Intensive Management of Type 2 Diabetes

Last month, Part 1 of this series reviewed the data linking tighter glycemic control with better health and longevity in patients with diabetes. These finding apply equally to type 1 and type 2 disease, but in type 2 insulin is not always necessary to achieve satisfactory control. The author details the nature of type 2 diabetes and the oral medications available to manage it.

By Jeff Unger, MD

As noted in last month's article on the type 1 form of the disease, diabetes mellitus is the sixth-leading cause of death and the most common chronic disease in the United States, affecting 16 million Americans, or 6% of the population. A new case of diabetes is diagnosed in this country every 40 seconds, and another American dies of diabetes-related complications every 3 minutes. The average life expectancy of a person who has diabetes is 15 years less than that of a person who does not have the disease; the chances of becoming disabled are six times higher in the diabetic population. Diabetes claims more lives than breast cancer and AIDS combined.

Over $113 billion is spent annually on diabetes-related illnesses. More than 80% of this money is spent on long-term complications such as blindness and procedures such as dialysis and amputations. Per capita expenses for diabetic patients are $10,071 annually, compared with $2669 for nondiabetic health care costs.

Several studies have demonstrated the importance of achieving optimal glycemic control in patients with diabetes. For type 1 patients, the results of the Diabetes Control and Complications Trial (DCCT), published in 1993, suggested that HbA1c levels be maintained below 7.2% to reduce the incidence of nephropathy, retinopathy, and neuropathy. Intensively managed type 1 patients were subsequently shown to gain an average of 15.3 years free of complications and 5.3 years of life expectancy in comparison with less tightly controlled patients.

In 1998, the United Kingdom Prospective Diabetes Study (UKPDS) established guidelines that called for HbA1c levels to be maintained in the range of 6.5% to 7.0% to achieve glycemic control in patients with type 2 diabetes, who account for 90% of the 10 million Americans who have diabetes. The trial investigators also suggested that a glycemic threshold does not exist, meaning that lowering HbA1c levels below 6.5% would most likely reduce a patient's chances of developing long-term complications even further. Unfortunately, the average HbA1c level among all diabetic patients in the United States remains elevated at 8.7%.

Approximately 90% of the diabetic patients in this country are cared for by primary care physicians, many of whom have had very little education in screening for, diagnosing, and treating this complicated disorder. Successful management of patients with type 2 diabetes specifically requires an understanding of the pathophysiology of insulin resistance, a strategy to promote lifestyle modifications, surveillance guidelines for controlling long-term complications, and knowledge of appropriate pharmacologic interventions. Pursuing an aggressive approach to diabetes management can lead to positive treatment outcomes as well as improved quality of life for these patients.

DIAGNOSING TYPE 2 DIABETES

Type 2 diabetes is an insidious disorder that appears to worsen slowly over time. The disease can occur in childhood, but most cases are diagnosed after age 40. The prevalence rate increases dramatically with age; 10.4% of people over age 65 have the disorder.

High-risk populations include American Indians, African Americans, Asian Americans, and Pacific Islanders. Screening everyone for diabetes using oral glucose tolerance testing is neither practical nor cost-effective. Instead, attention should be focused on screening individuals with multiple risk factors (see table below). High-risk individuals should receive a fasting plasma glucose test every one to three years.

Obesity is common in patients with type 2 diabetes. There is also a strong genetic basis for the disease; concordance among monozygotic twins is 90%.

Because patients often have the disease for many years before it is diagnosed, the development of long-term microvascular and macrovascular complications may be advanced by the time the diagnosis is made. Background diabetic retinopathy is found in about 60% of patients at the time of diagnosis.

If type 2 diabetes is discovered at an early stage and treated aggressively, disability and death can be prevented. Continuous glucose monitoring systems can easily track the characteristic patterns of type 2 diabetes (see figures below).

Sensor 1 (top) shows impaired glucose tolerance as demonstrated by postprandial elevations in glucose readings, which are seen consistently after each meal. Sensor 2 (center) shows impaired fasting glucose and nocturnal hyperglycemia. Note that if a blood glucose level is obtained after 10 AM, a patient might be reassured that he does not have diabetes, when in fact he is hyperglycemic for 10 hours each day. Sensor 3 (bottom) depicts the presence of diabetes. Blood glucose levels are rarely in the normal range. Both nocturnal hyperglycemia and postprandial hyperglycemia are present. *Interstitial glucose readings are obtained every five minutes and recorded by monitor worn by patient for three days. Each colored line represents series of 280 interstitial glucose readings, recorded over 24 hours.

