John E. Sutherland, MD

Glycemic control in diabetes begins with a patient’s adherence to several nonpharmacologic measures. Without such a commitment, success in controlling the disease will be difficult to achieve, and otherwise appropriate drug therapy will be hindered.

Most antidiabetic agents comparably reduce glycosylated hemoglobin (A_1c) levels. However, a particular agent may be preferred depending on a patient’s characteristics. And some circumstances call for combination therapy. This article reviews the advantages and disadvantages of the many pharmacologic treatments for glucose control and hyperglycemia in type 2 diabetes.

Benefits Of Diabetes Control

The benefits of diabetes control are detailed in this issue of THE JOURNAL OF FAMILY PRACTICE (“Strategies to reduce complications in type 2 diabetes,” pages 366–374). For every percentage-point reduction in hemoglobin A_1c, it is possible to achieve a 22% to 35% reduction in microvascular complications.^1,2 Cardiovascular disease can be reduced in patients with diabetes by treating hypertension^3,4 and hyperlipidemia, prescribing aspirin therapy, using angiotensin-converting enzyme (ACE) inhibitors, and with smoking cessation.^5,6

Targets For Glycemic Control

The American Diabetes Association’s (ADA) recommended targets for glycemic control are a preprandial blood glucose level of 80–120 mg/dL, a bedtime blood glucose level of 100–140 mg/dL, and a hemoglobin A_1c level of <7% (with a level of >8% requiring additional measures). Hemoglobin A_1c is the best determinant of glycemic exposure, and its mean value is a nationally recognized indicator of how well diabetes is being managed.⁷ The American College of Endocrinology has adopted a more aggressive approach by designating an A_1c level of 6.5% as both a target and action level.⁸

Self-monitoring of blood glucose

Self-monitoring of blood glucose (SMBG) is an integral component of diabetes therapy (strength of recommendation [SOR]: C) and should always be included in the management plan (SOR: C). The optimal frequency and timing of SMBG for type 2 diabetes is not known, but they should be sufficient to facilitate reaching glucose goals. The A_1c test should be performed at least semi-annually for patients with stable glycemic control, and quarterly for patients not meeting glycemic goals or those who are changing therapy. A_1c levels and mean plasma glucose levels can be approximately correlated (Table 1).⁷

TABLE 1
Correlation between hemoglobin A_1clevels and mean plasma glucose levels

Nonpharmacologic Therapy

Nonpharmacologic measures remain the cornerstone of managing type 2 diabetes. Hyperglycemia adversely and reversibly affects both insulin resistance and insulin secretion. Improvement in glycemic control can occur through dietary modification and regular exercise.

A recent meta-analysis of randomized controlled trials of diabetes patient education observed a net decrease in HbA_1c of 0.32% in intervention groups vs control.⁹ Interventions that included a face-to-face delivery, cognitive reframing teaching method, and exercise content were more likely to improve glycemic control.

Education

Lifestyle changes involving diet, exercise, and usually weight loss are key to effective management of diabetes. If patients are to change their behavior, they must be given detailed training.⁶ Self-management also necessitates that patients engage in problem solving. This requires that each aspect of the management plan is understood and agreed upon by the patient and providers, and that the goals and treatment plan are individualized and reasonable.

Diet: recommend soluble fiber, reduce calories

Medical nutrition therapy should be individualized and preferably provided by a registered dietitian familiar with diabetes (SOR: B). The goals of nutrition therapy, according to the ADA, are to attain recommended body weight and prevent or reverse obesity. The means of achieving these goals are nutrition assessment and modification of nutrient intake and lifestyle through healthy food choices and physical activity.⁷

A high intake of dietary fiber (particularly the soluble type) above the level recommended by the ADA improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations.¹⁰

Hypocaloric diets cause glucose plasma levels to fall, in some cases to a normal level with a weight loss of even 5 to 10 pounds.^7,11 Hypoglycemic medications are of course most effective in nonobese persons. But effectiveness is also improved if weight that is gained can be limited. Despite the clear benefit of weight loss, only a few patients are able to attain and maintain substantial weight loss. Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of body weight that is different from the usual weight.¹³ Part of the individualization of therapy is respect of personal and cultural preferences, lifestyles, and financial considerations.

