Full Speed Ahead — Progressing Toward Better Diabetes Management
By Rita E. Carey, MS, RD, CDE
Today’s Dietitian
Vol. 8 No. 7 P. 26

The prevalence of diabetes warrants continual advances in care—and research is spawning treatment options to meet that need.

Diabetes has afflicted humans for thousands of years (the earliest known record of diabetes is dated to an Egyptian papyrus of 1552 BC), yet effective treatments for the disease have been available for less than a century, with most of the major advances occurring in the last decade. Our understanding of the disease has come a long way in 10 years, and products introduced this year continue to add treatment options.

History of Home Glucose Monitoring and Insulin
Effective diabetes treatments and tools are truly recent inventions—a fact often illuminated in the stories of individuals who have had diabetes for most of their lives.

Bob, diagnosed with diabetes in 1942, is a member of a local diabetes support group. He often reminisces about the difficulties he and his family had in managing his blood glucose levels 60 years ago. Bob’s mother tested his urine for sugar several times per day—a process that involved mixing eight drops of urine with a solution in a test tube, boiling the tube in water for five minutes, and watching for a color change. When the mixture in the tube turned green, the concentration of sugar in his urine was low; dark orange to red indicated that sugar levels were high. He dreaded seeing red and often starved himself, trying to produce a green-tinted tube. Urine testing for glucose gave a delayed picture of what was happening in Bob’s blood, so he was often overdosed or underdosed with insulin.

Bob had to rely on urine testing for two decades, as the first home blood glucose monitors and strips were not available until the 1960s. Home glucose monitoring was a boon to diabetes management, as it provided a more accurate and timely profile of blood glucose levels and also opened the door to the development of many new pharmacologic treatments.

If Bob had been born before 1921, his diagnosis of diabetes would probably have been a death sentence, as exogenous insulin was not yet available. Insulin was originally derived from beef and pork pancreatic tissues. This insulin did save lives, but many people who used it suffered immunologic reactions (especially from beef insulin) and, because of its unreliable action, erratic blood glucose control. Advanced pork-insulin formulations, with more reliable action profiles (time of onset and peak activity), came on the market in the 1950s and beef-based insulin was discontinued in the United States. Thirty years later, biosynthetic human insulin (made via recombinant DNA technology) essentially eliminated the troublesome immune-related reactions many people who used animal insulin experienced.

After biosynthetic human insulin became available in the 1980s, interest in developing new treatment options waned. Biosynthetic insulin was far superior to pork insulin and provided greater glycemic control. The health and well-being of many people with diabetes vastly improved; but in retrospect, morbidity and mortality remained high, and blood glucose control needed further improvement.

It wasn’t until the results of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study in the 1990s confirmed that near-normal hemoglobin A1C levels in people with diabetes significantly reduced morbidity and mortality from the disease that interest in developing more effective treatments began to increase.1 The human insulin used in these studies frequently caused hypoglycemia as hemoglobin A1C approached the normal range. The unwanted side effect of good glycemic control challenged researchers to develop better insulin formulations that could more closely mimic normal endogenous insulin secretion.1 Insulin analogues and other new treatments are a direct result of the increased knowledge and awareness that came out of those studies.

Insulin Analogues — The Old and the New
A person without diabetes normally releases small amounts of insulin into his or her bloodstream throughout the day (basal insulin), as well as larger amounts when blood glucose levels rise at the start of meals (bolus insulin). Insulin analogues are made to mimic this normal activity of endogenous insulin. All insulin analogues are derived from biosynthetic human insulin that has been structurally modified to alter its rate of absorption into the bloodstream. Long-acting insulin analogues are released slowly into the bloodstream over 20 to 24 hours, thus mimicking the action of endogenous basal insulin while rapid-acting analogues are quickly absorbed for bolus, mealtime needs.

