. . . REPORTS. . .

Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings

Francis M. Collins, MD

Abstract ly 30%. The implications of these findings Diabetes mellitus affects approximately 17 mil- are profound in terms of long-term com- lion adults in the United States and has profound plications and their associated costs. Most implications in terms of long-term microvascular primary care providers and endocrinolo- and macrovascular complications and their associ- gists acknowledge that good glycemic con- ated costs. In type 2 diabetes, insulin resistance trol can prevent or at least delay many of and a relative β-cell defect are the underlying pathologic problems leading to hyperglycemia. the complications of diabetes. However, Notably, insulin resistance is also associated with prior to the Diabetes Control and 2 obesity, dyslipidemia, and hypertension. Diabetes Complications Trial (DCCT) and the can be defined as a disease of accelerated cardio- United Kingdom Prospective Diabetes vascular deterioration associated with elevated Study (UKPDS),3 limited evidence was blood glucose levels. Glycemic control has been available to support this belief. Earlier shown to reduce the long-term complications studies failed to show a significant preven- associated with diabetes. Although medical nutri- tive benefit, for the most part because the tion therapy and appropriately prescribed definitions of good glycemic control used increased physical activity are important compo- in the studies were set too high. Even for nents of a diabetes management plan, most those who believed that tight glycemic patients need medication to lower glucose to near- normal levels. Therapeutic options for treating control was beneficial, therapeutic choic- hyperglycemia include sulfonylureas and other es for monitoring and treating hyper- insulin secretagogues, biguanides, α-glucosidase glycemia were limited. inhibitors, thiazolidinediones, and insulin. An Today, many new therapies with differ- antidiabetic agent that improves insulin sensitivity ent mechanisms of action are available for is an excellent choice for early treatment of type 2 treating hyperglycemia in patients with diabetes because it may delay or prevent compli- type 2 diabetes mellitus, although the cations associated with this disease. Because of increase in therapeutic options also the progressive nature of type 2 diabetes, aggres- increases the complexity of decision mak- sive intervention early in the course of the disease, ing. In this article, the pathogenesis of type including combination therapy, is often necessary. 2 diabetes is reviewed and the advantages (Am J Manag Care. 2002;8:S460-S471) and disadvantages of the various antidia- betic drug classes are discussed to identify the appropriate role for each drug class.

iabetes mellitus affects approxi- . . . PATHOGENESIS OF TYPE 2 mately 17 million adults in the DIABETES. . . D United States, with the majority of these patients having type 2 diabetes mel- Type 2 diabetes mellitus is a complex, litus.1 In the past decade, the prevalence chronic, metabolic disease resulting from of diabetes has increased by approximate- insulin resistance in target tissues (prima-

