COVER STORY

The exploding problem of DIABETES

Pharmacists are making use of their unique position to help patients manage their disease

Like this nation's expanding waistline, the incidence of diabetes mellitus (DM) is growing at an alarming rate. The Centers for Disease Control & Prevention estimates that diabetes rates rose by 6% in 1999. Between 1990 and 1998, the number of DM patients increased by 33%. At the same time, CDC reported that obesity in American adults has risen by almost 60% since 1991. The most recent figures show 6% of that increase took place in 1998.

CDC does not believe the two increasing trends are a coincidence. The agency expects the number of new cases of DM to climb dramatically as Americans continue to put on weight. In essence, CDC warns, we have an epidemic of diabetes on our hands.

A rise of Type 2 DM in children and teenagers has been particularly alarming and has made headlines across the nation. The Third National Health & Nutrition Examination Survey (NHANES III) examined results of blood glucose tests for nearly 3,000 youngsters, aged 12 to 19. It then projected the national prevalence of diabetes for this age group and came up with a figure of 4.1 per 1,000. The same study found that certain areas of the United States had much higher increases in DM rates. For example, data from Cincinnati showed a dramatic rise in Type 2 DM in the 10 to 19 age group. The rate went from 0.7 per 100,000 in 1982 to 7.2 per 100,000 in 1994.

While diabetes is manageable, it is still the seventh-leading cause of death in the United States. It is also associated with a multitude of health problems: blindness, cardiovascular disease, neuropathy, nephropathy, and so on.

As if on cue, a host of new drugs for Type 2 DM has become available in the past several years. However, because there are so many of them and they've come out practically one on top of the other, it can be difficult keeping them all straight. What follows is a brief rundown of the players.

Fighting postprandial glucose spikes

The latest drug to hit the market is nateglinide (Starlix, Novartis). Similar to repaglinide (Prandin, Novo Nordisk), nateglinide is designed to reduce postprandial glucose (PPG) levels. That is, the drugs are taken before meals to stimulate insulin production.

Novartis and Novo Nordisk are going on the theory that PPG spikes contribute to the complications of DM. According to Keith Campbell, R.Ph., C.D.E. (certified diabetes educator), professor at Washington State University's College of Pharmacy, they may be right. "In the past couple of years, postprandial hyperglycemia has been better studied and is emerging as a major villain in the development of diabetes complications," he said. This has prompted diabetes educators to recommend glucose monitoring after meals in addition to before meals and at bedtime.

Other touted benefits of nateglinide are reduced risks of hypoglycemia and hyperinsulinemia. Novartis attributes these effects to the drug's rapid onset and elimination. Adverse reactions were minimal during clinical trials, with a few patients experiencing dizziness (3.6% versus 2.2% on placebo) and hypoglycemia (2.4% versus 0.4% with placebo).

Repaglinide is indicated for lowering blood glucose in Type 2 DM patients when diet and exercise modifications are insufficient to control hyperglycemia. Nateglinide has a similar indication, but only for patients who have not been on chronic therapy with other antidiabetic drugs. Both drugs are also indicated for combination therapy with metformin (Glucophage, Bristol-Myers Squibb), a biguanide. They appear to act synergistically with metformin, and their effect on PPG complements the biguanide's reduction of fasting plasma glucose (FPG).

The glitazones

Another new class of oral antidiabetic agents is a trio of thiazolidinediones: troglitazone (Rezulin, Parke-Davis), rosiglitazone (Avandia, GlaxoSmithKline), and pioglitazone (Actos, Lilly and Takeda). Because of problems with liver toxicity, the Food & Drug Administration limited use of troglitazone in March of 1999. A year later, the drug was withdrawn from the market. The FDA closely monitored the remaining two products and concluded they did not have the same risk for hepatotoxicity.

Sometimes called glitazones, these drugs decrease insulin resistance, increase insulin sensitivity, and lower hepatic glucose output. They have additive effects with metformin, insulin, and sulfonylureas and may have beneficial effects on lipids.