Physical activity: a little goes a long way

A regular physical activity program is recommended for all patients with diabetes who are capable of participating (SOR: B).⁷ It improves blood glucose control, reduces cardiovascular risk factors, aids weight loss, and enhances well being.⁷ A recently published prospective cohort study showed that walking at least 2 hours a week was associated with a 39% lower all-cause mortality (hazard rate ratio [HRR], 0.61; 95% CI, 0.48–0.78) and a 34% lower cardiovascular mortality (HRR, 0.66; 95% CI, 0.45–0.96) across a diverse spectrum of adults with diabetes. The NNT (to prevent 1 death per year) is 61 for patients who walk at least 2 hours/week.¹⁴

In prescribing a physical activity plan for a patient, consider cardiovascular disease risk factors or complications to minimize the risk of untoward events. Micro- and macrovascular disease are of course prevalent among persons with diabetes, often resulting in functional limitations that make exercise more difficult.

Other priorities

Other recommended components of care include daily aspirin use, foot care exams, tobacco cessation, pneumococcal and influenza vaccinations, and an annual dilated retinal exam.

Pharmacologic Therapy

The coexisting defects in type 2 diabetes mellitus are as follows:

• resistance to insulin action in muscle
• defective pancreatic insulin secretion
• unrestrained hepatic glucose production, aggravated by increased lipolysis in adipose tissue.

Drug therapy is aimed at each of these defects, and also at reducing carbohydrate absorption in the small intestine (Figure 1). As far as antihyperglycemic effect is concerned, no one category of antidiabetic agent is favored over another.¹⁵ Except for nateglinide and α-glucosidase inhibitors (AGIs), each of the drug categories leads to a similar reduction in A_1c.¹⁶ However, patient characteristics may lead to selection of a particular agent. Table 2 summarizes oral treatment options, their relative advantages and costs.

FIGURE 1
Drug therapies for coexisting defects in type 2 diabetes

TABLE 2
Pharmacologic treatments for type 2 diabetes: monotherapies

Sulfonylureas

Sulfonylureas directly increase insulin secretion by binding to the sulfonylurea receptor on pancreatic beta cells; they provide a relatively quick onset of action. First-generation sulfonylureas (eg, tolbutamide, chlorpropamide) and second-generation sulfonylureas (eg, glyburide, glipizide, glimepiride) are equivalent in their maximum hypoglycemic effect.¹⁷

Second-generation agents are used more commonly than first-generation. They all contain the sulfonylurea moiety, but different chemical substitutions in the basic molecule change pharmacokinetics, resulting in different durations of action.¹⁷ Second-generation agents are probably safer than first-generation drugs, being less likely to cause hyponatremia, disulfiram-like reactions, or prolonged hypoglycemia.¹⁸

At maximal doses, sulfonylureas lower A_1c levels by 1–2 percentage points and fasting plasma glucose concentrations by 60–70 mg/dL;¹⁵ however, the glucose lowering effect typically plateaus after half the maximal recommended dose is reached. Sulfonylureas have no consistent effect on dyslipidemia. In UK Prospective Diabetes Study (UKPDS) 33, though improved glycemic control with sulfonylureas (or insulin) led to a 25% reduction in microvascular endpoints (mostly less retinal photocoagulation) (P<.01), sulfonylureas (or insulin) did not significantly reduce death or all-cause mortality compared with diet treatment.²

Adverse effects. The primary adverse effects of sulfonylureas are weight gain and hypoglycemia. In UKPDS 33, weight gain at 10 years was 2.6 kg (99% confidence interval [CI], 1.6–3.6) with chlorpropamide and 1.7 kg (99% CI, 0.7–2.7) with glyburide, compared with patients receiving diet therapy (each P<.001).² In the same study, the rate of major hypoglycemic episodes (third-party help or medical intervention necessary) while on therapy was 0.4%/year for chlorpropamide and 0.6%/year for glyburide, compared with 0.1%/year for diet.

