Diabetes mellitus affects millions of people worldwide and has many very serious complications. Many studies have demonstrated that tight glycemic control lessens the risk of long-term microvascular complications, such as retinopathy, nephropathy, and neuropathy. Although tight glycemic control is the goal, many patients are not achieving the recommended hemoglobin A1c target of less than 7% with the available treatment options. Exciting new classes of medications for the treatment of type 1 or type 2 diabetes are currently in development. Some have been approved recently by the Food and Drug Administration, and others remain the subject of study in clinical trials. The authors review some of the more important new agents that have recently become available or are in the pipeline.

Diabetes mellitus affects more than 194 million adults worldwide,¹ including 20.8 million people in the United States, or 7% of the US population.² Approximately 90% to 95% of the patients have type 2 diabetes mellitus.² Diabetes is the sixth leading cause of disease-related death in the United States3 and

accounts for approximately $132 billion annually in direct and indirect medical expenses.⁴ According to the latest National Health and Nutrition Examination Survey, with current treatment regimens, only about 45% of patients are able to achieve the target hemoglobin (Hb) A1c level of less than 7% recommended by the American Diabetes Association.^5,6 Current treatment options include sulfonylureas, meglitinides, metformin HCl (Glucophage), alpha-glucosidase inhibitors, thiazolidinediones, and various insulin preparations.

Many new therapies are being investigated in the attempt to address the lack of glycemic control with available medicines, as well as new treatment modalities to prevent or slow the progression of diabetes. The authors review the new treatment options for diabetes that have recently become available or are currently in development (Table 1) and compare these new therapeutic modalities with the old medications (Table 2).

GLP-1 Agonists and DPP-IV Inhibitors
Glucagonlike peptide-1 (GLP-1) is a naturally occurring hormone factor secreted by the intestine in response to food ingestion. GLP-1 agonists have the following effects:

Insulin secretion. Activation of beta-cell GLP-1 receptors enhances the ability of the pancreas to release insulin in response to ingested glucose. What differentiates GLP-1 receptor agonists from other insulin secretagogues is that when glucose levels normalize in patients treated with GLP-1 receptor agonists, insulin secretion ceases. Therefore, hypoglycemic episode are less likely to occur.⁷

Glucagon production. Glucagon stimulates hepatic glucose release in response to low blood sugar levels. In patients with type 2 diabetes, inappropriate glucagon secretion often contributes to hyperglycemia. GLP-1 inhibits unnecessary postmeal glucagon release, thereby reducing the glucagon excess state observed in many patients with type 2 diabetes. Since GLP-1 agonists do not inhibit glucagon secretion when plasma levels of glucose are normal or low, the risks of defective counterregulation are minimized.⁷

Gastric emptying. GLP-1 slows the rate at which ingested food moves from the stomach to the small bowel. This prolongs the processes of digestion and facilitates nutrient absorption, thereby blunting postprandial glucose peaks.⁷

Beta-cell proliferation. Studies such as the United Kingdom Prospective Diabetes Study (UKPDS) have confirmed that patients with type 2 diabetes have deteriorating beta-cell function and eventual beta-cell death.⁸ As a result, multiple drug regimens and insulin are often required. GLP-1 agonists stimulate the formation of new beta cells and inhibit the death of existing cells; they also increase islet beta-cell proliferation. Clinical trials with GLP-1 agonists have demonstrated improvement in markers of beta-cell function.⁹

Appetite and weight change. GLP-1 acts on the hypothalamus to decrease appetite and promote a feeling of satiety. In clinical trials patients have either not gained weight or have experienced a significant, gradual weight loss.⁹

Exenatide (Byetta)—the first approved drug in this class—is a GLP-1 agonist originally isolated from the venom of the Gila monster. It received Food and Drug Administration (FDA) approval in April 2005 for the treatment of patients with type 2 diabetes who have not achieved glycemic control with metformin and/or a sulfonylurea. In three 30-week combination therapy trials involving several thousand patients who had not achieved glycemic control with metformin, a sulfonylurea, or both, 46%, 41%, and 34% of patients reached an HbA1c level of less than 7% with exenatide, 10 µg twice daily, added to their regimen compared with 13%, 9%, and 9% of patients, respectively, who received only baseline therapy plus placebo.^9-11 In these studies, HbA1c decreased by 0.5% to 1.5%. Exenatide is marketed as prefilled pens that deliver 5 µg or 10 µg of the drug, administered subcutaneously twice daily.