While hepatotoxicity isn't as much a problem with pioglitazone and rosiglitazone as with troglitazone, it may still occur. One interesting effect with the glitazones is the occurrence of ovulation in some women who were previously anovulatory.

The thiazolidinediones are still a very impressive class of drugs, according to Campbell, because they target insulin resistance. Of the two drugs available, he thinks pioglitazone may have an edge. "It is always given just once a day and seems to have a better effect on lipids than rosiglitazone does," he said. A study comparing the two drugs is under way.

The alpha-glucosidase inhibitors

The logic behind alpha-glucosidase inhibitors (AGIs) is pharmacologic ingenuity at its best. These drugs don't induce insulin secretion, nor do they decrease insulin resistance. They target ingested carbohydrates. But here's the best part: These drugs don't block glucose absorption, they simply delay it a bit.

A hallmark of Type 2 DM is the inability to produce insulin quickly in response to a meal. By blocking enzymes in the proximal small intestine, the AGIs buy some time. The carbohydrates are broken down and absorbed farther down the intestines. Theoretically, by this time, sufficient insulin has been released to handle the absorbed glucose.

When fiddling around with digestion, some very unpleasant side effects can occur. Such is the case with the AGIs. Carbohydrates that reach the large intestine can cause bloating, gas, and diarrhea. The distal small intestine can relieve these effects by producing new enzymes to metabolize the carbohydrates. It can take a month or more for the new enzymes to appear, so careful initiation and titration of AGI therapy is necessary to minimize gastrointestinal effects. Campbell believes this is the main reason the AGIs "have not caught on in the United States."

Both the AGIs, acarbose (Precose, Bayer) and miglitol (Glyset, Pharmacia), may be used with a sulfonylurea, metformin, or insulin. Effects are additive.

While AGIs don't cause hypoglycemia as monotherapy, they may increase the likelihood of the effect when combined with another agent (except for metformin).

New drug, old class

The sulfonylureas (SUs) have been the primary oral agents for Type 2 DM for nearly half a century. They may seem a bit stodgy in the presence of flashy new drugs, but "the sulfonylureas still have an important place in treatment," said Campbell. And, they boast a new member: glimepiride (Amaryl, Aventis).

Campbell believes glimepiride is the best SU to date. "It does not affect potassium channels in the heart, is the most potent, is taken once a day, and has a significant extra-pancreatic effect." Weight gain has been a problem with the SUs, but it does not appear to be as significant with glimepiride.

Still in development

There are a few drugs under investigation for diabetes. Pramlintide is a synthetic version of the hormone amylin. Amylin is found in pancreatic beta cells and is deficient in Type 2 patients. Studies assessing the addition of pramlintide to insulin therapy in both Type 1 and Type 2 DM patients resulted in better glycemic control and weight loss. Side effects were reported to be minimal.

A peptide found in the GI tract, glucagon-like peptide-1 (GLP-1), has been found to increase insulin secretion and decrease glucagon and hepatic glucose production. Practical use of the drug is limited as it is quickly metabolized after IV administration. Researchers are working on more stable forms of GLP-1.

An agonist of the GLP-1 receptor has been discovered in the salivary gland of the Gila monster lizard. Administration of the agonist, exendin-4, to Type 2 DM patients produced a decrease in PPG. It also reduced glucagon, triglycerides, and gastric emptying. Although these results seem promising, the drug must be administered subcutaneously two to four times daily, which would limit its usefulness.

Because most cases of Type 1 DM appear to be caused by autoimmune reactions, immunosuppressives (e.g., cyclosporine) have been used to delay onset of the disease. An investigational drug ISA(TX)247 (Isotech-nika) has demonstrated preventive effects in preclinical studies while apparently exhibiting less toxicity than other immunosuppressives. Isotechnika has completed phase I trials and will soon begin phase II studies.