S460 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2002 Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings rily adipose, muscle, and liver) and impaired β-cell function.4 Insulin resist- Table 1. Criteria for the Diagnoses of Diabetes, Impaired ance is an early measurable defect in the Fasting Glucose, and Impaired Glucose Tolerance majority of patients who are destined to develop type 2 diabetes and often pre- Diabetes ■ Plasma glucose level ≥200 mg/dL and symptoms of diabetes such cedes the onset of the disease by 1 to 2 as polyuria, polydipsia, or unexplained weight loss 5 decades. To compensate for the decrease OR in insulin-mediated glucose metabolism, ■ Fasting plasma glucose level ≥126 mg/dL the pancreas increases its secretion of OR ■ ≥ insulin. After a period of compensated 2-hour plasma glucose level 200 mg/dL during an oral glucose tolerance test (OGTT) insulin resistance, impaired glucose toler- β Impaired Fasting Glucose ance develops as -cell function begins to ■ Fasting plasma glucose level 110 mg/dL to 125 mg/dL decrease and insulin concentrations are Impaired Glucose Tolerance not sufficient to compensate for the ■ 2-hour plasma glucose level 140 mg/dL to 199 mg/dL during an insulin resistance, despite often continued oral glucose tolerance test (OGTT) above-normal insulin concentrations (ie, hyperinsulinemia). Ultimately, pancreatic Source: Reference 12. β-cell failure results in decreased insulin secretion. When these 2 defects, insulin resistance and β-cell failure, occur simul- taneously, hyperglycemia and overt clini- During the 1990s, several key studies cal type 2 diabetes result.6 demonstrated that lowering blood glucose Insulin resistance is strongly linked to levels in patients with diabetes significant- obesity, and insulin-resistant individuals ly reduced the incidence of microvascular exhibit pathophysiologic characteristics complications. The DCCT demonstrated such as dyslipidemia, hypertension, and that intensive treatment of patients with increased cardiovascular risk.7 Because of type 1 diabetes achieved a mean blood the association between insulin resistance glucose level of 155 mg/dL and hemoglo- and cardiovascular disease, medications bin A1c (HbA1c) level of 7.2%. The improve- that improve insulin resistance may be ment in glycemic control resulted in risk useful earlier in the treatment of type 2 reductions for retinopathy, nephropathy, diabetes.8 and neuropathy ranging from 35% to more than 70% compared with patients who 2 . . . were treated conventionally. In the IMPORTANCE OF GLYCEMIC UKPDS, the rate of microvascular compli- CONTROL. . . cations was decreased by 25% in patients Guidelines for the diagnosis of type 2 with type 2 diabetes who were treated diabetes and goals for control have intensively with a sulfonylurea, met- evolved over time. The first nearly univer- formin, or insulin compared with patients sally accepted definitions of diabetes were on conventional diet therapy.3,11 Intensive published in 1979 by the National therapy achieved a median HbA1c of 7.0%, Diabetes Data Group9 and in 1980 by the whereas conventional therapy resulted in 10 World Health Organization. At that a median HbA1c of 7.9%. The UKPDS data time, diabetes was defined as a fasting showed a continuous relationship between blood glucose concentration greater than blood glucose levels and the risks of 140 mg/dL, a 2-hour postprandial glucose microvascular complications; for each level greater than 200 mg/dL, or 2 random percentage point decrease in HbA1c the blood glucose levels greater than 200 risk for microvascular complications was mg/dL. These guidelines were somewhat reduced by 35%. conservative in part because of the belief More recent definitions of and guide- that labeling an individual as a diabetic lines for type 2 diabetes have been devel- might have adverse emotional, social, or oped and are focused on health financial consequences. maintenance and prevention of long-term

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Table 2. Guidelines for Glycemic Control for Individuals With Diabetes

Fasting Preprandial Postprandial Bedtime HbA1c (mg/dL) (mg/dL) (mg/dL) (mg/dL) (%)

Normal 70-100 <100 <140 <110 <6.0 ADA 80-110 80-120 <180 100-140 <7.0 ACE/AACE <110 <110 <140 — <6.5

ACE/AACE indicates American College of Endocrinologists/American Association of Clinical Endocrinologists;

ADA, American Diabetes Association; HbA1c, hemoglobin A1c. Sources: References 12, 13.

complications of diabetes (Table 1).12 One patients 45 to 75 years of age ranges from goal for glycemic control is to achieve 40% to 60%.14 The UKPDS demonstrated essentially normal, nondiabetic blood glu- that in patients with type 2 diabetes, inten- cose levels when fasting, before meals, and sive control of blood pressure (defined as at peak after meals (Table 2).12,13 <150/85 mm Hg) reduced all diabetes As our understanding of insulin resist- complications by 24%, deaths by 32%, ance and the pathogenesis of type 2 dia- strokes by 44%, heart failure by 56%, and betes has evolved, so have treatment microvascular complications by 37%.11 goals. Indeed, appreciation of the impor- This study found that each 10-mm Hg tance of control of hypertension and lipid decrease in mean systolic blood pressure metabolism as part of diabetes manage- was associated with a 12% risk reduction ment is very recent. Today, type 2 dia- for any diabetes-related complication. betes can be defined as a disease of The Joint National Committee on accelerated cardiovascular deterioration Prevention, Detection, Evaluation, and associated with elevated blood glucose Treatment of High Blood Pressure recom- level. With the advent of home glucose mends that blood pressure be less than monitoring and with the availability of 130/85 mm Hg.15 The American Diabetes newer agents for control of type 2 diabetes Association recently recommended that mellitus and associated conditions, many individuals with type 2 diabetes decrease patients are now able to achieve and blood pressure to less than 130/80 mm Hg maintain improved glycemia, blood pres- (Table 3).16 sure, and lipid levels, which should In the UKPDS, both a β-blocker markedly decrease risk for both microvas- (atenolol) and an angiotensin-converting cular and macrovascular complications. enzyme (ACE) inhibitor (captopril) Nevertheless, a concerted effort must be effectively reduced blood pressure.11 made by the patient, his or her family, and Treatment with an ACE inhibitor also numerous healthcare professionals to sus- has a favorable effect on microvascular tain long-term control. Third-party payers and cardiovascular outcomes in patients are beginning to realize that aggressive with diabetes.17 Recent data indicate that medical intervention and monitoring are angiotensin-receptor blockers (ARBs) needed to achieve long-term benefits of also provide similar beneficial effects.18-20 normalization of metabolic abnormalities Currently, the American Diabetes Associ- associated with type 2 diabetes. ation recommends ACE inhibitors, ARBs, β-blockers, or diuretics as initial drug therapy for hypertension.16 If the patient . . . BLOOD PRESSURE CONTROL. . . has microalbuminuria or clinical albumin- Hypertension is common in patients uria, an ACE inhibitor or an ARB is pre- with type 2 diabetes; the prevalence in ferred because of the ability to slow the