Other GLP-1 agonists currently in different stages of development include exenatide LAR, which (if approved) would allow once-weekly administration; liraglutide; and CJC-1131.

Dipeptidyl peptidase-IV (DPP-IV) is the enzyme that degrades native GLP-1; thus inhibiting DPP-IV may increase native GLP-1. The investigational DPP-IV inhibitor vildagliptin (LAF237) was shown in a phase 3 clinical trial to be as effective as, but better tolerated than, metformin in 780 patients with type 2 diabetes.¹² In another phase 3 trial involving almost 296 patients requiring insulin therapy, vildagliptin reduced the need for insulin by 50% compared with placebo.¹²

Cannabinoid-1 Receptor Antagonists
Rimonabant (Acomplia), currently under FDA review for a new drug application, is the first in a new class of agents that selectively blocks the cannabinoid-1 receptor in the endocannabinoid system, a biochemical endogenous signaling system. Stimulation of these receptors is believed to affect both their central and peripheral actions on lipids and glucose metabolism in adipose tissue, which helps regulate food intake, energy balance, and nicotine dependence.

Anandamide, which is thought to be the main fatty-acid agonist involved in the system, is produced in the postsynaptic target cells. It gains access to the extracellular space and activates the cannabinoid-1 receptors located on presynaptic nerve terminals. This activation blocks presynaptic cells from releasing excitatory neurotransmitters, thus inhibiting the release of gamma-aminobutyric acid and glutamate by suppressing calcium channels and interfering with synaptic vesicle release.¹³

Rimonabant has been shown to have significant effects on weight loss. It appears to be an effective treatment for obesity that also improves the lipid profile and other cardiac risk factors, including diabetes. The Rimonabant In Obesity (RIO)-Lipids trial included more than 1000 overweight or obese persons with dyslipidemia who were randomized to rimonabant, 5 mg/day or 20 mg/day, or placebo for 1 year, in addition to a low-calorie diet.¹⁴ Patients receiving rimonabant, 20 mg/day, lost 8.6 kg compared with only 2.3 kg in the placebo group (P <.001). About 58% of those in the rimonabant 20-mg/day group lost more than 5% of their body weight compared with only 20% of those in the placebo group. In addition, one third of patients treated with rimonabant 20 mg/day lost 10% or more of their body weight compared with only about 7% in the placebo group.

This dosage also resulted in a 50% reduction in the proportion of patients classified as having the metabolic syndrome (versus a 10% reduction with placebo) and produced greater improvements in waist circumference (–9.1 versus –3.4 cm), triglycerides (–16% versus –4%), high-density lipoprotein cholesterol (HDL-C) (+23% versus +12%), and total cholesterol:HDL-C ratio (–0.84 versus –0.50) compared with placebo (P <.001 for all). The results of the phase 3 RIO-Europe study15 and preliminary results from the phase 3 RIO-North America16 and RIO-Diabetes studies17 were consistent with those of RIO-Lipids.

Amylin Analogs
Amylin is a naturally occurring hormone that is made in the beta cells of the pancreas and is cosecreted with insulin in response to carbohydrates and amino acids after a meal. Recent studies have identified at least 4 physiologic effects of amylin that complement insulin in regulating postprandial glucose homeostasis:

1. Reduced postprandial glucagon secretion, which lowers endogenous glucagon-stimulated hepatic glucose output.¹⁸ Amylin, however, does not inhibit glucagon secretion during hypoglycemic episodes.¹⁹

