Oral Agents and Non-Insulin Injectables Flashcards
Premeal plasma glucose should be in what target range in a healthy person?
80-130
Postprandial (post-meal) plasma glucose should be in what range in a healthy person?
<180
Hemoglobin A1C should be in what range in healthy person?
<7%
What two drug classes increase insulin secretion?
Sulfonylureas (Glipizide, glyburide, glimepiride)
and Meglitinides (Repaglinide, nateglinide)
Which two drug classes increase insulin sensitivity?
Biguanide (Metformin) and Glitazones (pioglitazone)
Which drugs delay carbohydrate absorption?
Alpha glucosidase inhibitors (acarbose, miglitol).
Which drugs increase incretin effect?
“Mimetic” GLP-1 receptor agonist (exenatide, liraglutide)
“Enhance” DPP IV inhibitor (Sitagliptin, saxagliptin, linagliptin).
Pramlintide: MOA
Increase amylin
Colesevelam: MOA
Bile acid sequestrant
Bromocriptine: MOA
Dopamine agonist
SGLT-2 Inhibitors (Canagliflozin, dapagliflozin): MOA
Decrease renal glucose reabsorption.
Sulfonylureas and meglitindes: MOA
- They bind to potassium/ATP channels and cause outpouring of potassium from cell.
- Depolarization of cell occurs.
- Calcium comes in through calcium channel and causes beta cells to release insulin.
KEY POINT: Requires functional beta cells. Stimulates basal and postprandial insulin secretion.
Sulfonylureas and meglitindes: Safety and efficacy
Efficacy: Decreases HbA1c by 1-2%
Safety: Weight gain, allergy, drug interactions.
MAIN RISK: HYPOGLYCEMIA
Sulfonylureas and meglitindes: Additional issues
Enhance physiological route of insulin delivery.
Stimulate basal and postprandial insulin secretion. They DO NOT WORK FOR TYPE I DM.
High initial response rate but eventually beta cells tire out.
No lag time prior to response.
Titration frequency: Days to weeks
What are the sulfonylureas?
Glyburide, glipizide, glimepiride.
What are the meglitindes?
Repaglinide, nateglinide
Biguanides (Metformin): MOA
Insulin sensitizer (Liver>>muscle). Depends on presence of insulin. Reduces hepatic glucose production. Increases uptake of glucose by skeletal muscle.
Long explanation:
Metformin activates AMPK in liver and muscle. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Activation of AMPK, an enzyme that plays an important role in insulin signaling, whole body energy balance, and the metabolism of glucose and fats, was required for metformin’s inhibitory effect on the production of glucose by liver cells. In addition to suppressing hepatic glucose production, metformin increases insulin sensitivity, enhances peripheral glucose uptake (by inducing the phosphorylation of GLUT4 enhancer factor), decreases insulin-induced suppression of fatty acid oxidation, and decreases absorption of glucose from the gastrointestinal tract. AMPK is known to cause GLUT4 deployment to the plasma membrane, resulting in insulin-independent glucose uptake.
Biguanides (Metformin): Efficacy
Decreases HbA1C by 1-2%
No hypoglycemia
Decreased macrovascular complications.
Good lipid effects (modest lowering of TG, LDL).
Titration frequency: Weeks to months
Biguanides (Metformin): Risks and Contraindications
Adverse effects: Diarrhea, nausea, decreased B12.
Main risk: Lactic acidosis
Contraindications: Renal, cardiac, hepatic insufficiency, IV contrast
Biguanides (Metformin): What is effect on weight gain?
No weight gain; possibly modest weight loss.
Advantageous lipid effects. Cardiovascular protection.
Thiazolidinediones (TZD’s or glitazones): MOA
Insulin sensitizer (Muscle, adipose»liver). Allows insulin to work better at level of muscle.
May preserve beta cell function.
Slow onset of action, titration frequency: Weeks to months
Thiazolidinediones (TZD’s or glitazones): Efficacy
Decreases HbA1c by 1-1.5%
Thiazolidinediones (TZD’s or glitazones): Adverse effects
Edema, weight gain
Main risk: CHF, liver toxicity
Cannot use this drug in CHF patients.
Thiazolidinediones (TZD’s or glitazones): Effects on serum glucose, cancer risk, cardiovascular health, lipids?
CV data is conflicting for rosiglitazone.
Mixed lipid effects–Pioglitazone more favorable than rosiglitazone.
No hypoglycemia.
NO increased bladder cancer risk with pioglitazone.
Small increased fracture risk.
Glitazones: Specific Cellular Action
Glitazones activate PPARgamma mainly in fat cells leading to improvements in insulin sensitivity in other tissues.
Peripheral adipocytes increase uptake of FFA (reducing fact stored in muscle, liver, and visceral fat depots).
Secretion of adipokines is affected=adiponectin is increased; resistin and TNFalpha are decreased. IMPROVED INSULIN SENSITIVITY.