Impaired glucose tolerance, the first metabolic defect to develop, occurs in asymptomatic individuals in whom postprandial blood glucose levels rise to between 126 and 199 mg/dl. Over time, without treatment, an impaired fasting glucose level–that is, a fasting glucose level above 126 mg/dl–will develop in these patients. Normal fasting glucose levels are below 110 mg/dl. A patient who has fasting glucose levels above 110 mg/dl should be evaluated for diabetes (see table below). A random glucose level above 200 mg/dl, especially in a patient with hallmark symptoms such as polyuria, polydipsia, rapid weight loss, and blurred vision, clinches the diagnosis of type 2 diabetes.

MULTIPLE METABOLIC DEFECTS

Patients with type 2 diabetes have multiple metabolic defects. Insulin resistance may be present for many years before the development of overt hyperglycemia. It can manifest as decreased glucose uptake in muscle and adipose tissue in response to insulin, as well as increased hepatic glucose output. Insulin prevents the breakdown of glycogen to glucose in the liver. If the liver does not respond to elevated circulating insulin levels, glucose is produced continually, resulting in an increase in basal glucose levels. Pancreatic beta cells attempt to compensate for these elevated levels by producing even more insulin.

Unfortunately, high levels of circulating insulin can worsen a patient's impaired metabolic state. Insulin is a growth hormone. When insulin levels rise, patients tend to gain weight, develop hypertension, and suffer vascular damage at the cellular level. High circulating insulin levels also increase appetite, resulting in further weight gain and redistribution of fat cells to the abdomen. Patients become android obese (waist:hip ratio, >1.0 in men and 0.8 in women).

At the cellular level, down-regulation of insulin receptors occurs due to high circulating insulin levels. Pancreatic beta cells cannot sustain abnormally high insulin production for a prolonged period of time. Eventually, beta cell death occurs, possibly due to a combination of cell toxicity once blood glucose levels exceed 130 mg/dl and beta cell exhaustion. When beta cells are unable to maintain insulin production at a high enough level to control glycemia, blood glucose levels rise even higher, accelerating beta cell death. The fact that diabetes-related complications are frequently observed at the time of diagnosis suggests that glucose toxicity has been present for about five to seven years in asymptomatic individuals.

Patients with type 2 diabetes are not insulin dependent or at risk for ketosis under most circumstances. However, some patients may require insulin treatment to control hyperglycemia and the accompanying symptoms commonly seen with elevated blood glucose levels.

IMPORTANCE OF HOME GLUCOSE MONITORING

Appropriate treatment of patients with type 2 diabetes focuses on measures that reverse the metabolic disturbances involved in the pathogenesis of the disease. All aspects of insulin resistance should be addressed through treatment. Preservation of beta cell function is of utmost importance.

Patient education should begin with the first visit. Many patients do not understand the importance of managing diabetes intensively. Because they are asymptomatic, they may believe a fasting glucose level of 180 to 200 mg/dl is not necessarily bad. That is why home glucose monitoring is critical in the management of type 2 diabetes. Checking fasting and bedtime readings for the first seven days of each month will give the physician and patient an overview of glycemic control. Unlike patients taking insulin, who need frequent monitoring to determine their preprandial insulin dose, type 2 patients do not have to act on a single elevated glucose reading. Therefore, multiple daily readings, which could cause the patient some anxiety while at the same time increasing the cost of the treatment regimen, are not necessary.

Home blood glucose monitoring is also beneficial in promoting weight loss. Type 2 patients have a difficult time losing weight because their circulating insulin levels are elevated. A moderate reduction in caloric intake combined with an exercise program can result in an appreciable weight loss. A loss of only 7 lb can lower fasting blood glucose levels, which in turn would improve HbA1c readings.