2. Reduced gastric emptying, which lowers the rate of nutrient delivery to the small intestine.¹⁸

3. Reduced food intake, which lowers the amount of exogenous glucose entering the circulation.¹⁸

4. Reduced body weight, which may be, at least partially, caused by lower food intake.¹⁸

Pramlintide (Symlin) is a synthetic analog of human amylin. It was approved by the FDA in March 2005 as an adjunctive treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy but who have not achieved glucose control despite insulin therapy with or without a concurrent sulfonyl­urea agent and/or metformin. Clinical studies have demonstrated that pramlintide helps patients achieve lower blood glucose levels after meals, resulting in less fluctuation during the day and better long-term glucose control compared with insulin alone. On average, study participants used less mealtime insulin and lost more weight than patients taking insulin alone.^18,20 The recommended dose is 120 µg before meals for patients with type 2 diabetes and 30 µg or 60 µg before meals for patients with type 1 diabetes.

Dual-Acting PPAR Agonists
Peroxisome proliferator–activated receptors (PPARs) are nuclear transcription receptors. PPAR-alpha is highly expressed in liver and muscle; its activation leads to decreased plasma triglyceride and increased HDL-C levels. PPAR-alpha is the main target for the fibrate class of antilipid medications. PPAR-gamma activation enhances glucose uptake in skeletal muscles and in adipose tissue and is the main target of the thiazolidinedione drug class. In theory, activating both the alpha- and gamma-receptors will improve dyslipidemia and glycemic control.

The investigational agent ragaglitazar is a prototype of a new class of dual-acting PPAR-alpha and -gamma agonists. In a 12-week, double-blind, parallel, randomized, placebo-controlled study of 177 patients with type 2 diabetes who had hypertriglyceridemia, ragaglitazar (1-10 mg/day) significantly decreased levels of fasting plasma glucose (by up to 77 mg/dL), triglycerides (by up to 62%), low-density lipoprotein cholesterol (by up to 19%), and total cholesterol (by up to 16%) compared with placebo.²¹ There was also a significant increase in HDL-C levels of up to 31%. Tesaglitazar (Galida) is another dual-acting PPAR agonist that has entered phase 3 clinical trials.

Inhaled Insulin
Insulin was first used as a treatment for diabetes in 1922. Over the years, many different formulations have been developed. Despite their different properties, one aspect of an insulin regimen remained the same until very recently: it must be injected with a syringe and a needle.

In the past few years, however, new delivery devices with new formulations of insulin have been developed. The most recently approved agent is the inhaled insulin Exubera, which was approved by the FDA in January 2006 for the treatment of type 1 or type 2 diabetes in adults. Its onset of action is more rapid and its duration of action is similar to that of regular (injected) insulin. Studies have shown that Exubera provides similar efficacy and better patient satisfaction compared with standard subcutaneous insulin therapy (ie, at least 2 daily injections of mixed regular/NPH insulin).²²

Exubera was shown to improve glycemic control when substituted for or added to oral combination therapy in a study of 309 patients with type 2 diabetes who had HbA1c levels of 8% to 11%.²³ After 12 weeks, the addition of inhaled insulin to oral therapy allowed 32% of patients to achieve the target HbA1c level of less than 7% compared with oral therapy alone. Mean HbA1c levels decreased by 1.9% in the inhaled insulin plus oral therapy group, by 1.4% in the inhaled insulin monotherapy group, and by only 0.2% in the oral monotherapy group. Pulmonary safety appears to be maintained for up to 4 years.²⁴ However, the use of Exubera in patients with pulmonary disease is still being studied. The drug is contraindicated in patients with uncontrolled or severe asthma or with chronic obstructive pulmonary disease, and in those who smoke.

Conclusion
With the addition of new classes of medications, more options are becoming available for the management of diabetes mellitus. Agents still in phase 2 and 3 trials may soon join the list of pharmacotherapeutic treatments. As new hormones and receptors are discovered, novel modalities for the treatment of diabetes mellitus will continue to be developed. In the future, there will be more treatment options available for the growing number of patients with diabetes that target different pathways of metabolic homeostasis. But as with all of medicine, the best treatment is prevention. Recommending prevention measures to patients with known risk factors must become a clinical goal for all physicians.