S462 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2002 Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings development and progression of diabetic nephropathy.21 Table 3. Goals for Blood Pressure and Lipid Levels for Adults with Diabetes

. . . DYSLIPIDEMIA MANAGEMENT. . . Parameter Goal

Insulin resistance in adipose tissue Blood pressure (mm Hg) leads to the development of a character- Systolic <130 istic atherogenic lipid profile in individu- Diastolic <80 als with type 2 diabetes. Patients exhibit Triglycerides (mg/dL) <150 a pattern of lipid abnormalities that includes elevated levels of plasma HDL cholesterol (mg/dL) triglycerides, low levels of high-density Men >45 lipoprotein (HDL) cholesterol, and an Women >55 increased number of small, dense low- LDL cholesterol (mg/dL) <100 density lipoprotein (LDL) particles,22 each of which is an independent risk fac- tor for cardiovascular disease.23,24 HDL indicates high-density lipoprotein; LDL, low-density Diabetes is regarded as a coronary heart lipoprotein. disease equivalent and significantly Sources: References 12, 16. increases the risk for developing cardio- vascular disease.25 Lipid management of patients with type ing lipid profiles leads to reductions in 2 diabetes should be directed at lowering adverse cardiovascular outcomes. LDL cholesterol and triglyceride levels and raising HDL cholesterol levels to . . . EFFECT OF DIET AND EXERCISE. . . reduce macrovascular complications (Table 3).12,16 Management of lipids can be Medical nutrition therapy and exercise accomplished by diet, weight loss, exer- are essential components in the manage- cise, glycemic control and, if needed, ment of diabetes. For some patients, med- pharmacologic therapy.12 In several inter- ical nutrition therapy, weight reduction, vention trials, patients with diabetes who and increased physical activity may were treated with statins achieved signifi- improve hyperglycemia, hypertension, cant reductions in cardiovascular and dyslipidemia and reduce the risk for events.26-28 The Cholesterol And Recurrent cardiovascular disease. In patients with Events (CARE) trial demonstrated that diabetes, physical activity has been shown lowering cholesterol with pravastatin to increase muscle glucose uptake, reduced the relative risk of coronary decrease insulin resistance, and decrease events by 25% in patients with diabetes.26 serum triglyceride levels.30,31 Current evi- Similarly, the Scandinavian Simvastatin dence indicates that lifestyle modifica- Survival Study (4S) evaluated the effect of tions, such as improving diet and lowering cholesterol with simvastatin on increasing physical activity, lead to bene- mortality and morbidity in patients with fits in patients with impaired glucose coronary heart disease. A subgroup of 202 tolerance and may decrease the incidence patients with diabetes had a 55% reduc- of developing diabetes. The Diabetes tion in occurrence of a major coronary Prevention Program Research Group heart disease event compared with a 32% evaluated the effects of placebo, met- reduction in patients who did not have formin, or lifestyle modification in 3234 diabetes.28 Data from the Veterans Affairs individuals with impaired glucose toler- High-Density Lipoprotein Cholesterol ance.32 At the end of the 2.8-year study, Intervention trial showed that increasing the incidence of diabetes was 58% lower HDL cholesterol levels and lowering in the lifestyle group and 31% lower in triglyceride levels also reduced the risk for the metformin treatment group com- cardiovascular events.29 Clearly, improv- pared with the placebo group. Thus,

