Type 2 diabetes

Type 2 diabetes mellitus has been increasing in prevalence over the past few decades, nearing epidemic proportions, and the number of persons with this disease is projected to double by 2030. It is also well known that many individuals remain undiagnosed. Diabetes is considered a coronary heart disease risk equivalent, especially in patients with long-standing dysglycemia. Two major risk factors associated with type 2 diabetes are elevated blood pressure and hyperlipidemia. In managing type 2 diabetes, control of these comorbid conditions is considered as important as controlling blood glucose levels. Despite the availability of numerous therapeutic options, glycemic control and blood pressure and lipid targets remain suboptimal in many individuals. While traditional oral therapies may be effective at decreasing hyperglycemia, the need for new agents and formulations is apparent. At the American Heart Association 2008 abstract presentations, an interesting report noted the possible benefit of exenatide (Byetta) in controlling multiple cardiovascular risk factors, including blood pressure and lipids, potentially reducing morbidity and mortality in patients with type 2 diabetes. The report was presented by Richard M. Bergenstal, MD, executive director, International Diabetes Center at Park Nicollet, Minneapolis, MN, and supported by a grant from Amylin Pharmaceuticals, Inc, of San Diego, CA.

Exenatide trial results

Previous studies indicated that exenatide may be beneficial in reducing hemoglobin A1C (HgbA1C) levels when administered twice daily, demonstrating a decrease in body weight and subsequent improvements in blood pressure and lipid profiles. The trial reported by Dr Bergenstal evaluated a once weekly formulation of exenatide, which was administered to 120 patients with type 2 diabetes for 52 weeks (1 year). Baseline variables included an HgbA1C of 8.3 ± 1.0%, weight of 103 ± 19 kg, and a body mass index of 35.2 ± 5.0 kg/m2. After 1 year of treatment, there was an improvement in HgbA1C levels (-2.0 ± 0.1%) and in weight loss (-4.1 ±0.6 kg). Interestingly, significant improvements in both systolic and diastolic blood pressure were observed (-6.2 ± 1.2 mm Hg and -2.8 ± 0.8 mm Hg, respectively). These blood pressure changes occurred from an average baseline of 128/78 mm Hg and were statistically significant (P <.05). Additionally, subjects (n = 65) with higher systolic blood pressure (≥130 mm Hg at baseline) showed even greater improvements. These subjects had a mean blood pressure of 139/81 mm Hg at baseline and their systolic blood pressure decreased between 11.4 ± 1.9 mm Hg (P <.05) and their diastolic blood pressure decreased between 3.6 ± 1.2 mm Hg (P <.05).

In addition to controlling blood pressure, dyslipidemia must be curtailed in patients with diabetes for optimal cardiac risk reduction. Bergenstal and colleagues noted favorable improvements in serum lipids. The mean baseline total cholesterol level was 170 mg/dL, which decreased by 7.9 ± 2.3 mg/dL. The mean baseline low-density lipoprotein cholesterol level was 89 mg/dL and was decreased by 2.2 ± 2.4 mg/dL. High-density lipoprotein (HDL) cholesterol levels did not significantly increase. In fact, HDL cholesterol levels at the end of the trial decreased 0.3 ± 0.8 from a baseline of 44 mg/dL. Triglycerides, on the other hand, improved remarkably from the baseline of 179 mg/dL, decreasing by 40.1 ± 111.5.

Pharmacology of exenatide

Exenatide is a synthetic peptide with incretin-mimetic actions. This novel diabetic medication, which was originally identified in the Gila monster lizard (Heloderma suspectum), enhances glucose-dependent insulin secretion by the pancreatic beta cells by preventing inappropriate glucagon secretion and slowing gastric emptying, increasing satiety and promoting weight loss. Currently, exenatide is indicated as adjunctive therapy to improve glycemic control in type 2 diabetes patients who have not achieved adequate glycemic control using metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a combination of metformin and a thiazolidinedione.

Exenatide differs in chemical structure and action from conventional diabetic medications, such as insulin, sulfonylureas (including Dphenylalanine derivatives and meglitinides), biguanides, thiazolidinediones, and alpha-glycosidase inhibitors. Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide mimics the enhancement of glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins. The amino acid sequence of exenatide partially overlaps with human GLP-1 and has been shown to bind and activate the known human GLP-1 receptor. The mechanism of action consists of an increase in glucose-dependent synthesis of insulin and in vivo secretion of insulin from pancreatic beta cells involving cyclic AMP and/or other intracellular signaling pathways.

Exenatide promotes insulin release only when there are elevated glucose concentrations and improves glycemic control by reducing fasting and postprandial glucose levels. The insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Exenatide also moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia, resulting in decreased hepatic glucose output and decreased insulin demand. This novel agent does not impair the normal glucagon response to hypoglycemia.

Exenatide is administered as a subcutaneous injection because oral administration is ineffective. This GLP-1 analogue provides resistance to the rapid degradation seen with GLP-1 by DPP-IV. Unlike with DPP-IV inhibitors, there appears to be longer action. In addition to significant reductions in HgbA1C of 0.8% to 1.7%, this treatment is associated with an additional weight loss of 1.75 to 3.8 kg. The weight loss mechanism appears to be primarily through promotion of satiety, leading to reduced fluid intake and regulation of the gastric emptying rate, limiting postprandial glucose excursions. These beneficial metabolic responses are also accompanied by an increase in insulin secretion from pancreatic beta cells in a glucose-dependent manner with little or no associated hypoglycemia. There appears to be suppression of glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, which in turn suppresses hepatic glucose output.

Side effects and considerations

Previous studies have indicated that the most common adverse events with exenatide are gastrointestinal complications, particularly nausea. The cumulative incidence of nausea, which was predominately mild in intensity, occurred in 29% of the patients over the 52 weeks of therapy. Concern over the cardiovascular benefit of at least 1 recent antidiabetic agent (ie, rosiglitazone resulting in an increased risk of cardiovascular morbidity and potentially mortality) has suggested the need for close monitoring of the cardiovascular effects of antidiabetic agents, especially those with which we have limited long-term clinical experience. Newer type 2 diabetes treatments include GLP-1 based approaches with DPP-IV inhibitors, such as oral sitagliptin, and GLP-1 analogs, which must be given by injection.

Conclusions

Control of blood pressure is one of the most significant components of cardiovascular risk reduction in patients with type 2 diabetes. In Dr Bergenstal’s study, systolic blood pressure was reduced below 130 mm Hg in 71% of patients. Although exenatide’s ability to stimulate weight loss may have contributed to the reduction in blood pressure, an analysis of systolic blood pressure changes at 52 weeks revealed that patients treated with once weekly exenatide had reduced systolic blood pressure irrespective of whether or not they lost weight. It should be noted that changes in concomitant antihypertensive medicines were allowed only if deemed necessary by the investigators. Hopefully, future analyses of these data will determine to what extent antihypertensive medication contributed to the blood pressure control noted with exenatide.

The most common side effect of exenatide therapy was nausea, and a drawback is the need for the medication to be administered through subcutaneous injections; however, a once weekly formulation may make this option feasible for more patients in the future. Dr Bergenstal’s study indicates that treatment with exenatide on a once weekly basis is a generally well tolerated therapy that may offer numerous benefits, including significant improvements in glycemia, body weight, blood pressure, and lipid levels.

 

Keith C. Ferdinand, MD,
Association of Black Cardiologists,
Atlanta, GA, Emory University, Atlanta, GA
Published on Jan 22, 2009