Glyburide and chlorpropamide have active metabolites with renal elimination, and they should therefore be used with caution in patients with renal insufficiency. In 1971, the University Group Diabetes Project (UGDP) observed a twofold increase in the rate of cardiovascular death among patients receiving tolbutamide compared with those receiving insulin or placebo.¹⁸ This led to a decades long debate on the validity of this conclusion.¹⁹ More recently, UKPDS 33 did not demonstrate any increased cardiovascular mortality among patients receiving glyburide or chlorpropamide, and has largely negated this earlier concern.²

Cost. Sulfonylureas are the least expensive oral agents used to treat type 2 diabetes.

TABLE 3
Pharmacological treatments for type 2 diabetes: combination therapies

Non-sulfonylurea secretagogues

Like sulfonylureas, the non-sulfonylurea secretagogues (non-SU), repaglinide and nateglinide, stimulate beta cells to increase insulin secretion. However, the non-SU agents mediate their action through a different, adjacent site on the “sulfonylurea receptor.” Comparatively, the non-SU agents have a faster onset of action (20 minutes), shorter half-life (about 1.0–1.5 hours), and greater effects on postprandial glucose excursions than do sulfonylureas.²⁰ In contrast to the sulfonylureas, the extent of insulin release with non-SU agents is glucose dependent, and therefore they may have less risk of hypoglycemia several hours after meals.¹⁵

Repaglinide lowers the A_1c level by 1.7–1.9 percentage points, similar in efficacy to sulfonylureas. Nateglinide appears somewhat less efficacious and lowers A_1c by 0.6–1.0 percentage points.¹⁵ Nateglinide was significantly less effective than glyburide at lowering A_1c levels and the fasting plasma glucose in one 24-week study. Non-SUs added to sulfonylureas produce no additional benefit in glycemic control. The effect of non-SUs on microvascular or macrovascular endpoints is unknown.

Adverse effects. Hypoglycemia is the primary adverse effect of non-SUs. Confirmed hypoglycemia (plasma glucose <60 mg/dL) was observed in 2.4% of patients taking nateglinide compared with 0.4% of those receiving placebo. Mild or moderate hypoglycemia occurred in 16% of repaglinide patients, 20% of glyburide patients, and 19% of glipizide patients in one-year comparative studies. Further comparative studies are needed to determine if non-SUs produce significantly less hypoglycemia and weight gain than sulfonylureas.

Cost. Non-SUs must be dosed 3 times daily at the start of meals. One relative disadvantage is their increased cost compared with sulfonylureas.

Biguanides

The only biguanide marketed in the US is metformin. Its primary action is to inhibit hepatic glucose production and, to a much lesser extent, enhance insulin sensitivity in peripheral tissues.²¹ Metformin does not stimulate insulin secretion and does not cause hypoglycemia when used as monotherapy, but it can potentiate hypoglycemia in combination with insulin or insulin secretagogues.

Metformin is similar in efficacy to the sulfonylureas. It lowers A_1c by 1.5–2.0 percentage points and fasting plasma glucose by 60–80 mg/dL. Its antihyperglycemic efficacy is independent of patient age, duration of diabetes, or BMI.²²

In the UKPDS 34 study, a subgroup of obese patients was randomized to receive intensive control (group 1, metformin; group 2, a sulfonylurea or insulin) or conventional diet therapy (group 3). Despite a similar reduction in the A_1c level between the 2 intensive-treatment groups, patients treated with metformin had a 32% reduction for any diabetes-related endpoint (95% CI, 13–47; P=.002), 43% fewer diabetes-related deaths (95% CI, 9–63; P=.017), and a 36% reduction in all cause mortality, compared with the diet therapy group (95% CI, 9–55; P=.011).²³

Metformin also showed significant benefit when compared with patients receiving sulfonylurea or insulin (group 2). The absolute risk of any diabetes endpoint was 29.8 vs. 40.1 (events per 1000 patient-years; P=.0034), all-cause mortality (13.5 vs 18.9; P=.021), and stroke (3.3 vs 6.2; P=.032), respectively, for metformin vs sulfonylurea or insulin (group 2). Thus, metformin is the only oral hypoglycemic agent proven to reduce macrovascular risk in overweight patients with type 2 diabetes. For perspective, in overweight patients, metformin significantly reduced all-cause mortality (NNT per year=141; 95% CI, 115–183; P=.011), and any diabetes-related outcome (NNT per year=74; 95% CI, 63–90; P=.0023), compared with diet alone.^23,24

