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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13. Himmelman A, Jende J, Mellen A, Petersen AH, Dahl UL, Wollmer P. The impact of smoking on inhaled insulin. Diabetes Care 2003;26:677-682.

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19. 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 mellitus treated with metformin and a sulfonylurea. Diabetes Care 2005;28:1083-1091.

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Bad news: Transient nausea; Good news: Unrelated weight loss

Nausea is the most common side effect and occurs in 36% to 39% of patients with the 5-mcg dose and 45% to 50% of those with the 10-mcg dose, although it's usually transient.^17-19,22 Exenatide results in a moderate reduction in weight (approximately 2-4 pounds), which does not appear to be related to the adverse gastrointestinal effects. There's a risk of mild to moderate hypoglycemia when exenatide is used with a sulfonylurea, which is most likely due to the effects of the sulfonylurea.

FAST TRACK

Exenatide was more effective at reducing postprandial glucose, while glargine more effectively reduced fasting glucose

Exenatide reportedly results in low levels of antibodies in approximately 40% of patients but had no affect on glucose control.²² About 6% of patients may develop high antibody levels, which could result in a diminished response.²²

Exenatide is dispensed as a injection pen containing a 30-day supply of medicine. The patient will need to administer it subcutaneously in the thigh, abdomen, or upper arm no more than 60 minutes before morning and evening meals. The cost of exenatide is substantially higher than sulfonylureas, metformin, or insulin but comparable with pioglitazone and rosiglitazone.

The take-home message is... Exenatide is not currently recommended for use as initial therapy in type 2 diabetes. In clinical trials, exenatide 10 mcg twice daily achieved A_1c reductions of about 1%. Oral agents typically produce reductions of 1% to 2%, although the effects of combining oral agents may not always be additive.^23,24

At this point, exenatide is best suited for those whose A_1c is within 1% of their treatment goal, especially in those unable to take another oral agent or insulin (eg, due to renal or hepatic impairment or congestive heart failure) and those who have elevated postprandial glucose. Otherwise, adding an oral agent or insulin would likely produce the best results.

Sitagliptin (Januvia): It, too, focuses on GlP-1

Sitagliptin (Januvia), the first drug in a new class of agents called dipeptidyl-peptidase-4 (DPP-4) inhibitors, was just approved in October 2006 for the treatment of type 2 diabetes. This drug, like exenatide, focuses on the actions of GLP-1. Active GLP-1 is rapidly degraded by the DPP-4 enzyme. Inhibiting this enzyme results in an increased concentration and prolonged action of GLP-1.

There are some key differences between DPP-4 inhibitors and GLP-1 agonists such as exenatide. Specifically, DPP-4 inhibitors do not appear to have significant rates of nausea and vomiting, can be given orally, have no effect on gastric emptying, and are weight neutral. Limited evidence suggests that, like GLP-1 agonists, they may also improve chronic beta-cell function.²⁵ Side effects include stuffy or runny nose and sore throat, upper respiratory infection, and headache.

FAST TRACK

Exenatide is best suited for those whose A_1c is within 1% of their treatment goal

Published studies are sparse at this point. One dose finding study randomized 552 patients to one of five treatments: placebo, sitagliptin (25, 50, or 100 mg once daily), or 50 mg twice daily. Baseline A_1c ranged from 5.8% to 10.4% and after 12 weeks of treatment, the sitagliptin 100 mg once daily group had the largest reduction in A_1c. Reductions were dependent on baseline A_1c: Those with a baseline A_1c <7%, 7% to 8.5%, or 8.5% to 10% had reductions of 0.4%, 0.6%, and 0.8%, respectively.²⁶

Renal patients require a change in dose

The recommended dose of sitagliptin is 100 mg by mouth once a day as monotherapy or in combination with metformin or a thiazolidinedione. You'll need to reduce the dose in those patients with renal impairment.

The take-home message is... This newest class of medications exhibits some potential advantages and disadvantages when compared to the GLP-1 agonists. On the plus side, it does not appear to cause nausea and vomiting and can be given orally. On the downside, it has no effect on gastric emptying, which means it may not reduce postprandial glucose as much. In addition, it does not cause weight loss (although it does not cause weight gain either).

Pramlintide (Symlin): Shoring up deficiencies

FAST TRACK

On the plus side: sitagliptin doesn't appear to cause nausea and it can be given orally

Pramlintide is a synthetic analog of human amylin, a neuroendocrine hormone secreted by pancreatic beta cells. Amylin works in concert with insulin to suppress postprandial glucagon secretion and slow carbohydrate absorption by delaying gastric emptying. Amylin is cosecreted with insulin so patients with type 1 diabetes have an absolute deficiency of amylin while those with type 2 diabetes have a progressively declining production. Thus, pramlintide may be used in either type of diabetes.