Early this year, results of a diabetes vaccine study were published. The study used mice that were genetically engineered to develop Type 1 DM. When the vaccine was administered to very young mice, the incidence of Type 1 was decreased by 29%. Older mice that had insulitis and a marked autoimmune response (but not DM) were also immunized. More than 80% of these were disease-free at 58 weeks.

The new insulins

Insulin options have changed over the past 10 years. Animal-derived insulins have been disappearing, replaced by newer, human recombinant types. A few of these, even, have lost their shine as the ultra-long- and ultra-short-acting insulins have arrived. The new long-acting insulin glargine, Lantus (Aventis Pharmaceuticals), can be administered just once daily.

The new short-acting insulins, aspart (NovoRapid, Novo Nordisk) and lispro (Humalog, Lilly), can be administered with meals to mimic the normal insulin response.

Several companies have partnered to work on a version of inhalable insulin. The team that appears to have the upper hand includes researchers from Pfizer, Aventis, and Inhale Therapeutics. Their short-acting, inhalable insulin is in phase III trials. Lung inflammation is something the companies are watching closely, but early study results don't seem to support this side effect.

Advances in insulin delivery

An exciting development in insulin delivery is insulin pumps. Expensive, but convenient, the pumps can be programmed to give regular doses of insulin plus boluses. Currently only an exterior pump is available, but an implantable pump, designed by MiniMed, is in the later stages of clinical trials. Still in the developmental stage is a pump designed to deliver insulin osmotically across the skin.

Most recently, Novo Nordisk gained approval to market Innovo Dial-a-Dose. This insulin-injecting system uses Novolin PenFill cartridges and measures and tracks injections with an electronic memory chip.

Two new oral technologies are being researched. Endorex and Elan Pharmaceuticals are working on a liposome technology called Orasomes. The liposomes were created to transport medications safely through the stomach and small intestine and into the bloodstream. The companies hope to use the technology, which is currently being studied for oral vaccine use, to create oral versions of injectables, such as insulin.

ARIAD Pharmaceuticals has engineered an insulin gene for insertion into living cells. The cells containing this gene would produce insulin, but they would not secrete it until prompted to do so by a separate drug. This drug could be administered to the patient in tablet or sublingual patch form. The amount of insulin released from the cells would be proportional to the amount of drug administered. The approach has been successful in diabetic mice, but clinical trials are still several years off, according to ARIAD.

What about kids?

Of all the oral medications available to adults, not a single one is approved for use in children. At this point, insulin is the only antidiabetic indicated for pediatric use. Last year, the American Diabetes Association (ADA) assembled an expert panel to discuss the increased incidence and proper treatment of Type 2 DM in children. The panel prepared a consensus statement which was published in ADA's journal Diabetes Care. In the statement, ADA surmised that since the disease is essentially the same in kids and adults, the same drugs that work in adults would also work in children.

ADA suggested metformin as a first-line agent for pediatric use. Dosing at adult levels was recommended since most children with Type 2 DM are at or near adult weights. Treatment with the glitazones was discouraged based on the possibility of liver damage. Beyond this, the panel was unable to reach an agreement on drug therapy. In the event that metformin could not be used (such as in patients with kidney or liver disease) or was insufficient, no second-line agent was agreed upon.

Ouchless products

Despite studies indicating that efficient regulation of glucose levels helps prevent complications of DM, other studies reveal that very few patients have their glucose under control.

"Metabolic control matters in all types of diabetes patients," said Campbell. As many as 80% of DM patients die of cardiovascular disease, he said, and, sadly, less than 7% of them keep their glucose low enough to prevent complications.

Several newer glucose monitors are designed to measure glucose with a minimal amount of blood. Samples can be obtained from areas less sensitive than the fingertips, such as the arm or thigh. Examples of these models are the AtLast meter by Amira Medical, FreeStyle by TheraSense, and FastTake by LifeScan. Some of these newer meters also come with software so the readings can be downloaded to a computer for storage and comparison readings.

