The Diabetes Epidemic:Keys to Prevention, Guide to Therapy

Diabetes is epidemic! The numbersare truly alarming. In 1997, official datashowed that 16 million people in theUnited States had diabetes. Approximately1 million had type 1 disease,and 10.4 million had type 2 disease; theremainder had undiagnosed diabetes.¹If these numbers are projected outagainst an annual increase in diseaseprevalence of about 3.5%, it means thatby the year 2028, 50 million people willhave diabetes. However, the actual rateis closer to 7% each year. As such, approximately100 million Americans--roughly 1 of every 4--will have diabetesby 2028.

What factors underlie this epidemic?What strategies can we inferfrom the causative factors to help usbetter prevent and manage diabetes?The answers to those questions arethe focus of this article.

A BRIEF HISTORY LESSON
Thousands of years ago, humanswere hunter-gatherers. Survival dependedon one's ability to keep moving.With intermittent availability of food,those individuals who burned caloriesefficiently could, perhaps, go a few extradays without eating--or travel a fewmore miles to find sustenance. One benefitto this lifestyle: the genetic defectsthat manifest in type 2 diabetes--insulinresistance and defective beta-cell function--were either never expressed (becausefew people lived beyond age 20)or were not expressed until older age.

Today, of course, most of us haveample food and lifestyles that requiresignificantly less physical activity. Inthis setting, it is no surprise that morethan 50% of Americans are now obese.Obesity is a direct cause of insulin resistance.(If a person has a normal insulin-producing mechanism, diabeteswill not develop.) We now see type 2diabetes in children who are overweightand who lack outlets or motivationfor physical activity. Computers,video games, and dearth of physicaleducation programs in many schoolshave contributed to this phenomenon.

The aging of the general populationis another factor in the increase in diabetescases. As a person gets older, thebeta cell has more opportunity to fail.

Need for lifestyle changes. Giventhe factors that underlie the diabetesepidemic, it is obvious that the first andbest place to start preventing and managingdiabetes is with lifestyle changes.We need to simulate the old huntergathererstate (ie, intermittent starvation,marginal food availability, and theneed to keep moving). The data arenow irrefutable that people who regularlyengage in exercise (such as walking)and who control their diet can:

• Prevent or slow the onset of type 2diabetes if they are at risk or have impairedglucose tolerance (Table 1).^2-4
• Improve their clinical status if they alreadyhave type 2 diabetes.

Given the time constraints of officepractice, it is particularly difficultfor primary care clinicians to spendthe appropriate amount of time motivatingand educating patients aboutthe importance of diet and exercise.Diabetes educators and/or classes thatallow the patient to return as often asnecessary can help him or her achieveestablished goals.

Nutritional education. Datashow that glycosylated hemoglobin(HbA_1c) levels drop by a full percentagepoint in patients who make 3 visitsto a nutritionist. For many peoplewith type 2 diabetes, carbohydratecounting during meals helps controlpostprandial glucose levels. Theamount and type of carbohydratesthat are "allowed" at different mealsare governed by preprandial glucosemeasurements.

Physical activity. The patient'sphysical capabilities and cardiovascularand pulmonary status guide the level ofexercise. It was once thought that onlyaerobic activity was beneficial: we nowknow, however, that any regular activity--biking, walking, or running--lowersblood glucose, improves insulinsensitivity, and reduces cardiovascularrisk. Unfortunately, many schools donot have physical education as a regularpart of the curriculum.

DRUG THERAPY
Eventually, lifestyle measures willno longer effectively control blood glucoselevels, and drug therapy must assumea role. Our options in treatingpatients with the disease are to:

• Slow the digestion of carbohydrates.
• Stimulate the beta cell.
• Inhibit hepatic glucose output.
• Improve the sensitivity of peripheraltissues to insulin.

Tables 2 and 3 detail the targetguidelines for glucose levels and otherbiochemical indices for patients withdiabetes. Table 4 lists the various oralanti-diabetic agents available to helpmeet these targets.

Beta-cell stimulants. A numberof different types of agents stimulatethe release of insulin from the beta cellinto the bloodstream. Three classes ofagents act as secretagogues by closingthe potassium channel and openingthe calcium channel:

• Sulfonylureas. First-generation sulfonylureashave been used for nearly50 years. The most commonly prescribedsecond-generation drugs ofthis class are glyburide, micronizedglyburide, glipizide, glipizide GITS,and glimepiride.
• Meglitinides. Repaglinide, the onlyagent in this class, is fast-acting andtaken just before each meal.
• D-phenylalanine derivatives. Nateglinideis a fast-acting agent that is taken 1to 30 minutes before meals.

