Diabetes drug update: How 4 new options stack up

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Applied Evidence

Diabetes drug update: How 4 new options stack up

J Fam Pract. 2007 March;56(3):207-215

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References

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28. Ratner RE, Want LL, Fineman MS, Velte MJ, Ruggles JA, Gottlieb A, et al. Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes. Diabetes Technol Ther 2002;4:51-61.

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In clinical trials, pramlintide produced modest reductions in A_1c (0.1-0.62%) and more impressive reductions in postprandial glucose (64.8-126 mg/dL) in adults with type 1 or 2 diabetes ( TABLE 4 ).^27-34 In addition, it has been shown to minimize insulin dose increases and the weight gain associated with insulin.^27,29-31,34

What's in the pipeline

Inhaled insulin, exenatide, sitagliptin, and pramlintide are exciting developments in the management of diabetes. They offer potential advantages over currently available therapies, but also have their share of limitations. As we gain further experience with them, their roles may increase.

Other agents are also on the horizon and worth noting. Vildagliptin (Galvus), a DPP-4 inhibitor, is expected to become available shortly. Another drug, liraglutide, a synthetic GlP-1 analog with a longer half-life than exenatide, is currently in phase III trials. A long-acting exenatide, given once weekly, is in phase II trials.

Time will tell as to how these agents—both the recently approved ones and those in the pipeline—will aid in our battle against diabetes. What is clear is that our arsenal will continue to grow, and we we'll continue to make inroads—one patient encounter at a time.

TABLE 4
Pramlintide studies

STUDY	TYPE OF DIABETES	DESIGN	A_1C CHANGE FROM BASELINE (%)	PPG CHANGE FROM BASELINE (MG/DL)
Fineman (1999) ³⁰	Type 1	DB, PC, 26 wk	-0.2* (60 mcg 3x/day) -0.1 (90 mcg 2x/day) -0.1 (90 mcg 3x/day) 0.1 (placebo)	NA
Gottlieb (1999) ³¹	Type 2	DB, PC, 26 wk	-0.3 (90 mcg 2x/day) -0.4 (90 mcg 3x/day) -0.4* (120 mcg 2x/day) -0.1 (placebo)	NA
Nyholm (1999) ³²	Type 1	DB, PC, 4 wk	NA	-126 (1-hr) -72 (2-hr) (30 mcg 4x/day)
Whitehouse (2002) ²⁷	Type 1	R, DB, PC, 52 weeks	-0.39* (30-60 mcg 4x/day) -0.12 (placebo)	NA
Ratner (2002) ²⁸	Type 2	R, DB, PC, 52 weeks	-0.3 (30 mcg 3x/day) -0.5 (75 mcg 3x/day) -0.6* (150 mcg 3x/day) -0.2 (placebo)	NA
Hollander (2003) ²⁹	Type 2	R, DB, PC, 52 weeks	-0.35 (90 mcg 2x/day) -0.62* (120 mcg 2x/day) -0.22 (placebo)	NA
Levetan (2003) ³³	Type 1	R, DB, PC, 4 weeks	NA	-79.2 (1-hr) -64.8 (2-hr) (30 mcg 3x/day)
Ratner (2004) ³⁴	Type 1	R, DB, PC, 52 weeks	-0.29* (60 mcg 3x/day) -0.34* (60 mcg 4x/day) -0.04 (placebo)	NA
A_1c, glycosylated hemoglobin; PPG, postprandial glucose; DB, double-blind; PC, placebo-controlled; R, randomized; NA, not accessed.
*P<.05 vs placebo.

Nausea is a factor, as is slowed gastric emptying

FAST TRACK

While pramlintide offers a different approach to postprandial glucose, it doesn't appear to offer distinct advantages

The most common adverse effects include nausea, vomiting, and anorexia. Rates of nausea in studies have ranged from 9.5% to 59% with most cases being mild to moderate in nature and resolving in 2 to 8 weeks.^27-29

Pramlintide in itself does not cause hypoglycemia, however when administered with insulin, it does increase the risk of insulin-induced hypoglycemia. Pramlintide should not be used in patients with gastroparesis since it slows gastric emptying. Pramlintide should not be mixed with insulin in the same syringe as there is insufficient data to support the safety of doing so. Thus, it may increase the number of daily injections for patients.

Pramlintide may also interfere with agents that stimulate gastric motility and slow the absorption of other drugs. The manufacturer recommends separating the administration of analgesics and pramlintide by 1 to 2 hours since coadministration could delay the analgesic onset.

FAST TRACK

In the pipeline:

Vildagliptin (Galvus) may be available soon
Liraglutide, in phase III trials
Long-acting exenatide, in phase II trials

Starting pramlintide means reductions elsewhere

Pramlintide is supplied as a 5 mL vial containing 0.6 mg/mL. Immediately prior to each major meal, the patient will need to administer it subcutaneously into the abdomen or thigh (arm administration is not recommended due to varying absorption). When initiating pramlintide in a patient, you'll need to reduce the patient's rapid/short insulin (including fixed-mixed insulin such as 70/30) by 50%.

In type 1 diabetes, the pramlintide dose may be increased in 15-mcg increments, provided that the patient has not experienced clinically significant nausea for at least 3 days and his glycemic goals are not met. In type 2 diabetes, the initial pramlintide dose may be doubled, provided that the patient has not experienced clinically significant nausea for 3 to 7 days and his glycemic goals are not met. In either case, should the increase in dose result in intolerable nausea, you may need to drop the dose back to the previous dose.

The take-home message is... While pramlinitide offers a different approach (as compared with insulin) to lowering postprandial glucose, there is no evidence that it offers any distinct advantage to the patient. Thus, it may be best to simply increase the premeal insulin dose. Should continued weight gain be a major concern, then pramlintide could play a role as adjunct therapy to mealtime insulin. Further studies evaluating quality of life and patient acceptance are needed.