The take-home message is... While inhaled insulin offers comparative efficacy to subcutaneous regimens, there's a potential for short-term decreases in pulmonary function. The long-term effects are largely unknown. As a result, rapid or short-acting injectable insulins may be a safer alternative. Inhaled insulin's role in type 2 diabetes is less clear at this time. In patients with type 2 disease, it would be an option when considering the addition of insulin. However, there's limited data on using inhaled insulin in place of an oral agent.
Exenatide (Byetta): From the mouths of (gila) monsters
Exenatide is synthetic exendin-4, originally isolated from the saliva of the gila monster lizard. It binds to and activates the pancreatic GLP-1 (glucagon like peptide-1) receptor resulting in an increase in insulin secretion from beta cells in the presence of hyperglycemia. It also suppresses glucagon secretion, slows gastric emptying, and decreases food intake. Its use is limited to type 2 diabetes; it has no role in the management of type 1 diabetes.
Glycemic control with an eye toward cardiovascular risk
In 2002 diabetes affected 18.2 million individuals, or 6.3% of the US population.1 The prevalence is expected to double within the next 20 years along with significant increases in cardiovascular disease.1
There are 2 theories as to how diabetes increases cardiovascular mortality.35,36 The first suggests that beta-cell dysfunction and subsequent failure leads to elevated glucose that causes an increase in oxidative stress, and thus leads to cardiovascular disease. The second theory suggests that insulin resistance causes endothelial dysfunction along with inflammation and fibrinolysis and this leads to cardiovascular disease. It's likely that both of these theories are at work, since we know that elevated blood glucose levels can lead to elevated insulin levels and insulin resistance can cause beta-cell dysfunction.
The research on the diabetes/CVD link is intriguing. For instance, there is data suggesting that insulin sensitizing agents may have a positive effect on cardiovascular disease.37 In addition, trials are being conducted between sulfonylureas and thiazolidinediones to evaluate reductions in CVD.38 It may not be long before reducing cardiovascular morbidity and mortality becomes a goal of treatment in the management of our patients with diabetes.
Three large placebo-controlled trials evaluated the use of exenatide as adjunct therapy to a sulfonylurea or metformin in patients unable to achieve glycemic control ( TABLE 3 ).17-19 Hemoglobin A1c was reduced by 0.4% to 0.6% with 5 mcg twice daily and 0.8% to 0.9% with 10 mcg twice daily. The effects on fasting plasma glucose were less impressive, though not surprising due to the drug's mechanism of action.
One other trial compared exenatide, 10 mcg twice daily, to insulin glargine, one daily dose titrated to achieve fasting glucose less than 100 mg/dL in patients with type 2 diabetes uncontrolled on a sulfonylurea and metformin, which represents a relatively common clinical scenario.20 The reduction in A1c after 26 weeks was comparable between the 2 groups (1.11% for both).
Exenatide was more effective at reducing postprandial glucose, while glargine more effectively reduced fasting glucose. Weight increased by an average of 1.8 kg in the glargine group and decreased by 2.3 kg with exenatide. Rates of symptomatic hypoglycemia were similar between the 2 groups. Gastrointestinal symptoms were more common in the exenatide group, including nausea (57.1% vs 8.6%), vomiting (17.4% vs 3.7%), and diarrhea (8.5% vs 3%). This led to a significant difference in the number of subjects who withdrew from the study (19.4% for exenatide vs 9.7% for glargine). It's important to note that the mean baseline A1c values were only moderately elevated (8.2% in exenatide vs 8.3% in glargine) and thus not representative of those with very poor control.
One other research finding is worth mentioning here. GLP-1 administration has been shown to result in beta-cell proliferation and increased beta-cell mass in animals and in vitro studies.21 Thus, in theory, exenatide could slow the progression of type 2 diabetes. However, long-term studies are needed to address this.
TABLE 3
Exenatide studies
| VARIABLE | BUSE (2004)17 | DEFRONZO (2005)18 | KENDALL (2005)19 |
|---|---|---|---|
| BASELINE DATA | |||
| Number of patients | 377 | 336 | 733 |
| Age (yrs) | 55 | 53 | 55 |
| BMI (kg/m2) | 33 | 34 | 34 |
| A1c (%) | 8.6 | 8.2 | 8.5 |
| FPG (mg/dL) | 184 | 172 | 180 |
| Concomitant therapy | Sulfonylurea | metformin | Sulfonylurea + metformin |
| RESULTS—CHANGE FROM BASELINE | |||
| A1c (%) | 5 mcg dose: -0.5 | 5 mcg dose: -0.4 | 5 mcg dose: -0.6 |
| 10 mcg dose: -0.9 | 10 mcg dose: -0.8 | 10 mcg dose: -0.8 | |
| FPG (mg/dL) | 5 mcg dose: -5.4 | 5 mcg dose: -7.2 | 5 mcg dose: -9 |
| 10 mcg dose: -10.8 | 10 mcg dose: -10.1 | 10 mcg dose: -11 | |
| Weight (kg) | 5 mcg dose: -0.9 | 5 mcg dose: -1.6 | 5 mcg dose: -1.6 |
| 10 mcg dose: -1.6 | 10 mcg dose: -2.8 | 10 mcg dose: -1.6 | |
| BMI, body mass index; A1c, glycosylated hemoglobin; FPG, fasting plasma glucose. | |||