New lancet devices are designed to use finer lancets, and some, like the Microlet Vaculance by Bayer, have depth-adjustment settings. Others have done away with needles altogether. Cell Robotics uses a laser in its Lasette lancet device. The laser pierces a hole about the size of that made by the finest lancets, the company estimated.

Another new product is the GlucoWatch Biographer, developed by Cygnus Inc. It works by using a mild electrical current to extract a tiny portion of glucose from the skin; that portion is then converted to a glucose reading. This reduces the number of fingersticks needed throughout the day. It can test glucose levels every 20 minutes for 12 hours and store up to 4,000 readings.

A sticking point

Reimbursement is a touchy issue for diabetes educators, especially pharmacists. "Reimbursement is OK, but it's not great," said Stuart Haines, Pharm.D., BCPS, C.D.E. He educates patients at both of his Maryland practices. Pharmacists are paid for education, not consultation, he said. That is, third parties will pay for educating patients about their disease and how to manage it, but they are not always willing to reimburse for consulting services, such as drug therapy management. The result is payment much less than that given to physicians for the same services.

In January, the Health Care Financing Administration (HCFA) expanded Medicare benefits to cover outpatient diabetes self-management training. The new rules allow for reimbursement for diabetes self-management training outside hospital settings. Practitioners providing this service must already offer other Medicare-covered services and meet quality standards established by HCFA.

"The HCFA reimbursement decisions do damage to diabetes patients," said Campbell. "Few health-care providers can jump through all of the hoops to get approved for reimbursement. Pharmacists can, but it will take time and effort." He cited inordinate amounts of paperwork and tight restrictions on educator qualifications as barriers to patient education.

On a more positive note, some pharmacists have been successfully billing for their diabetes services. "Some bill directly," Campbell said. "Some work out details with the insurance provider after proving that they can improve outcomes of care in a cost-effective manner." Diabetes supply sales are another benefit of diabetes education. "If you improve how the patient feels, they will come to you for their supplies," he explained.

What pharmacists can do

Pharmacists are in the perfect position to help DM patients manage their disease. "Pharmacists are available at times when clinics are closed," Daniel Albrant, Pharm.D., president of Pharmacy Dynamics, Arlington, Va., pointed out.

Patrick McGowen, R.Ph., C.D.E., a pharmacist at Fair Oaks Pharmacy in Arroyo Grande, Calif., agreed. He sees his DM patients once a month or more. "Health-care professionals don't realize that pharmacists see patients more than most other providers," he said.

In California, a group of pharmacists conducted a study of a diabetes education program and its outcomes. The study was funded by a grant from the Tom Long Foundation and proposed by the University of the Pacific, Stockton, and the Santa Barbara Medical Foundation. Nine pharmacies in the Santa Barbara/San Luis Obispo area served as sites for the study—three of them Long's pharmacies, and six of them independents. John Hambright, Pharm.D., owns Lincoln Family Pharmacy in Stockton, and he served as project director for the study. Despite some difficulties coordinating independent pharmacies and physicians, the study went well. LifeScan helped out by donating money and 200 Profile meters that were downloadable to PCs.

McGowen of Fair Oaks Pharmacy was one of the pharmacists providing diabetes management services. He and the other participating pharmacists worked with approximately 300 patients for about a year and a half. They obtained baseline blood pressures, lipid levels, and HbA_1c measurements for all patients.

McGowen followed about 40 patients. "They all expressed a keen interest in learning about their disease," he said. In effect, he put them in charge of their diabetes, and improvements in their status were a direct effect of how hard they worked on it. The results were rewarding. "Our raw numbers were as significant as adding another drug," he said. Final results of the study are being tabulated and will be published by UOP.