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lifestyle changes are beneficial in all does not adequately lower blood glucose individuals, including those with or at risk levels, treatment with an oral pharmaco- for diabetes. logic antidiabetic agent usually becomes For some individuals with type 2 dia- necessary. During the past 6 years, the betes, particularly early in the course of number of distinct classes of oral antidia- the disease, a prudent diet and regular aer- betic agents has increased 5-fold.33 obic exercise may be all that is necessary Currently, the choices of oral agents to achieve good glycemic control or even available for lowering blood glucose to normalize blood glucose levels. include thiazolidinediones (TZDs), sul- However, in the natural history of type 2 fonylureas and other insulin secreta- diabetes mellitus, as insulin resistance gogues, biguanides, and α-glucosidase continues and the pancreas begins to fail, inhibitors (Table 4).33 diet and exercise alone become insuffi- cient. For most of these patients, medica- TZDs tion is necessary to lower glucose to TZDs are an exciting newer class of near-normal levels. antidiabetic agents. They are potent, selective agonists of peroxisome prolifera- ...... tor-activated receptor (PPAR) gamma. GAINING GLYCEMIC CONTROL The PPARs are primarily located in skele- When nonpharmacologic therapy, tal muscle, liver, and adipose tissue.34,35 including diet, weight loss, and exercise, PPARs also play a role in fatty acid metab-

Table 4. Oral Hypoglycemic Agents Available in the United States

Mechanism Hemoglobin Indication Category Agent of action A1C reduction (FDA approval status)

Thiazolidinediones Rosiglitazone Pioglitazone Insulin sensitizer 1% to 2% Monotherapy Combination with metformin, sulfonylureas insulin (pioglitazone only in combina- tion with insulin) Selected sulfonylureas Chlorpropamide Insulin secretagogue 1% to 2% Monotherapy Tolbutamide Glimepiride Combination with metformin, Glipizide GITS thiazolidinedione, Glyburide α-glucosidase inhibitor, insulin Other insulin Repaglinide Insulin secretagogue 0.6% to 2% Monotherapy secretagogues Nateglinide Combination with metformin Biguanides Metformin Decreased hepatic 1% to 2% Monotherapy glucose output Combination with sulfonylurea, other insulin secretagogue, thiazolidinediones, insulin α-Glucosidase inhibitor Acarbose Delayed glucose 0.5% to 1% Monotherapy Miglitol absorption Combination with sulfonylurea

FDA indicates Food and Drug Administration. Source: Reference 33.

