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Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #51: Pharmacotherapy of Type 2 Diabetes, Part 10

Richard S. Beaser, MD

Joslin_Diabetes_Deskbook

Medications that Increase Insulin Secretion:

SULFONYLUREAS
CLASS SUMMARY:
  • Action: Insulin secretagogues. Initial effects are to increase insulin secretory capacity. With establishment of long-term glucose control, this increase may not persist and other extrapancreatic effects, either direct or indirect, may also occur.
  • Required for efficacy: Some remaining endogenous pancreatic insulin secretory capacity
  • Manifestation on glucose patterns: General reductions in elevated glucose levels throughout the day
  • Potential effect on A1C: Below 1%-2 %
  • Significant adverse effects/side effects: weight gain, hypoglycemia (particularly in older individuals who may undereat or miss meals)….
  • Other potential adverse effects of note: Past concerns about increased risk of coronary events (stemming from the University Group Diabetes Project study) seem to have diminished with the findings of the United Kingdom Prospective Diabetes Study (UKPDS) showing no increased cardiac risk with sulfonylurea use. However, some suggestion that use of these medications in the acute post-infarct period worsens outcomes has led many to avoid their use in these situations, often switching to insulin therapy.
  • Typical patient with optimal efficacy: Type 2 diabetes with insufficient insulin secretory capacity (relative or absolute), yet enough beta-cell function remaining for some stimulation of further insulin secretion tobe possible.
  • Other effects:
    •  Weight: increases
    • Lipids: no significant effect
INDIVIDUAL MEDICATION SUMMARIES:

Capsule Information on First-Generation Agents Still in Occasional Use:

  • Tolbutamide (Orinase)
    • Short-acting sulfonylurea
    • Half-life 4.5–6.5 hours
    • Duration of action 6–10 hours
    • Metabolized in the liver to inactive metabolites, which are excreted via the kidney. This medication may be used in mild renal impairment.
    • Dose range 500–3000 mg daily, usually given 2–3 times daily
    • Comment: short duration and frequent dosing requirement make compliance an issue
  • Tolazamide (Tolinase)
    • Intermediate duration of action
    • Half-life 7 hours
    • Duration 16–24 hours
    • Metabolized in the liver to mildly active metabolites, which are excreted via the kidney
    • Dosing range 100–1000 mg daily, taken 1–2 times daily
  • Chlorpropamide (Diabinese)
    • Very long duration of action
    • Half-life 36 hours
    • Duration can extend for 2–3 days
    • Metabolized incompletely in the liver to metabolites with hypoglycemic activity, excreted via the kidney. Contraindicated with renal impairment.
    • Dosing range 100–500 mg/day, usually in a single dose
    • Adverse effect is the chlorpropamide-alcohol flush (Antabuse-like reaction)
    • Long duration of action makes it potent but hypoglycemia can persist for a long time
Second-Generation Agents:
A. GLYBURIDE (GENERIC)
 
ALTERNATE GENERIC NAME: GLYBENCLAMIDE
 
Brand Names: Diabeta, Micronase
Pharmacology:
  • Half-life biphasic: 4 and 10 hours
  • Duration of action 16–24 hours
  • Metabolized in the liver to weakly active and inactive metabolites, which are excreted in liver (50%) and bile (50%). This is different from other sulfonylureas, which have primarily a renal excretion.
  • Typical starting dose:
    • 2.5 to 5 mg daily, in single dose. Can start with 1.25 mg if there is concern about possible hypoglycemia or decreased drug clearance.
  • Typical dose titration pattern:
    • Range 1.25–20 mg daily
  • Optimal dose:
    • 10 mg/daily. Usually given once or twice daily
  • Tablet size:
    • Glyburide: 1.25 mg, 2.5 mg, 5 mg, 10 mg
  • Combination Tablets:
    • Metformin/glyburide (Glucovance)
      • glyburide 1.25 mg and metformin 250 mg
      • glyburide 2.5 mg and metformin 500 mg
      • glyburide 5 mg and metformin 500 mg
      • The utility of this combination tablet includes:
        • The ability to utilize low doses of both medications concurrently (some not otherwise available)
        • Improved adherence to treatment regimen and ease of use
        • Ability to "dual defect" of insulin resistance and insulin secretory deficiency, particularly early in the natural history in a conveniently dosed single tablet
  • Potential drug interactions:
    • Hypoglycemic effects may be potentiated by the following medications: NSAIDS, salicylates, sulfonamides, alcohol, fibrates, chloramphenicol, probenecid, allopurinol, coumarin, trimethoprim, monoamine oxidase inhibitors, ß-blockers. Interactions with ciprofloxacin causing a potentiation of hypoglycemic effect have been described.
    • Hyperglycemia may potentiated by the following medications: corticosteroids, thiazides, other diuretics, barbiturates, rifampin, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockingdrugs, and isoniazid. Interactions with miconazone and fluconazone causing hypoglycemia have been described.
  • Contraindications and precautions:
    • Known sensitivity to glyburide and in the treatment of diabetic ketoacidosis, with or without coma
    • Hypoglycemia
    • Pregnancy: category B — use only if clearly needed
    • Information for patients:
      • Discuss risks of hypoglycemia.