Many patients with type 2 diabetes, however, resist the idea of exercising. This is unfortunate, because exercise not only promotes weight loss but also improves glucose uptake into muscle cells and lowers insulin resistance. In type 2 patients who are not physically conditioned, a single episode of moderate exercise (walking 30 to 45 minutes, for example) can reduce blood glucose levels for up to 16 hours. Patients should be encouraged to check glucose levels before and after exercising to see for themselves the improvement that results. This practice will reinforce the importance of exercise in treating type 2 diabetes. Exercise, incidentally, has also been shown to delay and possibly prevent the onset of type 2 diabetes.

Smoking and alcohol consumption are two other potential complications that can interfere with glycemic control. Smoking, of course, is a significant risk factor for future cardiac events, especially in patients with preexisting diabetes, obesity, hypertension, hyperlipidemia, sedentary lifestyle, or a family history of coronary artery disease. All attempts should be made to have the diabetic patient stop smoking as quickly as possible. And because alcohol may interfere with the effects of certain oral antidiabetic agents, alcohol consumption should be kept below 4 oz daily or stopped altogether. Alcohol can also adversely affect triglyceride levels, raise blood pressure, and promote weight gain.

SULFONYLUREAS: MAINSTAY OF ORAL THERAPY

Although weight loss, exercise, smoking cessation, and decreased alcohol consumption are important, pharmacotherapy is often required to maintain HbA1c levels between 6.5% and 7% in patients with type 2 diabetes. If HbA1c levels fail to improve after three months of lifestyle modifications, then pharmacotherapy is advised.

Sulfonylureas have been the mainstay of oral therapy since the 1950s for treating type 2 diabetes (see table below). These drugs work by stimulating the release of insulin from the beta cells in the pancreas. On average, HbA1c levels drop 0.8% to 2.0% with sulfonylureas. Due to the insulin release induced by these drugs, patients tend to gain weight and may experience hypoglycemia (especially elderly patients being treated for the first time). For this reason, obese patients should avoid using sulfonylureas.

Approximately 20% of patients who begin sulfonylurea therapy will be unresponsive to the drug. About 10% of patients develop secondary failures each year, meaning that their blood glucose and HbA1c levels actually rise while they are taking the drug.

Sulfonylurea therapy should be initiated at the lowest effective dose and subsequently increased to the desired effect every two weeks. However, in a newly diagnosed, symptomatic patient, treatment can be started with glipizide XL 20 mg at bedtime. Patients should be advised to check their fasting and bedtime blood glucose levels daily. Within 7 to 14 days, glucose levels should be lower and symptoms should subside. The glipizide dose can then be reduced by 50% and maintained at that level or combined with a biguanide or thiazolidinedione.

Sulfonylureas should be taken one hour before eating or at bedtime. Normal insulin release from the pancreas takes place in two phases. In the first phase, which occurs before eating, a small amount of insulin is released to prime the bloodstream in preparation for the meal. As carbohydrates are consumed during the meal, blood glucose levels rise and the second phase of insulin release begins. This phase continues until postprandial glucose elevations return to normal.

Patients with type 2 diabetes have lost their first-phase insulin response and have a blunted and delayed second-phase release. Therefore, taking sulfonylureas one hour before meals will promote secretion of insulin from the pancreas and minimize postprandial hyperglycemia. Sulfonylureas can also be taken at bedtime, because they limit hepatic glucose production, which occurs during the fasting state.

MEGLITINIDES AND BIGUANIDES

The meglitinides (repaglinide and nateglinide) are nonsulfonylurea secretagogue agents whose mechanism of action is similar to the sulfonylureas. Although meglitinides stimulate insulin release from the pancreatic beta cells, they work through a different receptor. They have a very short half-life and much faster onset of action. Therefore, they must be taken 30 to 60 minutes before meals. If a meal is skipped, the drugs should not be used.

Postprandial hyperglycemia improves after meglitinide therapy, and there appears to be less risk of hypoglycemia. Weight gain may be only minimal. HbA1c levels improve 0.5% to 2%.

Repaglinide can be increased to a dosage of 4 mg before each meal. Nateglinide's preprandial dose is 120 mg.