Metformin induces weight loss (2–3 kg), preferentially involving adipose tissue in obese patients with type 2 diabetes over 4 to 6 months.^22,25 In UKPDS 34, weight gain was similar among those treated with metformin and diet (approximately 2 kg); weight gain over 10 years was less with metformin, however, than with sulfonylurea (approximately 4 kg) or insulin (approximately 6 kg).²³ Metformin also significantly improved levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides when compared with glyburide or placebo.²²

Risk of lactic acidosis. Lactic acidosis associated with metformin is a rare but serious adverse event, with an estimated prevalence of 3 cases per 100,000.²⁶ The product labeling notes most of these cases have occurred among patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion. Absolute contraindications include renal disease (serum creatinine ≥1.5 mg/dL [males] and ≥1.4 mg/dL [females]), congestive heart failure requiring pharmacological treatment, and acute or chronic metabolic acidosis. It should also be discontinued at the time of radiologic studies using intravascular iodinated contrast materials.

Additional “precautionary conditions” include age ≥80 years (unless measurement of creatinine clearance demonstrates that renal function is not reduced), hepatic disease, cationic drug use, conditions associated with hypoxia (eg, chronic obstructive pulmonary disease [COPD], acute myocardial infarction, dehydration, sepsis), excessive alcohol intake, and surgery, until patient’s oral intake is resumed.

Is the risk overstated? Despite these extensive precautions, published studies show that metformin is commonly prescribed to patients with absolute contraindications.^27,28 One recent study observed that 11.2% of Medicare beneficiaries hospitalized with congestive heart failure and concomitant diabetes were treated with metformin.²⁸ In the absence of advanced renal dysfunction, metformin rarely accumulates in the body,²⁹ and accumulation of metformin is rarely reported as a cause of lactic acidosis.^30,31 Rather, tissue hypoxia acts as a trigger in most cases. Metformin should therefore be discontinued whenever tissue hypoxia is suspected.³¹

A recent systematic review and meta analysis found no evidence that metformin was associated with an increased risk of lactic acidosis if the drug was prescribed under study conditions, taking into account contraindications.³² Refinement and clarification of the risk for lactic acidosis in these various populations is needed, to ensure optimal patient safety and to further assess this highly effective medication.

Common adverse effects associated with metformin are diarrhea and nausea, which can be minimized by administering the drug with meals and slowly titrating the dose, or perhaps by using the extended-release formulation.

Thiazolidinediones

Thiazolidinediones (TZDs) include rosiglitazone and pioglitazone. These agents, like metformin, do not increase insulin secretion but depend on the presence of insulin for their activity. TZDs are agonists at peroxisome-proliferator-activated receptor gamma (PPAR-γ) receptors in peripheral tissues such as skeletal muscle, where they increase glucose uptake.¹⁵ Thus, their predominant effect is to decrease insulin resistance.

TZDs have similar antihyperglycemic efficacy as sulfonylureas or metformin. They decrease A_1c levels by 0.6–1.9 percentage points and lower fasting plasma glucose levels by 50–80 mg/dL.¹⁵ They have a slower onset of action compared with other hypoglycemic drugs, and intervals of 3 to 4 weeks should be allowed between doses before increasing the dosage. TZDs also have favorable effects on lipid levels: HDL concentrations increase and triglyceride concentrations decrease with their use.³³ It is not known whether they decrease macrovascular or microvascular complications, although such studies are underway.

Adverse effects. TZDs are typically well tolerated, though weight gain of 1–3 kg, edema (4%–5%) and anemia (1%–2%) can occur. Weight gain and edema are more pronounced when TZDs are used in combination with insulin. Anemia is likely due to increased plasma volume rather than any significant hematological effect.

Due to adverse events related to volume expansion, TZDs are not recommended for patients with New York Heart Association class III or IV heart failure. A recent consensus statement from the American Heart Association and the ADA stresses that before administering TZD treatment, the physician should explore the possible presence of cardiac disease, use of other drugs that cause fluid retention, and the pathogenesis of any existing edema or dyspnea.³⁴

Although troglitazone was removed from the market due to its association with hepatocellular injury, pioglitazone and rosiglitazone are not as convincingly associated with liver injury.¹⁵ In preapproval clinical studies, less than 0.5% of patients treated with rosiglitzone and pioglitazone had elevations in alanine transaminase (ALT) >3 times the upper limit of normal.