ALTERNATE FORMULATION OF GLYBURIDE: MICRONIZED FORMULATION OF GLYBURIDE

Brand name: Glynase PresTab
  • Differences in action/pharmacology from glyburide: The micronized glyburide provides somewhat greater bioavailability per milligram than standard glyburide, with peak drug levels occurring at 2–3 hours (4 hours for glyburide)
  • Differences in dosing:
    • Dosing: while 3 mg of micronized glyburide has a somewhat similar efficacy to 5 mg of glyburide, the actual peak drug availability curves differ slightly and some retitration is often necessary when a switch is made
  • Typical starting dose:
    • Usual starting dose 1.5 to 3 mg daily, in a single dose
  • Typical dose titration pattern:
    • Dosing range 1.5 to 12 mg daily
  • Optimal dose:
    • Optimal dose 6 mg daily, in single or divided dose
  • Tablet size: 1.5 mg, 3 mg, 6 mg
Other categories: Same as for glyburide — see above
 
B. Glipizide (Generic)
 
Brand name: Glucotrol
Pharmacology:
  • Half-life of 2–4 hours
  • Duration of action 12–24 hours
  • Metabolized in liver to inactive metabolites with excretion primarily via kidney and small amounts in bile
  • Typical starting dose:
    • 5 mg daily, in single dose. Can start with 2.5 if there is concern about possible hypoglycemia or decreased drug clearance.
  • Typical dose titration pattern:
    • Dosing range 2.5–40 mg daily
  • Optimal dose:
    • 20 mg/daily. Usually given once or twice daily.
  • Tablet size:
    • Glipizide: 5 mg, 10 mg
  • Combination Tablets (brand name in parentheses):
    • Metformin/glipizide (Metaglip)
      • glipizide 2.5 mg and metformin 250 mg
      • glipizide 2.5 mg and metformin 500 mg
      • glipizide 5 mg and metformin 500 mg
    • The utility of this combination tablet includes:
      • Improved adherence to treatment regimen and ease of use
      • Ability to "dual defect" of insulin resistance and insulin secretory deficiency
  • Potential drug interactions:
    • Hypoglycemic effects may be potentiated by the following medications: NSAIDS, salicylates, sulfonamides, alcohol, fibrates, chloramphenicol, probenecid, allopurinol, coumarin, trimethoprim, monoamine oxidase inhibitors, ß-blockers. Interactions with ciprofloxacin causing a potentiation of hypoglycemic effect have been described.
    • Hyperglycemia may potentiated by the following medications: cort-icosteroids, thiazides, other diuretics, barbiturates, rifampin, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. Interactions with miconazone and fluconazone causing hypoglycemia have been described.
  • Contraindications and precautions:
    • Contraindications with known hypersensitivity to the drug and in the treatment of diabetic ketoacidosis, with or without coma
    • Precautions: metabolism and excretion slowed with renal or hepatic disease; can cause hypoglycemia
      • Pregnancy: category C — not indicated for use
  • Information for patients:
    • Discuss risks of hypoglycemia.

ALTERNATE FORMULATION OF GLIPIZIDE: THE GLIPIZIDE "GITS" (GASTROINTESTINAL THERAPEUTIC SYSTEM), OR GLIPIZIDE XL

Brand name: Glucotrol XL
  • Differences in action/pharmacology from glipizide: These tablets consist of an osmotically active drug core surrounded by a semi-permeable membrane. Drug is released into the gastrontestinal tract through an orifice in the membrane at a controlled rate during the transit of the tablet. This formulation produces a constant drug release, resulting in even drug availability over the 24-hour duration of action period.
  • Typical starting dose:
    • Usual starting dose 5 mg daily, in a single dose
  • Typical dose titration pattern:
    • Dosing range 5 to 20 mg daily, usually in single dose
    • Start with 5 mg daily, and titrate up to 10 mg daily
  • As the added advantage of going to 20 mg daily is not great, once the 10 mg dose is reached, usually another medication is added rather than increasing to glipizide XL 20 mg daily as the next step
  • Optimal dose:
    • Optimal dose 10 mg daily, in single dose
    • Maximum dose 20 mg daily in a single dose
  • Tablet size:
    • 2.5 mg, 5 mg, 10 mg
  • Information for patients
    • Discuss risks of hypoglycemia.
    • Tell patients that they must swallow this pill whole. They might see pill casing pass out in the stool — this is normal.
    • Do not cut pill in half or crush.
    • Other categories: Same as for glipizide — see above.
C. GLIMEPIRIDE (GENERIC)
 
