Moving on with the non insulin drugs are the Biguanides. The main drug in this category is Metformin. What are some features and MOA of this drug?
MOA: reduces glucose levels primarily by inhibiting gluconeogenesis, it inhibits gluconeogenesis by reducing gene expression of gluconeogenic enzymes.
- -as a result of improvement in glycemic control, serum insulin concentrations decline slightly
- -associated with a decrease in weight
- -given orally and well absorbed and excreted in urine
What are the uses of Metformin?
- First line pharmacological therapy in type 2 DM
- -can be used along or in combo with sulfonylureas, thiazolidinediones and/or insulin
- Lower insulin resistance can result in ovulation and pregnancy in women with PCOS
- -leading treatment even though it is not approved (Even though clomiphene is the best treatment)
What are the AE of Metformin?
- GI (n/v/d): in 20% of patients
- Contraindicated in patients with renal or hepatic disease
- Cardiovascular collapse, acute congestive heart failure or acute MI
- Discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.
- Alcohol potentiates the effect of metformin on lactate metabolism.
- Interferes with B12 absorption
The next non insulin drug to discuss are the Thiazolidinediones (Tzds and Glitazones). These drugs are Pioglitazone and Rosiglitazone (both Tzds). What is the MOA?
MOA: Tzds decrease insulin resistance
- -agonists of peroxisome proliferator-activated receptor gamma; these receptors are found in muscle, fat and liver. These receptors modulate the expression of genes involved in lipid and glucose metabolism, insulin signal transduction and adipocyte differentiation.
- -in diabetic patients Tzds promote glucose uptake and utilization in adipose tissue and modulate synthesis of lipid hormones and cytokines
- -slow onset and offset of activity over weeks or even months
What are some additional features of Thiazolidinediones?
Less effective as monotherapy than sulfonylureas and metformin in decreasing FPG and HbA1C levels
Effects on lipids of pioglitazone are more favorable than those of rosiglitazone
What are adverse effects of Thiazolidinediones?
- Cause or exacerbate congestive heart failure in some patients (do not give to CHF patients)
- Troglitazone was the first Tzd to be approved but was found to be associated with severe hepatic toxicity, no longer used.
- Pioglitazone and Rosiglitazone have not shown signs of hepatotoxicity.
What are other uses of Thiazolidinediones?
Relief of insulin resistance evoked by Tzds can cause ovulation to resume in premenopausal women with PCOS.
Next non insulin drug are the alpha glucosidase Inhibitor. The drug is called Acarbose. What is the MOA?
Complex starches, oligosaccharides and disaccharides must be broken down into individual monosaccharide molecules before being absorbed and this is done via enteric enzymes, including pancreatic alpha amylase and alpha glucosidases
- -acarbose is a competitive inhibitor of the intestinal alpha glucosidases and reduces the postprandial digestion and absorption of starch and disaccharides
- -the consequence of enzyme inhibition is to minimize upper intestinal digestion and defer digestion of the ingested starch and disaccharides to the distal small intestine, thereby decreasing both postprandial hyperglycemia and hyperinsulinemia
What are uses for Acarbose?
Type 2 DM as monotherapy or in combo with sulfonylureas, metformin or insulin
–given orally and taken just prior to ingesting a meal
What are the AE for Acarbose?
Hypoglycemia may occur with concurrent sulfonylurea treatment
–should be treated with glucose and not sucrose, whose breakdown may be blocked
Excreted via kidneys
Reversible hepatic enzyme elevation and should be used in caution in the presence of hepatic disease. Periodical liver function monitoring is required
Moving on to the next non insulin drugs are the incretin analogs: Exenatide. What are some features?
Analog of incretin glucagon-like polypeptide (GLP-1)
Resistant to Dipeptidyl Peptidase IV, the enzyme that degrades incretins
MOA: enhances glucose dependent insulin secretion, suppresses postprandial glucagon release, slows gastric emptying, decreases appetite and may stimulate beta cell proliferation.
What are the uses and AE of Exenatide?
Type 2 DM along with diet and exercise control
AE: n/v/d ; dont use in patients with gastroparesis
Next non insulin drug are Inhibitors of DPP-IV: Sitagliptin. What are some features?
Selective Inhibitor of DPP-IV
–increases circulating GLP-1 and insulin levels, and decreases glucagon levels
Type 2 DM with diet and exercise and given orally
Next non insulin drug are Analogs of Amylin: Pramlintide. What are some features?
Synthetic Analog of Amylin that is Injectable
–amylin is a peptide that is co secreted with insulin from pancreatic beta cells in response to nutrient stimuli. Control nutrient intake as well as nutrient influx to the blood by inhibiting food intake, gastric emptying and glucagon secretion
Adjunctive therapy with insulin
What are the adverse effects of Pramlintide?
Used in combo with insulin, pramlintide has been associated with severe hypoglycemia
Again do not use in patients with gastroparesis
The next non insulin drug are Bile Acid Sequestrants: Colesevelam. What are some features?
Used to lower LDL cholesterol
Used in adjunct with diet and exercise in the treatment of type 2 DM
AE: constipation, nausea, dyspepsia, increase serum TG levels, and interfere with absorption of other oral drugs
The last non insulin drug is SGLT2 inhibitors: Canagliflozin. What are some features?
Glucose is filtered by the glomerulus and reabsorbed in the proximal tubule by the action of SGLT
–SGLT 2 is responsible for most glucose reabsorption
This drug inhibits SGLT2 leading to decreased glucose reabsorption, increased glucose excretion and decreased blood glucose levels
Reduces HbA1c by 0.6-1% when used along or in combo with oral agents or insulin
Contraindicated in patients with GFR greater than 45