The incidence of hepatitis or acute liver failure from troglitazone was compared with rosiglitazone, pioglitazone, metformin, and glyburide, by analysis of spontaneously reported adverse events to the Food and Drug Administration (FDA) MEDWATCH database during the first 15 months of marketing of each drug.^35,36 The incidence of hepatitis per million prescriptions was 21.5, 14.7, 9.4, 2.9, and 4.1, respectively, while the incidence of acute liver failure per 100,000 prescriptions was 4.6, 0.9, 0.8, 0.2, and 0. It appears that postmarketing data support preclinical studies, in that the incidence of acute liver failure is an order of magnitude higher for troglitazone vs. other TZDs.³⁵ However, the FDA recommends avoiding their use in patients with baseline ALT levels >2.5 times the upper limit of normal. The FDA recently reduced the recommended frequency for ALT monitoring for pioglitazone (and is currently considering the same for rosiglitazone). Serum ALT is recommended prior to initiation and then periodically thereafter.

Cost. TZDs are expensive relative to other hypoglycemic agents.

α-glucosidase inhibitors

The α-glucosidase inhibitors (AGIs), acarbose and miglitol, act through competitive, reversible inhibition of membrane-bound intestinal α-glucosidase, which hydrolyzes complex carbohydrates to glucose and other monosaccharides. This inhibition delays glucose absorption and decreases postprandial hyperglycemia.³⁷ Thus, they have a nonsystemic mechanism of action.

These agents cause a modest reduction in the A_1c level (0.5–1.0 percentage points) and are thus less effective than sulfonylureas, metformin, or TZDs. They do not reduce fasting plasma glucose levels, but reduce postprandial hyperglycemia by 50 mg/dL.³⁸ No long-term studies have evaluated whether AGIs reduce diabetes-related macrovascular or microvascular outcomes.

Adverse effects. While AGIs are virtually free of serious toxicities, patient tolerability can be a problem due to adverse gastrointestinal effects. In indirect comparisons from placebo-controlled trials, patients treated with miglitol and acarbose commonly reported abdominal pain (11.7%, 19%), diarrhea (28.7%, 31%), and flatulence (41.5%, 74%), respectively. Systemic accumulation of AGIs has been shown to increase in proportion to the degree of renal insufficiency, and their use is not recommended for patients with serum creatinine >2.0 mg/dL. However, whether such patients are at greater risk of any toxicity is unknown. Acarbose at doses above 100 mg 3 times daily has been associated with elevated serum transaminase levels; however, this risk appears negligible at standard doses.

Insulin

Insulin is the oldest therapy for diabetes, and it has no upper dose limit.³⁹ It increases insulin levels and can reduce A_1c levels by 1.5 to 2.5 percentage points. Though half of diabetes patients need insulin eventually for optimal control, historically it has been introduced late in the disease process unless patients have severe hyperglycemia (fasting blood sugar >350 mg/dL) or ketonuria.³⁸ However, it is effective in gaining initial control, decreasing gluconeogenesis and increasing glucose uptake. Disadvantages are weight gain, hypoglycemia, and patient reluctance to give injections.

When insulin is indicated. Patients who exhibit persistent hyperglycemia despite oral hypoglycemic therapy may stop the oral drug(s) and begin insulin. By combining insulin with oral therapy, lower insulin doses may be used to achieve desired control vs using insulin alone.⁴⁰ For some patients a basal supplement of insulin may be sufficient and can be given as a single dose at bedtime, without an oral hypoglycemic drug.⁴¹

Insulin regimens. Various insulin regimens are available: very rapid acting (lispro and aspart), rapid acting (regular), intermediate acting (isophane insulin [NPH] and lente) and very long acting (ultralente and glargine). Glargine insulin (Lantus) has more predictable absorption than NPH, lente, and ultralente. Lantus, compared with NPH, has been associated with less nocturnal and postprandial hypoglycemia.^38,42,43 This is consistent with the peakless and longer duration of glargine compared with NPH.⁴⁴ A recent randomized controlled trial demonstrated that morning insulin glargine lowered A_1c levels more than a bedtime dose of NPH (–1.24 vs –0.84; 95% CI, 0.23%–0.58%) or a bedtime dose of glargine (–1.24 vs –0.96%; 95% CI, 0.11%–0.46%).⁴⁵ Glargine’s only relative disadvantage is increased cost.