Lispro (Humalog) and aspart (NovoLog), the first rapid-acting insulin analogues to be developed, have been joined this year by a new analogue known as insulin glulisine (Apidra). Regular human insulin (nonanalogue) tends to associate with itself when injected into skin, forming large molecules that are slowly absorbed into the bloodstream. Each of the rapid-acting insulin analogues sport a different structural change, which prevents self-association and promotes rapid absorption.2,3

Studies done to date suggest that all three rapid-acting analogues are essentially equivalent, with no major differences in onset of action or duration.4 Product literature for rapid insulin estimate an onset of action five to 15 minutes after injection, with peak activity occurring in 45 to 90 minutes and an overall duration of approximately three to four hours. Some people, however, experience more drawn-out durations and longer peak times.5

Per product information guidelines, glulisine should be administered 15 minutes before a meal or within 20 minutes of its start. It may be mixed with NPH in a single syringe but should be drawn up first and used within 15 minutes. Opened vials, whether stored in the refrigerator or at room temperature, must be used within 28 days.6 Glulisine may be dosed using a fixed sliding scale or, preferably, determined using premeal blood glucose levels and carbohydrate counting. Recommendations for storage and dosing of glulisine are similar to those made for lispro and aspart, and all three are approved for use in insulin pumps.

Insulin detemir (Levemir) is the second of the long-acting insulin analogues to enter the market. Insulin glargine (Lantus) was developed first and was approved by the FDA in 2000. Glargine is human insulin modified to be soluble at an acidic pH. When injected into the skin, the physiologic pH of the body causes the insulin to form precipitates that release small amounts of insulin over the course of a day.

In contrast, the day-long action of insulin detemir is derived from changes made in the molecule that increase its tendency to self-associate and bind to albumin at the injection site. Product representatives claim that detemir may be superior to glargine because it does not form precipitates, which may dissolve at an irregular rate and, therefore, may produce a smoother, more reliable basal insulin profile.

Studies comparing both detemir and glargine to NPH have found that treatment with long-acting analogues produce similar to slightly better glycemic control with less nocturnal hypoglycemia than treatment with NPH.7,8 One study also found that detemir did not induce weight gain in participants, unlike NPH. Researchers concluded that weight gain may have been avoided because individuals using detemir in the study had to cover fewer hypoglycemic episodes with excess intakes of food.8

As is the case with the rapid-acting analogues, detemir and glargine seem to offer similar action profiles and guidelines for use. Both should be used within 28 days of opening, are designed to be used once daily, and cannot be mixed in the same syringe with other types of insulin. Some people have experienced reduced coverage 18 to 20 hours after a glargine injection and opt to split their dose into two daily injections. Others believe that glargine peaks six to 10 hours after dosing. It will be interesting to see how individual experience with detemir compares.

Exubera — The First Inhaled Insulin
Administering insulin via injection has disadvantages, notably convenience and the burden of taking multiple daily injections. The development of alternative methods of insulin administration, starting recently with inhaled insulin, may improve treatment outcomes for many people with diabetes. Exubera is a powdered form of insulin taken into the lungs via inhalers. The large vascular bed in the lungs and high permeability of the alveoli facilitate the rapid absorption of insulin into the bloodstream. Studies show that inhaled insulin has an onset of action similar to the rapid insulin analogues, with peak activity occurring 30 to 90 minutes after administration.9 Inhaled insulin has a longer duration, however, which may or may not benefit overall glycemic control.9

Many researchers believe inhaled insulin will be most beneficial for people with type 2 diabetes who need insulin to reduce postprandial glucose levels or for people with insulin-dependent type 2 diabetes on a basal-bolus insulin treatment regimen. Inhaled insulin may also be beneficial for those who experience high fasting glucose levels consequent to the dawn phenomena.

Some concern has been expressed regarding the safety and usefulness of inhaled insulin for people with type 1 diabetes. This concern is related mainly to unpredictability in rates of absorption in the lungs. Colds, flu, and congestion can apparently alter absorption rates. Also, individuals who smoke or who have smoked within six months should not use inhaled insulin. It is contraindicated for people with asthma and other pulmonary diseases, and lung function tests are recommended before initiating inhaled insulin therapy. These should be repeated every six to 12 months thereafter.10 A major side effect in studies using inhaled insulin has been persistent cough, though it may decrease over time. Limited studies have found that inhaled insulin may provide glycemic control comparable to basal-bolus injection regimens with possibly fewer hypoglycemic episodes, less weight gain, and better compliance among participants.9,11

New Therapies Mimicking Glucagon-Like Peptide 1 and Amylin
Exogenous insulin alone may not adequately control postprandial rises in blood glucose in people with diabetes. Post-prandial glucose levels are normally moderated in people without diabetes by several factors working alongside insulin, including glucagon-like peptide 1 (GLP-1) and amylin. The function of these factors is impaired in diabetes, and this understanding has led to the development of the two non–insulin-related therapies that were approved in 2005: exenatide (Byetta) and pramlinitide (Symlin).