Hepatic glucose output inhibitors.The mechanism of action of theseagents in the liver is not clear, but theymay work through the mitochondria.

• Biguanides. Agents such as metformininhibit hepatic gluconeogenesisand increase peripheral insulin sensitivity.Keep in mind that biguanidescannot be used if the serum creatininelevel is above 1.5 μg/dL in men andabove 1.4 μg/dL in women.

Combination agents. Metformin/glyburide combines the inhibitionof hepatic gluconeogenesis withbeta-cell stimulation.

Thiazolidinediones. These agentsincrease tissue sensitivity to insulin.Rosiglitazone and pioglitazone (the "glitazones")are currently available. Theseagents must not be given to patientswhose alanine aminotransferase or aspartateaminotransferase levels are elevatedmore than 2.5 times normal. Also,liver function needs to be monitored periodicallyin persons taking these agents.

α-Glucosidase inhibitors. Acarboseand miglitol both slow the digestionof carbohydrates so that glucoseis absorbed more slowly into thebloodstream.

Peroxisome proliferator activatedreceptors (PPAR). There are atleast 3 PPARs (alpha, beta, andgamma) now being widely studied.When a drug such as a glitazone actson the PPAR receptor, it synergizeswith a retinoid receptor to stimulate activityin the nucleus; this results in thetransport of glucose into the cell. Thisis an exciting area of research, and inthe next few years most newer oralagents will be of this variety.

Insulin. Table 5 outlines the actionsof insulin preparations.

A MULTITUDE OFTHERAPEUTIC CHOICES
Almost any combination ofagents may be used to achieve thedesired therapeutic goals. It has beencalculated that there are some 31possible combinations of medications(Figure 2).

Along with many other endocrinologists,I initially prescribe lowdosages of 2 drugs that act throughdifferent mechanisms to lower bloodglucose levels. A number of factors influencemy choice of agents for a particularpatient, including his:

• Blood glucose and HbA_1c levels.
• Current clinical condition.
• Weight.
• Level of physical activity.

If the blood glucose level is above250 μg/dL and the HbA_1c is above8.5%, I generally prescribe a sulfonylurea,possibly paired with metforminor a glitazone. The sulfonylurea worksquickly; metformin takes a few dayslonger to act. The latter agent maytake 4 to 6 weeks for full effect.

I usually give metformin and a glitazoneto patients with blood glucoselevels lower than 250 μg/dL and anHbA_1c below 8.5%. I ask them to be patientas the regimen becomes effective.The shorter-acting potassiumchannel closing drugs (ie, the secretagogues)can also be combined withmetformin and the glitazones.

Both physician and patient needto realize that there are many therapeuticchoices; one is never lockedinto a particular mode of treatment.The United Kingdom Prospective DiabetesStudy^5,6 showed that the progressivecourse of type 2 diabetes isinexorable. Despite the initial efficacyof the starting regimen, more medicationwill eventually need to be added.

I usually prescribe insulin at theoutset of treatment if I am concernedthat oral agents will take too long tocontrol blood glucose levels. This approacheliminates the effect of "glucosetoxicity"(Box). Typically, the firstinsulin I prescribe is a longer-actingpreparation, such as NPH. However,glargine may be the better option: it isgiven at 10 to 11 PM (or with dinner orin the AM) to lower the fasting glucoseto accepted goals. A very short-actinginsulin, such as Lispro, taken beforeeach meal can be tried. If a patient isusing insulin multiple times, I stop thesulfonylureas but might continue givinga sensitizer, such as metformin ora glitazone.

Glargine is a new synthetic, 24-hour, once-a-day formulation that actsas a basal insulin. This formulationmay help reduce hypoglycemia in patientswith type 1 diabetes; the unexpectedpeaks that can arise with NPH,Lente, and Ultralente will not occur. Ifglargine is combined with Lispro, thepatient can always control insulin actionimmediately.

Results of the Heart OutcomesPrevention Evaluation (HOPE) trialraise interesting questions related tooptimal therapy for patients with diabetes.^7,8 In that study, a large group ofpeople with diabetes or heart diseasewere given ramipril (an angiotensinconvertingenzyme [ACE] inhibitor)or placebo. Recipients of the ACE inhibitorhad better outcomes in diabetesand heart disease. The questionis, Should persons with newly diagnoseddiabetes immediately begin takingan ACE inhibitor because of theagent's endothelial protective qualities?Appropriate studies are in place to answerthis question.

We can look forward to some extraordinarytechnology within the nextseveral years. Noninvasive monitoring;implantable pumps and sensors; isletcelltransplantation; and alternate insulindelivery systems, such as inhaledinsulin and an oral spray, in which insulinis absorbed through the buccalmucosa, are on the horizon.