S464 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2002 Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings olism and appear to have beneficial effects abnormalities, defined as an alanine on vascular endothelium unrelated to glu- aminotransferase (ALT) level elevation cose or lipid metabolism.22 of more than 3 times the upper limit of The principal function of TZDs in dia- normal, was 0.32%, which is compara- betes management is the sensitization of ble to that seen in placebo-treated target tissues to the effects of insulin. patients (0.17%).41 Very low rates of liver Unlike secretagogues, which stimulate abnormalities also have been observed insulin release, the TZDs improve insulin in patients treated with pioglitazone.42 sensitivity, thereby enhancing the effec- Hepatotoxicity associated with troglita- tiveness of endogenous and exogenous zone has been suggested to be related to insulin.34 Endogenous insulin concentra- properties specific to that molecule, such tions are usually reduced by TZDs. The 2 as side chains or the metabolic pathway, presently available TZDs, rosiglitazone and not to the common thiazolidine-2,4- and pioglitazone, improve glycemic con- dione structure shared by rosiglitazone 40 trol and generally lower HbA1c levels as and pioglitazone. much as a sulfonylurea or metformin.33 TZDs, alone or in combination with Rosiglitazone and pioglitazone are effec- other agents, may cause fluid retention. tive when used as monotherapy and may Because of this, patients with heart failure be administered in combination with should be observed for signs and symp- metformin or sulfonylureas to further toms of worsened cardiac status; patients 32 reduce blood glucose and HbA1c levels. with New York Heart Association class III In addition to their ability to decrease or IV cardiac status should not receive insulin resistance and lower glucose and TZDs. In addition, therapy with a TZD insulin concentrations, TZDs offer other can cause weight gain of an extent similar benefits for patients with type 2 diabetes. to that observed with older sulfonylureas. TZDs are associated with favorable effects The increased weight may primarily on lipids, including an increase in HDL involve an increase in peripheral subcuta- cholesterol and reductions in triglyceride neous fat with a decrease in abdominal and free fatty acid levels. The TZDs also (visceral) fat.43,44 Such an effect may have reduce blood pressure and appear to important beneficial implications given reduce atherosclerotic risk factors the association between abdominal fat, through several mechanisms.22 insulin resistance, and cardiovascular disease.45 Limitations and Long-term Safety of Thiazolidinediones. The TZDs have a Sulfonylureas and Other low incidence of adverse effects and are Insulin Secretagogues generally well tolerated. TZDs are associat- Sulfonylureas are the oldest of the oral ed with minimal risk for hypoglycemia antidiabetic agents. Sulfonylureas stimu- because they do not stimulate insulin late insulin release by binding to the sul- secretion.36 Troglitazone, the first TZD to fonylurea receptor on pancreatic β cells be approved for clinical use, was with- and increasing basal and postprandial drawn from the market because of a rare insulin secretion. Some studies have sug- and potentially fatal idiosyncratic hepato- gested that sulfonylureas may enhance toxicity. Because of this, liver enzyme lev- peripheral sensitivity to insulin, although els should be measured before initiating most investigators believe that this is most therapy with a TZD, every 2 months for likely caused by improvement in glucose the first year of therapy, and then period- toxicity.33,46 Current agents are equally effi- ically thereafter.36-39 However, recent data cacious when administered in equipotent suggest that hepatotoxicity is not a class doses; sulfonylurea therapy leads to a mean effect.40 In clinical trials, more than decrease of approximately 1% to 2% in 33 6000 patients received rosiglitazone for HbA1c. The principal differences among 6 months or longer. In these rosiglitazone- the sulfonylureas are duration of action treated patients, the incidence of liver and metabolism. Most sulfonylureas are

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approved for use as monotherapy and in duration of activity of the nonsulfonylurea combination with insulin, as well as all secretagogues suggests that these agents other oral agents except nonsulfonylurea might cause less frequent and less severe secretagogues. hypoglycemia than occurs with some of Two nonsulfonylurea insulin secreta- the sulfonylureas. Notably, the prevalence gogues are available: repaglinide and of hypoglycemia is particularly important nateglinide. Because neither is a sul- in elderly patients who are already at an fonylurea, these agents can be used in the increased risk for adverse sequelae. In a sulfa- or sulfonylurea-allergic patient. Both population-based study of 19 932 patients repaglinide and nateglinide are taken 65 years of age or older, 586 patients expe- before meals and primarily affect post- rienced a serious hypoglycemic event prandial glucose levels. The mechanism of involving hospitalization, emergency action of these agents is very similar to department admission, or death during that of sulfonylureas; however, they are 33 084 person-years of treatment.50 distinguished by their short metabolic half- Studies have shown that death occurs in lives. Although both repaglinide and approximately 5% of patients with dia- nateglinide are rapid-acting insulin secreta- betes who are hospitalized for medication- gogues, they differ in their pharmacodynam- mediated hypoglycemia.51 ic effects. Repaglinide rapidly stimulates These agents do not appear to cause insulin secretion by the pancreas in a dose- long-term toxicity. More than 3 decades dependent manner. Insulin release is glu- ago, the University Group Diabetes Project cose dependent and diminishes at low reported that treatment with a sulfonylurea, glucose concentrations.47 Nateglinide has a tolbutamide, increased the risk for cardio- more rapid onset of action and shorter vascular mortality, and a long-standing class duration of action than repaglinide, which warning has existed for all sulfonylureas.52,53 may result in lower meal-related glucose Subsequent studies have not confirmed excursions compared with repaglinide and this finding, and in the more recent placebo.48 The efficacy of repaglinide is UKPDS, increased mortality was not shown similar to that of the sulfonylureas. Studies in patients treated with sulfonylureas.3 of nateglinide may suggest somewhat less Hypoglycemia and weight gain may be less 33 efficacy at lowering HbA1c. The nonsul- frequent with the use of the newer sulfony- fonylurea secretagogues are approved for lureas glipazide GITS and glimepiride. use as monotherapy and in combination with metformin. Biguanides Currently, metformin is the only Limitations and Long-term Safety of biguanide available in the United States. Insulin Secretagogues. All agents that Phenformin, the first biguanide, was stimulate release of endogenous insulin removed from the market in the 1970s can cause weight gain and hypoglycemia. because of the risk for lactic acidosis. In This is a direct result of the increase in contrast to the sulfonylureas, metformin insulin production. Weight gain is typical- does not stimulate insulin secretion. ly more pronounced with sulfonylureas Although the precise mechanism of action than with the other insulin secretagogues. of metformin is still debated, decreased Weight gain typically ranges from 2 to 5 hepatic gluconeogenesis is thought to be kg and can be especially problematic in the primary therapeutic effect of met- patients with type 2 diabetes, many of formin in type 2 diabetes.33,54 3 whom are already overweight. Metformin decreases HbA1c levels by The potential for clinically significant approximately 1% to 2%. In comparative hypoglycemia with sulfonylureas, particu- trials, metformin and sulfonylureas appear larly with use of the longer-acting agents, equivalent in their ability to lower glu- chlorpropamide and glyburide, limits their cose.33 Metformin rarely causes hypo- usefulness in certain patients with type 2 glycemia because it does not significantly diabetes.49 The rapid action and short change insulin concentrations. In addition,

