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What are the classes of oral agents used to treat diabetes and what are their MOA?
- Biguanides: inhibit gluconeogenesis, improve insulin sensitivity, decrease intestinal absorption of glucose
- Secretagogues: increase insulin secretion from pancreas (meglitinides are glucose-dependent, sulfonylureas are not)
- DPP-4 inhibitors: increase glucose-dependent insulin secretion from pancreas, decrease glucagon secretion from alpha cells to decrease gluconeogenesis
- Thiazolidinediones (PPAR agonists): increase insulin sensitivity, decrease hepatic glucose output
- Alpha-glucosidase inhibitors: inhibit carbohydrate aborption in intestines
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What are the biguanides used in diabetes?
Metformin
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What is the expected A1c reduction from Metformin?
1-2%
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What are the secretagogues used in diabetes?
- Sulfonylureas:
- Glyburide
- Glipizide
- Glimepiride
- Meglitinides:
- Repaglinide
- Nateglinide
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What is the expected A1c reduction from the secretagogues?
- Sulfonylureas: 1-2%
- Meglitinides: 1-2% (0.5-1.5% for Nateglinide
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What are the DPP-4 inhibitors used in diabetes?
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What is the expected A1c reduction from DPP-4 inhibitors?
- Sitagliptin 0.6-1.4%
- Saxagliptin 0.4-1%
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What are the TZDs used in diabetes (PPAR agonists)?
- Rosiglitazone
- Pioglitazone
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What is the expected A1c reduction from DPP-4 inhibitors?
- Rosiglitazone 0.1-0.9%
- Pioglitazone 0.3-1.9%
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What are the Alpha-glucosidase inhibitors used in diabetes?
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What is the expected A1c reduction from Alpha-glucosidase inhibitors?
- Miglitol 0.22-0.84%
- Acarbose 0.56-0.7%
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What is the place in therapy for Metformin in diabetes?
- 1st line
- Wt neutral or negative
- Monotherapy or combination therapy
- Decreases FBG
- Decreases TG and LDL slightly
- Increases HDL slightly
- Pregnancy category B
- Has other uses; don't assume pt is diabetic
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What is the place in therapy for Sulfonylureas in diabetes?
- Monotherapy or combination therapy
- Decrease FBG
- Relatively rapid glucose lowering
- Work best in non-obese pts and younger pts (40-65yo or recent dx)
- Not for those on > 40 units/d of insulin
- Less than 5yr diabetes hx
- Don't work very well if A1c is really high
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What is the place in therapy for Meglitinides in diabetes?
- Combination therapy
- Decrease PPG (short onset of action and short half-life)
- Does not supply basal insulin
- Pregnancy category C
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What is the place in therapy for DPP-4 inhibitors in diabetes?
- Monotherapy or combination therapy
- Wt neutral
- Pregnancy category B
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What is the place in therapy for TZDs in diabetes?
- Monotherapy or combination therapy
- Metabolic syndrome or non-alcoholic fatty liver disease
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What is the place in therapy for Alpha-glucosidase inhibitors in diabetes?
- Monotherapy or combination therapy
- Decrease PPG
- GI SE may limit use
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What are the patient-specific factors that affect oral antidiabetic drug selection?
- All are CI with DKA or Type I diabetes
- Renal dysfunction (Metformin > 1.4 in women and > 1.5 in men, Sulfonylureas, adjust DPP-4 inhibitors, Alpha-glucosidase inhibitors > 2)
- Hepatic dysfunction (Metformin, Sulfonylureas, TZDs, Alpha-glucosidase inhibitors)
- Hx of acidosis (Metformin)
- Pregnancy (Sulfonylureas, Meglitinides, Alpha-glucosidase inhibitors)
- Duration of dx (Sulfonylureas < 5y)
- Insulin (Sulfonylureas < 40 units/d)
- CHF (TZDs)
- HTN (TZDs)
- IBD (alpha-glucosidase inhibitors)
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Which oral antidiabetics cause wt gain?
