MPP II 3.8 - EN. PANCREAS PHARM PART 2

Endocrine Pancreas Pharmacology II

• Learning objectives include identifying drug targets, mechanisms, and clinical uses for synthetic amylin analogs and incretin mimetics, as well as oral diabetes agents.
• A goal is to compare and contrast the oral agents and associate the plasma insulin effect and hypoglycemia risk for each drug.

Treating Type 2 Diabetes (T2D)

• Treatment starts with lifestyle modifications.
• Oral antihyperglycemic drugs are most effective when insulin resistance is low.
• Exogenous insulin is also another treatment option.

Synthetic Amylin Analogs

• Amylin hormone is co-secreted with insulin from β cells after food intake.
• It delays gastric emptying and lowers glucagon secretion.
• Pramlintide is a synthetic amylin analog indicated as an adjunct to mealtime insulin for T1D or T2D, administered via subcutaneous injection.
• Pramlintide allows reducing the mealtime insulin dose by 50% to avoid severe hypoglycemia, nausea, and vomiting.

Incretin Mimetics

• Incretin mimics are metabolic hormones that lower blood glucose levels.
• The two types are, Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).
• Incretin hormones account for 60-70% of postprandial insulin secretion.
• Exenatide, is an injectable incretin mimetic used for T2D.

Incretin Mimetic Actions

• Incretin mimetics are analogs of GLP-1, acting as GLP-1 receptor agonists to improve insulin secretion, lower postprandial glucagon secretion, slow gastric emptying, reduce food intake by enhancing satiety, and promote β-cell proliferation.
• These actions can reduce weight gain and postprandial hyperglycemia, and lower HbA1c levels.
• Being polypeptides, they must be administered subcutaneously.
• Adverse effects of increasing mimetics are nausea, vomiting, diarrhea, and constipation, with the possibility of pancreatitis.

Oral Agents Overview

• Useful for T2D patients not controlled by diet alone.
• Long-standing disease may require a combination of oral agents with or without insulin.

Oral Agents: Sulfonylureas

• Insulin secretagogues promote insulin release from the β cells of the pancreas.
• Second-generation drugs in current use are glyburide, glipizide, and glimepiride.

Sulfonylureas Mechanisms

• The mechanism of action includes stimulating insulin release from the β cells of the pancreas.
• Sulfonylureas block ATP-sensitive K+ channels, resulting in depolarization, Ca2+ influx, and insulin exocytosis.
• They are given orally.
• They bind to serum proteins.
• They are metabolized by the liver.
• They are excreted in the urine and feces.
• The duration of action ranges from 18 to 24 hours.
• Adverse effects include weight gain, hyperinsulinemia, and hypoglycemia.
• Used with caution in hepatic or renal insufficiency due to the risk of hypoglycemia.

Oral Agents: Glinides

• Glinides are insulin secretagogues, and include repaglinide and nateglinide.

Oral Agents: Glinides Actions

• Glinides stimulate insulin secretion by binding to a distinct site on the β cell, closing ATP-sensitive K+ channels, and resulting in the release of insulin.
• Should not be used in combination with sulfonylureas because of overlapping mechanisms
• Glinides have a rapid onset and short duration compared to sulfonylureas.
• They are effective in the early stage of insulin release after a meal and are “postprandial glucose regulators”.

Glinides: Pharmacokinetics and Adverse Effects

• Glinides should be taken before a meal and are absorbed after oral administration.
• Glinides are metabolized to inactive products by cytochrome P450 3A4 (CYP3A4).
• Adverse effects include hypoglycemia and weight gain.
• Use with caution in patients with hepatic impairment.

Oral Agents: Biguanides

• Metformin is classified as an insulin sensitizer and is a "first-line" medicine for T2D.
• Decreases liver glucose production while increasing glucose uptake and use by target tissues, thus lowering insulin resistance.
• It does not promote insulin secretion, unlike sulfonylureas.
• Metformin is absorbed orally, not bound to serum proteins, and not metabolized.
• Excretion occurs via the urine.
• Adverse effects are largely gastrointestinal.
• Is contraindicated in renal dysfunction due to the risk of lactic acidosis.
• Use with caution in patients over 80 and those with heart failure.