Brand names: Amaryl
Pharmacology:
  • Half-life: 3–7 hours
  • Duration of action 24 hours
  • Metabolized in liver to weakly active metabolites. Excreted by kidney (60%) and bile (40%).
  • Typical starting dose:
    • 1–2 mg daily, in single dose at breakfast or the main meal. People who are potentially sensitive to these medications should start with 1 mg.
  • Typical dose titration pattern:
    • Dosing range 1–4 mg given once daily
  • Optimal dose:
    • 2 mg/daily. Usually given as a single dose.
  • Maximum dose 4 mg/daily, given as a single dose.
  • Tablet size: 1 mg, 2 mg, 4 mg
  • Combination Tablets (brand names in parentheses):
    • pioglitazone/glimepiride (Duetact)
      • pioglitazone 30 mg and glimepiride 2 mg
      • pioglitazone 30 mg and glimepiride 4 mg
    • rosiglitazone/glimepiride (Avandaryl)
      • rosiglitazone 4 mg and glimepiride 1 mg
      • rosiglitazone 4 mg and glimepiride 2 mg
      • rosiglitazone 4 mg and glimepiride 4 mg
  • Potential drug interactions:
    • Hypoglycemic effects may be potentiated by the following medications: NSAIDS, salicylates, sulfonamides, alcohol, fibrates, chloramphenicol, probenecid, allopurinol, coumarin, trimethoprim, monoamine oxidase inhibitors, ß-blockers. Interactions with ciprofloxacin causing a potentiation of hypoglycemic effect have been described.
    • Hyperglycemia may potentiated by the following medications: corticosteroids, thiazides, other diuretics, barbiturates, rifampin, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. Interactions with miconazone and fluconazone causing hypoglycemia have been described.
  • Contraindications and precautions:
    • Known sensitivity to glimepiride, and in the treatment of diabetic ketoacidosis, with or without coma
    • Hypoglycemia
    • Pregnancy: category C — not indicated
  • Information for patients:
    • Discuss risks of hypoglycemia.

D. GLICLAZIDE (GENERIC) — NOT AVAILABLE IN THE UNITED STATES

Brand name: Diamicron
Summary:
  • Half-life 6–12 hours
  • Duration of action 16–24 hours
  • Metabolized in liver to metabolites that are probably inactive, and excreted by kidney (70%) and bile (30%)
  • Dosage 80–160 mg given 1–2 times daily
5. MEGLITINIDES
 