Glitazones (Pioglitazone): What are advantages?
Lack of hypoglycemia as monotherapy or when given with other agents that do not increase insulin levels.
Preserve beta cell function.
Glitazones (Pioglitazone): What are disadvantages?
Weight gain
Potential fluid retention/CHF
Expensive
Increased LDL (Rosi)
Alpha-glucosidase inhibitors (Acarbose): MOA
These delay carbohydrate resorption and block absorption higher in gut.
Force absorption to only happen in ileum. SO much less is absorbed.
Titration frequency: Weeks to months
Alpha-glucosidase inhibitors (Acarbose): Efficacy
Decreases HbA1c 0.5-1%
Alpha-glucosidase inhibitors (Acarbose): Adverse effects
Flatulence
Main risk: Rare liver enzyme elevation
Adherence is poor. Cost is high. Small effect (best in those on high carb diet).
What are incretins?
Incretins are gut derived peptide hormones.
GLP=Glucagon like peptide
GIP=Glucagon inhibitory peptide
Their release is stimulated by nutrient intake.
In type II DM, secretion and/or actions of incretins is abnormal.
Explain the incretin effect.
Incretin effect: When I give IV glucose, plasma insulin doesn’t go up in healthy people. Glucose doesn’t pass through gut and stimulate hormones (the incretins) which usually tell beta cells “Hey! Make insulin!” IV glucose bypasses the gut!!!
Diabetes: Both when you give through IV AND through GI tract, they don’t have much incretin effect (unlike a healthy person).
Incretin GLP-1: Physiologic Functions
ncretins: Tell alpha cells to stop secreting glucagon.
Tell beta cells to make more insulin.
Beta cells are aware of glucose levels though. If glucose levels are low, they are not going to make more insulin.
Tell stomach to slow peristalsis (people eat less because they feel full).
Incretins tell CNS “I’m FULL!” Promotes satiety and reduction of appetite.
Incretin “Mimetic”/GLP-1 Receptor Agonist: Exenatide and Liraglutide: MOA
Binds enogenous GLP-1 receptors in pancreas, autonomic n.s., or directly in brain to cause:
1) Enhance insulin secretion
2) Decrease postprandial glucagon
3) Slow rate of gastric emptying
4) Increase satiety
Incretin “Mimetic”/GLP-1 Receptor Agonist: Exenatide and Liraglutide: Efficacy
Decreases HbA1c by 1.0-1.5%
People also tend to lose weight on these drugs over time.
Incretin “Mimetic”/GLP-1 Receptor Agonist: Exenatide and Liraglutide: Adverse Effects
Nausea, pancreatitis
Incretin “Mimetic”/GLP-1 Receptor Agonist: Exenatide and Liraglutide: Dosing Info
INJECTION
Exenatide=Twice daily
Liraglutide=Once daily
Exenatide LAR, dulaglutide: Once weekly
Incretin Enhancer: Oral DPP IV Inhibitor: MOA
Prolongs effects of endogenous incretins (Sitagliptin, linagliptin, saxagliptin).
They prevent incretins from becoming inactive and lower postprandial glucose.
Minimal side effects and they don’t cause hypoglycemia.
Incretin Enhancer: Oral DPP IV Inhibitor: Disadvantages
Very expensive.
Effect on A1c is not as good as other drugs.
Amylin: MOA
Regulator of glucose influx into bloodstream. Inhibits glucagon secretion from alpha cells. No effect on beta cells.
Reduces appetite by acting on CNS.
Slows gastric emptying of stomach contents.
37 amino acid neuroendocrine hormone.
Co-located and co-secreted with insulin from pancreatic beta cells (deficient in Type I and Type II DM).
Pramlintide: Synthetic amylin analogue: Pros
Weight loss.
Used in Type I and Type II DM. Used in conjunction with insulin because would not sufficiently treat Type I DM as monotherapy.
Pramlintide: Synthetic amylin analogue: Cons
Injection with each meal.
Nausea initially. T1DM>T2DM.
Expensive.
Need 2 injections each meal for people on mealtime insulin.
Lowers HbA1c 0.5-1%.
Bromocriptine: Dopamine Agonist: Pros
MOA uncertain.
Lowers A1c 0.4-0.5% when added to sulfonylurea or as monotherapy.
Bromocriptine: Dopamine Agonist: Adverse Effects
Nausea, vomiting, dizziness, headache
SGLT-2 Inhibitors: Canagliflozin and Dapagliflozin: Pros
MOA: Promote renal excretion of glucose.
Lowers A1c: 0.5-1.0%
Promotes sustained weight loss.
Lowers BP.
SGLT-2 Inhibitors: Canagliflozin and Dapagliflozin: Adverse Effects
Increased risk for UTI and vulvovaginal candidiasis.
Why? SGLT2 receptors in kidney normally reabsorb glucose from urine. But if people are taking a SGLT2 inhibitor, extra glucose is in urine and this can lead to lots of UTIs.