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What is the Tier 1 progression of treatment with oral meds in diabetes?
- Lifestyle + Metformin
- Add basal insulin OR Sulfonylurea
- Add bolus insulin
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What is the Tier 2 progression of treatment with oral meds in diabetes?
- Lifestyle + Metformin
- Add Pioglitazone OR GLP-1 agonist
- Change added med to Sulfonylurea OR basal insulin
- Add bolus insulin
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What is the normal dose for Metformin in diabetes?
- 500mg BID to TID (may be titrated up to 1000mg)
- 500mg QD ER (may be titrated up to 1000mg)
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What is the normal dose of sulfonylureas in diabetes?
- Glyburide 1.25-10mg QD or BID
- Glipizide 2.5-20mg QD or BID
- Glimeperide 1-8mg QD
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What is the normal dose of Meglitinides in diabetes?
- Repaglinide 0.5-1mg (16mg max)
- Nateglinide 60-120mg (360mg max)
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What is the normal dose of DPP-4 inhibitors in diabetes?
- Sitagliptin 25-100mg QD
- Saxagliptin 2.5-5mg QD
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What is the normal dose of TZDs in diabetes?
- Rosiglitazone 2-8mg QD or BID
- Pioglitazone 15-45mg QD
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What is the normal dose of Alpha-glucosidase inhibitors in diabetes?
- 25mg for 2 weeks
- 25mg BID weeks 3-4
- 25mg TID weeks 5-12
- then 50-100mg TID
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How should Metformin be monitored?
- FBG
- A1c q 3mo until controlled, then q 6mo
- Renal fx baseline and q 6mo
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How should sulfonylureas be monitored?
- FBG
- A1c q 3mo until controlled, then q 6mo
- Renal fx periodically
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How should meglitinides be monitored?
- FBG
- A1c q 3mo until controlled, then q 6mo
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How should DPP-4 inhibitors be monitored?
- FBG
- A1c q 3mo until controlled, then q 6mo
- Renal fx annually
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How should TZDs be monitored?
- FBG
- A1c q 3mo until controlled, then q 6mo
- LFTs baseline, then q 3-6mo for first yr, then yearly
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How should alpha-glucosidase inhibitors be monitored?
- FBG
- PPG
- Hypoglycemia sx
- A1c q 3mo until controlled, then q 6mo
- LFTs periodically
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What are the SE and DI of Metformin?
- SE:
- NVD (take with food, titrate slowly, XR formulation better)
- Wt loss
- Bloating
- Metallic taste
- Lactic acidosis
- Malabsorption of B12 and Folic acid
- CI:
- Radio contrast dye
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What are the SE and DI of sulfonylureas?
- Hypoglycemia
- Wt Gain
- Rash (still can use in Sulfa allergy)
- NV (take with food)
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What are the SE and DI of Meglitinides?
- NV (take with food)
- Hypoglycemia (better than Sulfonylureas)
- Gemfibrozil
- 3A4 inhibitors/inducers
- Highly protein-bound drugs (Phenytoin, Furosemide, Metformin)
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What are the SE and DI of DPP-4 inhibitors?
- Hypoglycemia (decrease sulfonylureas or meglitinides if used in combination)
- URT infection
- Pancreatitis (Sitagliptin)
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What are the SE and DI of TZDs?
- Wt gain
- Edema - increast risk of ischemic heart disease
- Increase fracture risk
- Increase LDL
- Increase HDL
- Decrease TG (Pioglitazone only)
- Hepatotoxicity
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What are the SE and DI of alpha-glucosidase inhibitors?
- Explosive flatulence, diarrhea, abdominal pain (improves with time; titrate slowly)
- Elevated liver enzymes (esp at high doses > 300mg/d)
- Because of MOA, must treat hypoglycemia with Glucose, not candy or juice, etc
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