S466 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2002 Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings metformin decreases triglyceride, total, inhibition of the intestinal enzyme α-glu- and LDL cholesterol levels and decreases cosidase.58-60 By blocking this enzyme in free fatty acid oxidation.46 Data from the the proximal bowel, disaccharide, oligosac- UKPDS also suggested that treatment with charide, and polysaccharide absorption is metformin leads to reductions in delayed so that the increase in postpran- macrovascular complications.3,11 Metformin dial glucose levels is lessened. The 2 is approved for use as monotherapy and in presently approved α-glucosidase inhibitors combination with insulin, sulfonylureas, are acarbose and miglitol. nonsulfonylurea secretagogues, and TZDs. The α-glucosidase inhibitors generally

lower HbA1c levels by approximately 0.5% Limitations and Long-term Safety of to 1%, making them less effective than sul- Biguanides. Lactic acidosis is a rare but fonylureas, metformin, or TZDs. However, potentially fatal adverse effect associated the α-glucosidase inhibitors are appealing with metformin and can be caused by drug because they lower postprandial glucose accumulation. The estimated incidence levels by a mechanism that does not of lactic acidosis with metformin is 1 per require systemic absorption, and they do 30 000 patient-years, approximately 100 not cause hypoglycemia or weight gain.33 times less than that with phenformin ther- They are approved for use as monothera- apy.55,56 The risk for lactic acidosis may be py and in combination with sulfonylureas. minimized by strictly following prescrib- Fat absorption can be reduced with ing guidelines. However, a recent study orlistat,61 an intestinal lipase inhibitor noted that many patients continue to developed for long-term management of receive metformin despite having con- obesity. Orlistat improves glycemic control traindications, such as elevated serum by limiting calorie intake and absorption, creatinine concentration, that increase the and it may have other important effects on risk for development of lactic acidosis.57 lipid metabolism. Currently, this agent is Because of its almost exclusive renal only approved for weight reduction. route of excretion, metformin must not be used in people with any degree of renal Limitations and Long-term Safety of impairment (serum creatinine level ≥1.4 Calorie-Absorption Blockers. Because mg/dL in women or ≥1.5 mg/dL in men). α-glucosidase inhibitors and lipase inhibitors Other contraindications to metformin are not systemically absorbed, they appear therapy include metabolic acidosis or a to have few, if any, long-term consequences condition in which there is a high risk for that are not directly related to their mech- acidosis, including but not limited to anism of action. Adverse gastrointesti- dehydration, hepatic impairment, diabetic nal effects associated with α-glucosidase ketoacidosis, sepsis, acute congestive inhibitors occur in approximately 30% of heart failure, cardiogenic shock, or acute patients and include increased intestinal myocardial infarction. Metformin should gas formation, loose stools, and abdominal be used with caution in patients older discomfort.46 Although the α-glucosidase than 75 years of age. inhibitors are approved for use as monotherapy in patients with type 2 dia- Calorie-Absorption Blockers betes, they are rarely used alone because Diet and exercise limit weight gain or of their limited ability to reduce overall increase weight loss by decreasing caloric glucose levels. Malabsorption of certain intake and increasing caloric expenditure, nutrients, particularly fat-soluble vitamins respectively. In addition, 2 therapeutic and any fat-soluble medications, is a pon- classes of medications that limit calorie tential problem with orlistat.61 absorption can be used in the management of type 2 diabetes: carbohydrate blockers Insulin and fat blockers. Insulin therapy is indicated in patients Absorption of complex carbohydrates with type 2 diabetes who present with can be delayed and partially prevented by severe hyperglycemia or who continue to