REPAGLINIDE SUMMARY
 
Brand name: Prandin
  • Action: stimulates the glucose-dependent postprandial insulin release from functioning β-cells
  • Pharmacology:
    • Completely absorbed from GI tract
    • Peak serum level at about 1 hour, dissipation in 3–4 hours
    • Peak insulin response is seen 10 minutes after administration
    • Metabolism: Cytochrome P-450 system, specifically 3A4. Metabolites are not active.
    • Most eliminated by GI route.
  • Required for efficacy: Functioning β-cells
  • Manifestation on glucose patterns: Primarily reduces postprandial glucose excursions. However, impact on overall control can also lead to reductions in fasting and preprandial glucose levels as well.
  • Potential effect on A1c: less than 1.6%–1.9% vs. placebo; somewhat greater in drug naïve patients
  • Significant adverse effects/side effects:
    • Hypoglycemia
  • Other side effects of note:
    • Weight: increase
    • Lipids: no significant effects
  • Typical patient with optimal efficacy: Type 2 diabetes with loss of postprandial, particularly first-phase, insulin release, manifest by significant elevations in glucose levels between the pre-and postprandial period. Useful for patients with erratic meal schedules or who skip meals, particularly if they have been having difficulty with hypoglycemia using sulfonylureas.
  • Tablet Sizes: 0.5 mg, 1 mg, 2 mg
  • Dosing: Starting dose:
    • Drug-naïve (no prior antidiabetes medication): 0.5 mg, 0–30 minutes before each meal (15 minutes is ideal)
    • Prior antidiabetes therapy: 1–2 mg 0–30 minutes before each meal (15 minutes is ideal)
  • Dose Titration:
    • Maximum efficacy at each dosing level seen in 1–2 weeks
    • Titrate upward to maximum of 4 mg before each meal
    • Can be given for up to 4 meals per day. Doses may vary before specific meals, adjusted for food quantity and differing response. If meal is omitted, medication is omitted.
  • Indicated also for use with metformin
  • Optimal dose:
    • Most of the therapeutic efficacy is seen in the first half of the dosing range, i.e., up through 2 mg preprandially
  • Other clinical effects:
    • Weight: decrease
    • Lipids: reduces: triglycerides, LDL, total cholesterol
    • Coagulation: decreased plasminogen activator inhibitor
  • Drug interactions:
    • Increases repaglinide metabolism: rifampin, barbiturates, carbamazepine
    • Decreases repaglinide metabolism: antifungals, erythromycin
    • Increases repaglinide effect: NSAIDs, ß-blockers, sulfonamides, salicylates, chloramphenicol, Coumadin, MAOIs, probenecid
    • Decreases repaglinide action: corticosteroids, calcium channel blockers, oral contraceptives, thiazide diuretics, thyroid preparations, estrogens, phenothiazines, phenytoin, rifampin, isoniazid, phenobarbital, sympathomimetics
  • Contraindications and precautions:
    • Known hypersensitivity to repaglinide
    • Type 1 diabetes and ketoacidosis
    • Hepatic insufficiency can cause elevated repaglinide blood levels as well as decrease gluconeogenesis, leading to hypoglycemia. Use cautiously, and have longer intervals between dose adjustments to allow full assessment of response.
    • Renal insufficiency: initial doses do not need to be adjusted, but sub-equent increases should be made with caution. Repaglinide not tested in people with creatinine clearance 20 mg/ml or on hemodialysis.
    • Pregnancy category C
  • Key advice to patients:
    • Contact healthcare professional if deterioration of glucose control occurs.
    • Explain risk of hypoglycemia.
    • Explain premeal dosing instructions (0–30 minutes premeal, 15 minutes being ideal), adjustments for missed meals (skip dose) or meals of various sizes (may adjust per individualized needs).

6. D-PHENYLALANINE DERIVATIVES NATEGLINIDE SUMMARY

Brand name: Starlix
  • Indications: Monotherapy or in combination with metformin.
  • Action: Stimulates the rapid, glucose-dependent postprandial insulin release from functioning β-cells
  • Pharmacokinetics: Stimulates pancreatic insulin secretion within 20 minutes of oral administration. Peak levels at 1 hour after dosing, and return to baseline at 4 hours after dosing.
  • Metabolism: In the liver, primarily by CYP2C9 (70%) with some contribution by CYP3A4 (30%), to 3 major and several minor metabolites, none active. There is no significant interaction with other medications metabolized through similar mechanisms.
  • Elimination: 83% urinary excretion, of which 84% is metabolized drug, 16% is intact drug.
  • Manifestation on glucose patterns: Primarily reduces postprandial glucose excursions. Significantly lesser effect of fasting glucose levels.
  • Potential effect on A1C: Below 0.45% vs. baseline in non-drug naïve patients, with initial study A1C level 8.3%. Additional efficacy when used in combination with metformin.
  • Significant side effects:
    • Mild hypoglycemia
  • Other side effects of note:
    • Weight: slight increase
    • Lipids: no significant effects on fasting lipids. Can decrease postprandial triglycerides
  • Typical patient with optimal efficacy: Type 2 diabetes with a predominant defect of loss of first-phase insulin release, as manifest by significant elevations in glucose levels between the pre-and postprandial period. This might be the thinner patient with type 2 diabetes, with fasting glucose levels above 125 mg/dl, but not close to 200 mg/dl or above. Also, for patients on biguanide or thiazolidinedione with suboptimal control, but who need insulin stimulatory effect to be meal-targeted to avoid hypoglycemia.
  • Dosing:
    • 120 mg 1–30 minutes before meals. If no meal is eaten, no dose is taken. This is the usual dose for most patients, and no titration needed. Response is glucose dependent, not dose dependent.
    • Taking medication after meals results in reduced drug levels
    • For patients with A1C values close to target and for whom only minimal additional drug effect is desired, the 60-mg tablet is available
    • Indicated also for use with metformin
    • Same doses for patients with renal impairment and mild hepatic dysfunction
  • Additional precaution: Response to drug is dependent on glucose load. Therefore, if inadvertent overdose is taken without food, minimal hypoglycemia is likely to occur. However, if one attempts to "treat" such an overdose with glucose, the glucose load will stimulate a brisk insulin secretory response and the resultant hypoglycemia is likely to be worse!

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