizing fascitis of the perineum

• Glycosuria = hypotension

• Risk of breast & bladder cancer + decrease in bone mineral density

• Euglycemic diabetic ketoacidosis

What does inhibition of SGLTs cause?

• Glycosuria

• Low blood glucose & A1C levels

• Modest weight loss

• 2nd choice in patients with diabetic nephropathy or HR

Contraindications of SGLT-2 inhibitors?

* Chronic kidney disease
* eGFR less than 30
* T1D/T2D that are very insulin deficient & prone to ketosis

Which drugs have moderate efficacy?

DPP-4 inihbitors & SGLT-2 inhibitors

What drugs have an increased risk for hypoglycemia?

Sulfonylureas & insulins

What drug is best for severe insulin resistance?

Pioglitazone

Weight gain medications?

Sulfonylureas, insulin, & pioglitazone

Weight neutral medications?

Metformin & DPP-4

Weight loss medications & cardiovascular benefits?

GLP-1 agonists & SGLT-2 inhibitors

SGLT-2 inhibitors reduce progression of what?

Diabetic nephropathy or HF

What drugs have shown improved cardiovascular outcomes?

Liraglutide, empagliflozin, & canagliflozin

What can a short acting secretagogue be helpful in?

Control glucose levels & reduce hyperglycemia after a carb-rich meal