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have hyperglycemia despite adequate in cartridge and pen systems. Alternative treatment with oral antidiabetic agents.62 delivery systems are being actively The UKPDS data suggest that eventually explored. The most promising of these are almost everyone with type 2 diabetes inhaled immediate-acting insulin delivery treated with diet, sulfonylureas, or met- systems, which will provide a time course formin will need insulin because of the similar to insulin lispro or insulin aspart progressive nature of the disease.63 Over and eliminate the need for needle and time, the ability of the pancreas to secrete syringe.68,69 Another rapid- to intermedi- insulin diminishes, resulting in the β cell ate-acting insulin is a buccal delivery sys- simply not secreting enough insulin. At tem. Options being explored for basal or that point in time, exogenous insulin long-acting insulin include an insulin administration becomes necessary. Both patch and oral insulin. The effectiveness patients and physicians have a significant and availability of these alternative deliv- degree of reluctance to initiate insulin ery methods remain to be seen. therapy. Psychological barriers encom- pass both the act of injection and the fear ...... on the patient’s part that the diabetes has COMBINATION THERAPY gotten worse. Newer insulin preparations Because of the pathogenesis of type 2 and delivery systems may help overcome diabetes, which involves both insulin some of these barriers. Moreover, prelimi- resistance and at least a relative β-cell nary studies suggest that early use of TZDs deficiency, combination therapy for opti- may be able to preserve pancreatic β-cell mal glycemic control of patients with this function and therefore may delay or elim- disease is a logical and often necessary inate the need for insulin in some approach. Over time, patients who ini- patients.64 tially respond to monotherapy often Almost all insulin in use today is pro- require the addition of another antidia- duced by recombinant DNA technology. betic agent to reduce hyperglycemia.46,63 Insulin from animal sources has been Addition of a second oral agent from a essentially eliminated because of increased different class improves glycemic control purity and specificity of synthetic insulin. and demonstrates an additive reduction

Currently, several modified insulin in HbA1c. The most frequently used oral analogs are available, and all of them have combinations include a TZD with a sul- 1 or more amino acid substitutions or fonylurea, a sulfonylurea with met- additions that provide for more tailored formin, and a TZD with metformin.33 activity profiles.65-67 Insulin lispro and Currently, no evidence indicates that insulin aspart are rapid-onset, short-dura- any specific combination is more effec- tion insulins. Insulin glargine is an insulin tive than another in its ability to lower analog with a very prolonged duration of glucose levels. Although not approved by action and flat activity curve. Several the US Food and Drug Administration, other similar insulin preparations are in the triple combination of a TZD, met- early clinical development. formin, and a sulfonylurea improved Premixed insulins, such as 70/30 glycemic control in 1 placebo-controlled human insulin, 50/50 human insulin, and study.70 75/25 insulin lispro protamine/insulin Because TZDs improve insulin resist- lispro can be useful in some patients with ance, a fundamental defect underlying type 2 diabetes who require insulin. type 2 diabetes, using a TZD early in the However, administration of the basal and management of patients with this disease prandial or mealtime insulins as separate may be reasonable. In some cases, using a components has the potential to achieve TZD in combination with either met- better glycemic control. The mixtures, formin or a sulfonylurea, medications that along with other insulin preparations such have different mechanisms of action, may as human NPH, regular, extended zinc be necessary. The additive effect of a TZD suspension, and lispro, are also available in combination with metformin or a sul-