Metformin, a biguanide, works by reducing hepatic glucose output, enhancing insulin sensitivity in hepatic and muscle tissue, and possibly slowing carbohydrate absorption from the gut. This drug has several effects that are helpful in managing the insulin resistance associated with type 2 diabetes. First, it appears to decrease appetite, resulting in weight loss rather than weight gain. For this reason, obese patients with type 2 diabetes should take metformin as their first-line drug. Second, it has a positive effect on improving triglyceride and low-density lipoprotein (LDL) cholesterol levels. Third, results of the UKPDS showed a reduction in cardiovascular events in patients who were intensively managed with metformin. The reason for this is uncertain, but it is an important finding because 75% of type 2 patients die from cardiovascular disease. Fourth, metformin reduces HbA1c levels 1.5% to 2.0%.

Metformin's side effects (metallic taste, nausea, and diarrhea) are minimal; they tend to occur more often when the drug is taken on an empty stomach. Therefore, patients should always be advised to take metformin with food. This drug should not be used by patients with an elevated serum creatinine (>1.4 mg/dl in women and 1.5 mg/dl in men), because of an increased risk of lactic acidosis. In addition, metformin should be withheld for approximately 48 hours after intravenous contrast procedures. Other contraindications include cardiogenic or septic shock, congestive heart failure that requires drug therapy, severe liver disease, and pulmonary insufficiency with hypoxemia or severe tissue hypoperfusion.

Metformin therapy should be initiated at 500 mg twice daily with meals and increased to a maximum of 2000 mg daily, although raising the dosage above 1500 mg/day may not result in significant improvement in glycemic control. A new extended-release product (glucophage XR) allows for more convenient once-daily dosing.

THIAZOLIDINEDIONES AND ALPHA-GLUCOSIDASE INHIBITORS

The thiazolidinediones (TZDs) work by enhancing insulin sensitivity in both muscle and adipose tissue and to some extent by reducing hepatic glucose production. These drugs improve insulin resistance and can also have a positive effect on lipid metabolism. The two drugs in this class are rosiglitazone and pioglitazone. Monotherapy with these agents has resulted in a 0.5% to 1.5% reduction in HbA1c levels. Pioglitazone can decrease triglyceride levels by 33% and increase high-density lipoprotein cholesterol levels; however, the TZDs have minimal effect on LDL cholesterol levels.

The primary adverse effects of the TZDs are weight gain and peripheral edema. These drugs do not result in hypoglycemia when used as monotherapy, and they are safe to use in patients with impaired renal function because they are metabolized in the liver and excreted in the feces. The drugs should be administered with caution to patients with liver dysfunction because TZDs and their metabolites can accumulate in the liver. They should not be taken by patients with serum transaminase levels above 2.5 times the upper limit of normal. Due to the risk peripheral edema, TZDs should be avoided in patients with New York Heart Association class III or IV functional status. Patients taking TZDs should have serum transaminases monitored every two months for the first year and periodically thereafter (see table below).

Thiazolidinedione therapy should be initiated at a low dosage (4 mg daily for rosiglitazone and 15 mg daily for pioglitazone). Reduction in insulin resistance may take four to six weeks to take effect, so the dosage should be increased slowly until optimal glycemic control is achieved.

The alpha-glucosidase inhibitors (AGIs) include acarbose and miglitol. They act by inhibiting the enzyme alpha-glucosidase found in the brush border cells that line the small intestine. This action delays the breakdown of carbohydrates into glucose and retards absorption of glucose into the systemic circulation. The AGIs can lower HbA1c levels by 0.7% to 1.0% and are used most successfully by patients who experience significant postprandial hyperglycemia. Unfortunately, their usefulness is blunted by often intolerable gastrointestinal side effects–namely, abdominal pain, bloating, flatulence, and diarrhea. These side effects will dissipate once the drug is stopped.

When initiating AGI therapy, it is best to begin with 25 mg taken once daily with the biggest meal of the day. After one week, a twice-daily dosage can begin and, if tolerated, it can be increased to three times daily during the third week. If HbA1c levels do not improve, a slow increase to the maximum dose of 100 mg three times a day can be considered.

The AGIs are contraindicated in patients with cirrhosis or a serum creatinine level above 2.0 mg/dl and in those with inflammatory bowel disease. Although hypoglycemia is not typically seen with monotherapy, low blood glucose levels may occur when these drugs are used in combination with other agents. Because AGIs delay absorption of complex carbohydrates, only pure glucose should be used to treat hypoglycemia in symptomatic patients.