Self-assessment test
1. Which of the following agents has been shown to improve beta-cell function?
A. Exenatide
B. Rimonabant
C. Pramlintide
D. Acarbose

2. Which of the following agents works primarily by promoting weight loss?
A. Exubera
B. Exenatide
C. Rimonabant
D. Vildagliptin

3. All the following agents have received FDA approval for the treatment of type 1 diabetes, except:
A. Exubera
B. Exenatide
C. Pramlintide
D. Lispro

4. Which of these agents has NOT been approved for the treatment of type 2 diabetes?
A. Exenatide
B. Pramlintide
C. Exubera
D. Vildagliptin

5. All the following statements about inhaled insulin are correct, except:
A. It has a more rapid onset of action than injected insulin
B. It has a shorter duration of action than injected insulin
C. It may be used as monotherapy
D. It may be used as adjunctive therapy with oral medications

References
1. The International Diabetes Federation. Facts & Figures. Did You Know? Available at www.idf.org/home/index.cfm?unode=3B96906B-C026-2FD3-87B73F80BC22682A

2. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: United States, 2005. Available at www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf

3. Hoyert DL, Heron M, Murphy SL, et al. Deaths: final data for 2003. Available at www.cdc.gov/nchs/products/pubs/pubd/hestats/finaldeaths03/finaldeaths03.htm

4. Hogan P, Dall T, Nikolov P. Economic costs of diabetes in the US in 2002. Diabetes Care. 2003;26:917-932.

5. Harris MI, Eastman RC, Cowie CC, et al. Racial and ethnic differences in glycemic control of adults with type 2 diabetes. Diabetes Care. 1999;22:403-408.

6. American Diabetes Association. Standards of medical care in diabetes—2006. Diabetes Care. 2006;29(suppl 1):S4-S42.

7. Larsen PJ, Holst JJ. Glucagon-related peptide 1 (GLP-1): hormone and neurotransmitter. Regul Pept. 2005;128:97-107.

8. Turner RC. The UK Prospective Diabetes Study. A review. Diabetes Care. 1998;21(suppl 3): C35-C38.

9. 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;28:1092-1100.

10. Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-2635.

11. 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;28:1083-1091.

12. Novartis presents positive Phase III data on key compounds and highlights strong late-stage development pipeline [press release]. Basel, Switzerland: Novartis; September 20, 2005. Available at http://hugin.info/134323/R/1012406/157718.pdf

13. Boyd ST, Fremming BA. Rimonabant—a selective CB1 antagonist. Ann Pharmacother. 2005;39: 684-690.

14. Despres JP, Golay A, Sjostrom L, for the Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353: 2121-2134.

15. Van Gaal LF, Rissanen AM, Scheen AJ, et al, for the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365:1389-1397.

16. Pi-Sunyer FX. Effect of rimonabant on weight reduction and weight maintenance: RIO-North America (RIO-NA) trial. Paper presented at the American Heart Association Scientific Sessions 2004; November 7-10, 2004; New Orleans, La.

17. Scheen AJ. Rimonabant in patients with type 2 diabetes: results from the RIO-Diabetes trial. Paper presented at the American Diabetes Association 65th Annual Scientific Sessions; June 10-14, 2005; San Diego, Calif.

18. Hollander PA, Levy P, Fineman MS, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care. 2003;26:784-790.

19. Silvestre RA, Rodriguez-Gallardo J, Jodka C, et al. Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas. Am J Physiol Endocrinol Metab. 2001;280:E443-E449.

20. 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;21:1204-1212.

21. Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care. 2004;27: 1324-1329.

22. Hollander PA, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care. 2004;27: 2356-2362.

23. Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2005;143:549-558.

24. Skyler J, for the Exubera Phase II Study Group. Sustained long-term efficacy and safety of inhaled insulin during 4 years of continuous therapy. Poster presented at the American Diabetes Association 64th Annual Sessions; June 5-8, 2004; Orlando, Fla.