Haines is associate professor at University of Maryland School of Pharmacy, as well as a clinical pharmacy specialist at both the VA hospital and the Joslin Diabetes Center. In his practice at the VA, Haines manages his own group of DM patients. At Joslin, he works with a team of endocrinologists, fellows, nurse educators, and dietitians to help optimize drug therapy. He interviews and examines patients and obtains complete drug histories. He then develops a plan to address any drug-related problems and to meet ADA's goals for blood sugar, lipids, and blood pressure.

ASHP is so impressed with Haines' practice that it is using it as a model for a diabetes training program. ASHP wants pharmacists to be able to develop and administer their own diabetes management programs.

Tim Robertson, R.Ph., C.D.E., of Ukrop's Supermarket pharmacy in Richmond, Va., has been an educator in the small chain's new diabetes education program. Ukrop's pharmacists have joined forces with Virginia Commonwealth University and Hanover Family Physicians to create the program, which began offering classes in the fall of 2000. Diabetes patients, whether customers or not, are offered a series of seven classes. Topics include nutrition, medication, exercise, blood sugar monitoring, and goal setting. Individual counseling sessions are available also. "It's a lot, and it's probably more than we can get paid for at this point," said Robertson.

Ukrop's is preparing to apply for ADA recognition of the program. The application is extensive, according to Robertson, and requires six months' worth of data on the effectiveness of the program. However, recognition by ADA means the ability to bill Medicare.

Many experts believe that pharmacists can be key players in the battle against diabetes. "We're going to prove that pharmacists will rise to the occasion," said Hambright. "Seize that opportunity."

Jillene Magills-Lewis, R.Ph.

The author is a writer based in the state of Washington.

Top five diabetes products in 2000 by total sales

Diabetes, oral

• Glucophage

• Avandia

• Actos

• Glucotrol XL

• Amaryl

Diabetes, insulin

• Humulin N

• Humulin 70/30

• Humalog

• Humulin R

• Novolin 70/30

Source: IMS Health

Oral diabetes agents by class

Agents

Mechanism of action

Sulfonylureas

first-generation
chlorpropamide (Diabinese, Pfizer)
tolazamide (Tolinase, Pharmacia)
tolbutamide (Orinase, Pharmacia)

second-generation
glimepiride (Amaryl, Aventis)
glipizide (Glucotrol, Pfizer)
glyburide (DiaBeta, Aventis; Glynase and Micronase, Pharmacia)

Thiazolidinediones

pioglitazone (Actos, Lilly and Takeda)
rosiglitazone (Avandia, GlaxoSmithKline)

Alpha glucosidase inhibitors
acarbose (Precose, Bayer)
miglitol (Glyset, Pharmacia)

Is a C.D.E. title worth it?

Many pharmacists have become certified diabetes educators (C.D.E.s) through the National Certification Board of Diabetes Educators (NCBDE). Keith Campbell, pharmacy professor at Washington State University, helped create this board and wrote the pharmacology chapter of the study manual for the certification exam. To qualify for the exam, pharmacists must spend at least 1,000 hours working with diabetes patients, and they must be graduated for two years or more.

"It is useful to keep track of the time you spend working with patients," Campbell said. "Also, let the other health-care providers, such as physicians, nurses, and dietitians, in your area know what you are doing. Get them to write you letters supporting your application." The C.D.E. exam is given twice a year. Application forms are available from NCBDE.

"As far as the hours go, it took me every bit of the five years," said Tim Robertson, R.Ph., C.D.E., a staff pharmacist at Ukrop's Supermarket pharmacy in Richmond, Va., referring to the time he set aside for meeting the 1,000-hour requirement. Like other C.D.E.s, though, he felt it was worth it.

Campbell listed recognition of expertise, employment opportunities, and improved relations with physicians as benefits of earning the C.D.E. "It also opens up opportunities to get reimbursed for involvement with diabetes patients," he added.

 

Jillene Lewis. THE EXPLODING PROBLEM OF DIABETES. Drug Topics 2001;9:49.