Oral Agents: Thiazolidinediones (TZDs)

• TZDs are insulin sensitizers.
• Requires insulin for action but TZDs do not encourage its release from the β cells; there is no risk of hyperinsulinemia.

TZDs: Mechanism of Action

• TZDs reduce insulin resistance by acting as agonists for PPARγ.
• Activating PPARγ regulates the transcription of insulin-responsive genes which result in increasing insulin sensitivity in adipose tissue, the liver, and skeletal muscle.
• They effect cholesterol levels.
  • Rosiglitazone increases LDL cholesterol and triglycerides
  • Pioglitazone decreases triglycerides.
• TZDs increase HDL cholesterol.
• Can be used as monotherapy or with other glucose-lowering agents or insulin.

TZDs: Pharmacokinetics, Adverse Effects

• Are well absorbed after oral administration and are extensively bound to serum albumin.
• TZDs undergo extensive metabolism by different CYP450 isozymes.
• Adverse effects include a few cases of reported liver toxicity. Periodic monitoring of liver function is recommended.
• Weight gain can occur, and subcutaneous fat may increase and lead to fluid retention.

Oral Agents: α-Glucosidase Inhibitors

• Acarbose and miglitol are oral agents used for T2D.
• Sometimes referred to as "starch blockers”.

α-Glucosidase Inhibitors: Mechanism of Action

• These agents act on α-glucosidase enzymes located in the intestinal brush border.
• Carbohydrates are broken down into glucose and other simple sugars to be absorbed.
• Agents reversibly inhibit α-glucosidase enzymes.
• When taken at the start of a meal, digestion of carbohydrates is delayed, resulting in lower postprandial glucose.
• They do not encourage insulin release or increase insulin sensitivity.
• They do not cause hypoglycemia when used as monotherapy.

α-Glucosidase Inhibitors: Pharmacokinetics and Adverse Effects

• Acarbose is poorly absorbed, while miglitol is very well absorbed.
• Excreted unchanged by the kidney.
• They can lead to flatulence, diarrhea, and abdominal cramping.
• Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs.

Oral Agents: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

• These are orally active, and used for T2D.

DPP-4 Inhibitors: Mechanism of Action

• They inhibit the enzyme DPP-4, responsible for the inactivation of incretin hormones (GLP-1).
• The activity of incretin hormones is extended.
• Insulin release increases in response to meals.
• Inappropriate secretion of glucagon is reduced.

DPP-4 Inhibitors: Pharmacokinetics and Adverse Effects

• These inhibitors may be used as monotherapy or in combination with sulfonylureas, metformin, TZDs, or insulin.
• They do not cause satiety and are weight neutral, unlike incretin mimetics.
• DPP-4 inhibitors are well tolerated.
• A common adverse effect is headache.

Oral Agents: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

• SGLT2’s are responsible for reabsorbing glucose in the tubular lumen of the kidney.

SGLT2 Inhibitors: Mechanism of Action

• They lower the reabsorption of glucose, increase urinary excretion of glucose, and lower blood glucose.
• They lower reabsorption of Na+ and cause osmotic diuresis.
• May reduce blood pressure.

SGLT2 Inhibitors

• Canagliflozin, dapagliflozin, and empagliflozin are typically used to treat type 2 diabetes.
• Generic names end with the suffix “-gliflozin".
• Inhibit SGLT2, responsible for reabsorbing filtered glucose in the PCT.
• Blocking SGLT2 also decreases reabsorption of sodium and causes osmotic diuresis.
• Empagliflozin met an exploratory end point of statistically significant reduction in HF versus placebo in a clinical trial.

SGLT2 Inhibitors: Dosing and Adverse Effects

• Given once daily in the morning
• Avoid in patients with renal dysfunction.
• Common adverse effects are female urinary tract infections and urinary frequency.
• Hypotension, particularly in the elderly or patients on diuretics is another side effect.