Exenatide is the genetic copy of a substance called exendin-4 that was first isolated in the venom of the Gila monster. Exenatide mimics the actions of native GLP-1, which is normally produced and released from the small and large intestines within minutes of food ingestion. GLP-1 controls blood glucose by stimulating insulin secretion, slowing gastric emptying, reducing glucagon release, and enhancing the sense of satiety. It is evident that in people with diabetes, GLP-1 function is somewhat impaired. This causes decreased insulin secretion, elevated glucagon levels, faster gastric emptying (unless the individual suffers from gastroparesis), and an impaired sense of satiety after meals.12

Exenatide is indicated for adults with type 2 diabetes who have not realized good glycemic control with metformin and/or sulfonylureas. Exenatide is an injectable medication used in conjunction with oral medications. The dosing strategy usually begins with five micrograms twice per day for one month, followed by 10 micrograms twice daily thereafter.12 Nausea and vomiting are common side effects that may or may not subside over time. Studies indicate that exenatide produces improvements in glucose control equivalent to those realized with therapies combining metformin and/or sulfonylurea with insulin glargine. An advantage exenatide seems to have over insulin is reduced weight gain and even weight loss. The gastrointestinal effects, however, may cause people to discontinue its use.12

Pramlinitide is an amylin analogue that functions in a similar fashion to exenatide. Amylin is produced in pancreatic ß-cells and, therefore, is diminished in people with diabetes. Its gluco-regulatory effects are similar to those exhibited by GLP-1. It is an injectable medication indicated for use in people with type 1 diabetes or insulin-dependent type 2 diabetes. When pramlinitide is injected 15 minutes before a meal, it slows gastric emptying, suppresses the release of glucagon, and improves satiety after a meal. Like exenatide, its major side effect is nausea, which may subside over time. Pramlinitide may also offer the benefit of weight loss, something many people using insulin therapy find challenging.

These therapies hold incredible promise for people with diabetes. More therapeutic options provide for flexibility and greater opportunities to individualize treatment. Products that address amylin and GLP-1 deficiencies as well as aberrations in insulin production may improve glycemic control in people who may have previously been unable to achieve it. And most importantly, renewed interest in helping people obtain optimal glucose control will continue to lead to the development of new and better therapeutic products. There are more waiting in the wings. Who knows what next year will bring?

— Rita E. Carey, MS, RD, CDE, is a clinical dietitian and diabetes educator at Yavapai Regional Medical Center and the Pendleton Wellness Center in Prescott, Ariz.

References
1. Hirsh I. Insulin analogues. N Engl J Med. 2005;352:174-183.

2. Franz MJ (Ed). Diabetes Management Therapies, Fifth Edition.

3. Dailey G, Rosenstock J, Moses RG, et al. Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Diabetes Care. 2004;27:2363-2368.

4. Bloomgarden ZT. Insulin treatment and type 1 diabetes topics. Diabetes Care. 2006;29:936-944.

5. Warshaw H. Rapid acting insulin. Timing it just right. Diabetes Self-Management. 2005;22(1):20,22,24-26.

6. Prescribing information for Apidra per Aventis Pharmaceuticals. http://products.sanofi-aventis.us/apidra/apidra.html

7. Davies M, Storms F, Shutler S, et al. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes. Diabetes Care. 2005;28:1282-1288.

8. Home P, Bartley P, Russell-Jones D, et al. Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes. Diabetes Care. 2004;27:1081-1087.

9. Rave K, Bott S, Heinemann L, et al. Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care. 2005;28:1077-1082.

10. FDA News. FDA approves first ever inhaled insulin combination product for treatment of diabetes. January 2006.

11. Hollander P, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insulin compared with subcutaneous insulin therapy in patients with type 2 diabetes. Diabetes Care. 2004;27:2356-2362.

12. Riddle M, Drucker D. Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1. Diabetes Care. 2006;29:435-449.