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Ana Emiliano, M.D. and Brian Pinto, Pharm.D.
01-21-2011
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Incretin mimetics (exenatide and liraglutide) - Type 2 diabetes (T2DM), although exenatide not approved for use with insulin therapy
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Amylin analogues (pramlintide)- Type 1 diabetes (T1DM) and T2DM on insulin therapy
- Incretin mimetics (exenatide, liraglutide): Stimulate glucose-dependent insulin secretion, low gastric emptying; inhibit glucagon secretion; and suppress appetite
- These agents (exenatide, liraglutide) are glucagon-like peptide agonists, binding to the GLP-1 receptor, as the mechanism for stimulating glucose-dependent insulin release.
- Amylin analogue (pramlintide): Slows gastric emptying; suppresses an exaggerated postprandial rise of glucagon (as seen in T2DM); induces satiety
- This agent (pramlintide): acts as the naturally occuring gastric protein amylin, which is co-secreted with insulin by pancreatic beta cells.
- Evaluate renal function prior to starting an incretin mimetic.
- Exenatide: start at 5 mcg subcutaneously twice daily (within 60 minutes prior to a meal) and, after one month, increase to 10 mcg twice daily if tolerated (maximum daily dose)
- Liraglutide: start at 0.6 mg subcutaneously once daily for one week and then increase to 1.2 mg once daily (maximum dose 1.8 mg once daily)
- Pramlintide: in T1DM, start at 15 mcg subcutaneously immediately before each meal and reduce insulin dose by 50% to avoid hypoglycemia. If no significant nausea, titrate at 15-mcg increments as tolerated every 3-7 days, recommended dose 60 mcg immediately before meals. In T2DM, start at 60 mcg subcutaneously immediately before each meal; titrate to recommended dose of 120 mcg with each meal.
- Can be administered subcutaneously using a pen-injector or vials. To convert mcg (pen-injector) to units (vials), divided dose in mcg by 6 (i.e. 120 mcg = 20 units).
brand
name
| generic
| Mfg
| brand
forms
| cost*
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| Byetta | exenatide | Amylin Pharmaceuticals, Inc. | subcutaneous injection
solution
10 mcg/0.04 mL | $271 for 30 days |
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5 mcg/0.02 mL | $265 for 30 days |
| Victoza | liraglutide | Novo Nordisk, Inc. | subcutaneous injections
solution
18 mg/3 mL | $280 for two 3 mL pens; $400 for three 3 mL pens |
| Symlin | pramlintide | Amylin Pharmaceuticals, Inc. | subcutaneous injection
solution
600 mcg/mL | $228 for 5 mL vial |
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1000 mcg/mL | $312 for a box with two 2.7 mL pens |
*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP).
AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's
information, and the McKesson database.
^Dosage is indicated in mg unless otherwise noted.
- Exenatide: do not use in patients with GFR<30 mL/min. Monitor serum creatinine in patients with GFR between 30 - 50 mL/min after medication initiation or dose titration.
- Liraglutide: use with caution in patients with renal impairment
- Pramlintide: no dose adjustment for moderate to severe kidney disease (GFR 20-50 mL/min). Unknown if pramlintide is safe in dialysis patients.
- Exenatide and liraglutide: no need for adjustment but caution recommended
- Pramlintide: no studies assessing safety of use in liver disease
- Exenatide, liraglutide and pramlintide are category C
- Incretin mimetics and pramlintide: excretion in human breast milk unknown. Caution when contemplating use in nursing mothers as infant risk cannot be ruled out.
- Incretin mimetics: Pancreatitis uncommon. If severe abdominal pain develops, discontinue medication and exclude pancreatitis. Severe, necrotizing and hemorrhagic pancreatitis have been rarely reported per FDA reports.
- Liraglutide: increases risk of medullary thyroid cancer in rodents. Unclear if liraglutide poses same risk to humans, but should not be used in patients with a personal or family history of medullary thyroid cancer or patients with multiple endocrine neoplasia type 2 (MEN 2) (http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=17581).
- Pramlintide, exenatide and liraglutide: avoid in patients with gastroparesis, due to the drugs' effect in slowing gastric emptying.
- Pramlintide: black box warning regarding the need to reduce the insulin dosage with drug initiation to avoid severe hypoglycemia. Avoid use in patients with hypoglycemia unawareness.