S468 THE AMERICAN JOURNAL OF MANAGED CARE OCTOBER 2002 Current Treatment Approaches to Type 2 Diabetes Mellitus: Successes and Shortcomings fonylurea has been demonstrated numerous tality associated with this disease. Until clinical trials.70-74 recently, many patients have fallen short Insulin therapy is often effective in of these treatment goals because of a vari- patients with type 2 diabetes who are not ety of factors, including medication side adequately controlled with oral agents effects, as well as lack of adherence and alone or in combination.46 A significant understanding of both patients and physi- number of individuals receiving oral cians. New therapeutic options are now antidiabetic therapy have elevated fasting available, and aggressive intervention glucose levels but are essentially normo- may prevent or delay the onset of glycemic during the day. In these patients, microvascular and macrovascular compli- the oral antidiabetic agent contributes to cations. The TZDs are an exciting newer adequate meal-stimulated insulin secre- class of antidiabetic agents that, in addi- tion, but suppression of hepatic gluconeo- tion to effectively lowering glucose levels, genesis is inadequate overnight. In these improve insulin resistance, lipid profiles, cases, a modest dose of an intermediate- and blood pressure. or long-acting insulin (such as human NPH, zinc suspension, extended zinc sus- ...... pension, or insulin glargine) at bedtime is REFERENCES beneficial.46 Insulin may be coadminis- 1. Harris MI, Flegal KM, Cowie CC, et al. Prevalence tered with oral antidiabetic agents.33,46,75 of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults: the Third National Health and Nutrition Examination Survey, 1988-1994. . . . CONCLUSION. . . Diabetes Care. 1998;21:518-524. 2. The Diabetes Control and Complications Trial Type 2 diabetes is a complex and cost- Research Group. The effect of intensive treatment of diabetes on the development and progression of long- ly disorder. In the treatment of type 2 dia- term complications in insulin-dependent diabetes betes, the most important principle to mellitus. N Engl J Med. 1993;329:977-986. consider is total metabolic management 3. UK Prospective Diabetes Study (UKPDS) Group. of the patient. To date, the management Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and of diabetes has not been well focused on risk of complications in patients with type 2 diabetes primary prevention of cardiovascular (UKPDS 33). Lancet. 1998;352:837-853. complications. Diabetes is a disease of 4. Ferrannini E. Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes melli- accelerated cardiovascular deterioration tus: problems and prospects. Endocr Rev. 1998;19: associated with elevated blood glucose 477-490. level. Often, attention is given to these 5. Warram JH, Martin BC, Krolewski AS, Soeldner areas only after a cardiovascular event has JS, Kahn CR. Slow glucose removal rate and hyperin- sulinemia precede the development of type II diabetes occurred. Optimal treatment requires in the offspring of diabetic parents. Ann Intern Med. proactive and preventive management of 1990;113:909-915. the complications and associated condi- 6. DeFronzo RA, Bonadonna RC, Ferrannini E. tions, such as hyperglycemia or hypo- Pathogenesis of NIDDM: a balanced overview. Diabetes Care. 1992;15:318-368. glycemia, hypertension, dyslipidemia, 7. Bloomgarden ZT. Insulin resistance: current con- vascular abnormalities, sedentary lifestyle, cepts. Clin Ther. 1998;20:216-231. and poor diet. 8. DeFronzo RA, Ferrannini E. Insulin resistance: a For many patients, the initial diagnosis multifaceted syndrome responsible for NIDDM, obe- sity, hypertension, dyslipidemia, and atherosclerotic of diabetes or dyslipidemia comes at the cardiovascular disease. Diabetes Care. 1991;14: time of a first myocardial infarction or 173-194. after undergoing coronary artery bypass 9. National Diabetes Data Group. Classification and surgery. Increased awareness of risk fac- diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes. 1979;28:1039-1057. tors for type 2 diabetes and early screen- 10. WHO Expert Committee on Diabetes Mellitus. ing of persons at high risk are needed. WHO Expert Committee on Diabetes Mellitus These steps, along with more aggressive second report. Geneva, Switzerland: World Health Organization; 1980. Technical Report Series, treatment to goal levels for glucose, No. 646. blood pressure, and lipids, will be neces- 11. UK Prospective Diabetes Study (UKPDS) Group. sary to decrease the morbidity and mor- Tight blood pressure control and risk of macrovascu-

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