COMBINATION THERAPY

Combination therapy involving multiple oral agents is prudent in many patients with type 2 diabetes. Improvement in glycemic control is often additive when two or more drugs from different classes are combined (see table below, for clinical efficacy of the individual drug classes). Standard drug combinations include a sulfonylurea with metformin, a sulfonylurea plus a TZD or AGI, metformin with repaglinide, or an AGI and metformin with a TZD. Also available is Glucovance, which combines glyburide with metformin in a single tablet. This drug should be taken with meals and its dosage increased to target improvement in HbA1c levels.

If the target HbA1c level is not attained using a combination of oral agents or if the patient is becoming increasingly symptomatic, insulin therapy should be initiated (see figures below).

Effect of Metformin in Monotherapy and Combination Therapy as Documented by Continuous Glucose Sensor Monitoring

Target blood glucose range is 80-120 mg/dl. This patient's HbA1c on metformin alone was 6.8%. Note frequent levels of prolonged hyperglycemia occurring after meals and nocturnally.		Same patient after glipizide XL 2.5 mg at bedtime was added to metformin. Improvement in glycemic control is clearly demonstrated. HbA1c dropped to 6.1%.

The target HbA1c level advocated by the UKPDS is 6.5% to 7%. Patients who remain above that level for three to six months are at increased risk for microvascular and macrovascular complications. Adding a third oral agent to the regimen usually does not result in a significant improvement in HbA1c levels in such patients. Also, the cost of multiple oral agent therapy may be prohibitive. In some cases, adding a fourth drug to the regimen would most likely result in no appreciable difference in symptoms or HbA1c levels (see figure, below).

Combination therapy. This is a continuous glucose sensor tracing of a 54-year-old patient taking metformin 2500 mg, glipizide XL 20 mg, and pioglitazone 45 mg daily. Her HbA1c is 9.8% and she is symptomatic. Note that target blood glucose readings between 80-120 mg/dl are never achieved during three days of monitoring. This patient should be placed on insulin therapy.

It should be noted that most type 2 patients eventually will need insulin therapy as their pancreatic beta cell function deteriorates, during which their beta cell mass is reduced to less than 20% and their insulin resistance worsens.

In addition to reaching a target HbA1c level of 6.5% and 7%, patients should maintain fasting blood glucose levels below 110 mg/dl. In order to achieve an HbA1c of 7%, only 49% of home blood glucose readings must be between 70 and 110 mg/dl. If 42% of the readings are within this target range, HbA1c levels will fall between 8% and 8.5%. In other words, every reading doesn't have to be perfect in order to achieve intensive control of type 2 diabetes.

Insulin therapy may be initiated using NPH insulin at bedtime while continuing metformin. Because insulin is a growth hormone, high doses will result in weight gain, which can be minimized with the use of metformin. Split-dose insulins (humulin 50/50, humulin 70/30, and humalog mix 75/25) are readily available; they can also be helpful in managing type 2 patients. Multiple daily injections of insulin and continuous subcutaneous insulin therapy using an insulin pump are also appropriate for many type 2 patients. In the future, many of these patients will be treated with inhaled insulin, implantable infusion pumps, new insulin analogs, and an artificial pancreas consisting of various sensors and pumps, allowing the patient to achieve optimal glycemic control without fear of becoming hypoglycemic. (For more information regarding insulin therapy in the treatment of diabetes, see Part 1 of this series, "Intensive Management of Type 1 Diabetes," in the September issue.)

Although diabetes is a disorder of carbohydrate metabolism, improvement in blood pressure, lipid levels, and protein excretion is as important as optimal HbA1c levels (see table below). Unless contraindicated, all patients with type 2 diabetes should begin prophylactic aspirin therapy and have annual fundoscopic eye examinations (starting at the time of diagnosis) and regular checkups for peripheral neuropathy.

COMPLEX METABOLIC DISORDER

Type 2 diabetes is a complex metabolic disorder that results in significant morbidity and mortality. Improvement in metabolic control is essential to prevent long-term microvascular and macrovascular complications. Diet, exercise, home monitoring, smoking cessation, and lifestyle adjustments should be considered first-line therapy in all type 2 patients. If HbA1c levels do not improve with these measures, oral agents should be administered. Continuous glucose monitoring systems are helpful in tightening glycemic control and documenting the effects of antidiabetic agents on fasting and postprandial glucose levels. Most type 2 patients will eventually require insulin therapy.