- Incretin mimetics and pramlintide: nausea, which usually improves over time
- Incretin mimetics: hypoglycemia, especially with sulfonylureas
- Exenatide, liraglutide: diarrhea, headache
- Pramlintide: abdominal pain, arthralgia
- Exenatide: angioedema, rash
- Liraglutide: angioedema
- Hypoglycemia when combined with hypoglycemic agents
- Exenatide and liraglutide: slow gastric emptying and may impact absorption of oral medications
- Pramlintide may enhance the anticholinergic effects of anticholinergic drugs.
- Exenatide causes a dose-dependent weight loss averaging ~1.4 kg, may be preferred for patients with comorbid obesity (DeFronzo, Kendall)
- Average weight loss with pramlintide is 0.5-1.4 kg (Ratner, Hollander)
- Liraglutide reported to cause weight reduction of 2-2.5 kg (Nauck)
- Thus, the weight loss effect of these agents is a major aspect of their attractiveness.
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HbA1c reduction with exenatide and liraglutide ~1% (Nauck), proportional to starting HbA1c.
- In individual studies, HbA1c reduction with pramlintide use in T2DM was 0.62% (Hollander) and in T1DM was 0.3% (Ratner).
- Both incretin mimetics and amylin analogues are administered through subcutaneous injection only; may not be preferred in patients who are fearful of injections.
- Recent study found that combination of exenatide and insulin glargine effective in achieving normal blood glucose without significant hypoglycemia (Buse)
- Nauck M, Frid A, Hermansen K, et al.;
Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study.;
Diabetes Care;
2009; Vol.
32; pp.
84-90;
ISSN:
1935-5548;
PUBMED: 18931095
Rating:
Basis for recommendation
Comments:A double-blind, double-dummy, placebo and active-controlled trial for 26 weeks, including 1091 type 2 diabetes patients randomly assigned to 0.6, 1.2 and 1.8 mg daily of liraglutide added to metformin, or placebo added to metformin, or glimepiride added to metformin. While patients in the 1.8 mg and 1.2 mg liraglutide and in the glimepiride groups achieved a hemoglobin A1C reduction of 1%, only patients taking liraglutide achieved a significant weight loss (1.8-2.8 Kg), whereas patients in the glimepiride group gained on average 1.0 Kg.
- DeFronzo RA, Ratner RE, Han J, et al.;
Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.;
Diabetes Care;
2005; Vol.
28; pp.
1092-100;
ISSN:
0149-5992;
PUBMED: 15855572
Rating:
Basis for recommendation
Comments:Triple-blind, randomized, placebo-controlled trial involving 336 subjects with type 2 diabetes, who were given 0, 5 or 10 mcg of exenatide for 30 weeks. There was a mean hemoglobin A1C reduction of 0.78 0.1% and an average weight loss of 2.8 0.5 Kg in the group receiving exenatide 10 mcg twice daily.
- Kendall DM, Riddle MC, Rosenstock J, et al.;
Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.;
Diabetes Care;
2005; Vol.
28; pp.
1083-91;
ISSN:
0149-5992;
PUBMED: 15855571
Rating:
Basis for recommendation
Comments:This 30-week double-blind, randomized, placebo-controlled trial including 733 subjects showed that patients on 10 mcg of exenatide twice daily achieved better glycemic control (mean hemoglobin A1C reduction of 0.8 0.1%) than patients taking 5 mcg or taking placebo. The weight loss was significant in both 5 and 10 mcg arms of exenatide therapy, averaging 1.6 Kg 0.2.
- Ratner RE, Dickey R, Fineman M, et al.;
Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial.;
Diabet Med;
2004; Vol.
21; pp.
1204-12;
ISSN:
0742-3071;
PUBMED: 15498087
Rating:
Basis for recommendation
Comments:Double-blind, placebo-controlled, randomized, multicenter, 52-week trial of 651 patients with type 1 diabetes, to which placebo injections three to four times a day or various doses of pramlintide three to four times daily were added to their baseline insulin regimen. Patients taking pramlintide 60 mcg three to four times a day achieved a hemoglobin A1C reduction of 0.29% and 0.34%, respectively, compared to the placebo group. The pramlintide group as a whole lost an average of 0.4 Kg versus a gain of 0.8 Kg in the placebo group.
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