Combination products. Combination insulin options are 70 NPH/30 regular, 50 NPH/50 regular, and 75 lispro protamine/25 lispro. Many combinations of insulin regimens have been used successfully. The typical range of insulin needed for monotherapy is 0.4–1 U/kg/d. Once-daily injection of intermediate acting or long acting insulins at bedtime or before breakfast, once-daily or twice-daily combinations of intermediate and rapid acting insulins, and more complex regimens have been used to good effect.

Using prandial insulin at each meal with separate basal insulin adds flexibility to meal times and doses administered.⁴³ With multiple-dose intensive insulin therapy, a basal dose suppresses hepatic glucose output and the bolus doses enhance postprandial glucose uptake. This intensive insulin treatment reduces mortality among critically ill patients in surgical intensive care units and for those with acute myocardial infarction.^46,47 An algorithm for using progressive therapy in diabetes mellitus is shown in Figure 2.⁴⁸

FIGURE 2
ADA recommendations for the treatment of type 2 diabetes

Combination Therapy

Over time glycemic control becomes more difficult, even with maximum monotherapy for patients with healthy lifestyles. It was shown in UKPDS 49 that monotherapy with sulfonylurea, metformin, or insulin eventually fails in most cases—by 3 years after diagnosis, about 50% of patients need more than monotherapy; 75% by 9 years.⁴⁹ In UKPDS 33, the median A_1c level increased steadily over 10 years with both conventional therapy and intensive therapy (Figure 3).²

Several options are available when monotherapy fails. Based on expert opinion, the principle is to combine drugs with different mechanisms of action to achieve an additive effect for glycemic control. Combination products may simplify the treatment regimen and improve adherence. In many instances, they may also cost less.⁵⁰

Successful combinations. The combination of sulfonylurea and metformin has proven effective in many studies.^22,51,52 One study showed that initial treatment with glyburide/metformin improved glycemic control better than either glyburide or metformin monotherapy (SOR: A).^53,54 The addition of the non-SU secretagogues repaglinide and nateglinide to metformin significantly improved glycemic control, with repaglinide showing superiority over nateglinide.⁵⁵ A TZD added to a sulfonylurea has also significantly improved A_1c and fasting blood sugar results.⁵⁶ Patients whose diabetes was inadequately controlled with diet alone or diet plus a sulfonylurea showed improvement with the addition of the AGI miglitol, compared with addition of placebo.⁵⁷ The AGI acarbose has shown to be an effective addition to diet, metformin, sulfonylurea, and insulin.⁵⁸ A TZD added to metformin has also been shown to improve glycemic control.⁵⁹ A non-SU added to patients inadequately controlled with a TZD has also been effective.⁶⁰

The early addition of insulin when maximal sulfonylurea therapy is inadequate has been effective.^61-63 When introducing insulin, a nighttime regimen of NPH or glargine, 10 units at bedtime, is an appropriate dose (SOR: C). This is easier and less costly than often assumed, and helps improve glycemic control.⁶⁴ Most patients require combination therapy as their disease progresses.³⁹

FIGURE 3
Glycemic control in type 2 DM

Improving Outcomes

Cumulative survey data reveal a wide gap between guideline recommendations and the care patients receive.⁶⁵ One study showed that physicians initiated treatment changes only after the A_1c level had reached 9.0% or higher instead of the 8.0% level recommended by ADA.⁶⁶ How can the quality of management be improved?

In private practices and institutions, many interventions have been shown to improve outcomes in diabetes mellitus. Education measures work, and they include chart audits, reminder cards, pharmacist collaboration, flow sheets, and nursing initiatives.^67,68 Effective disease-management programs have also used clinical guidelines, outcomes reporting, coverage of glucose meters and strips, and the support of clinical leadership.⁶⁹

Computerized systems that track patients and recommended laboratory tests have improved screening rates and glycemic and blood pressure control.⁷⁰ Monitoring patients’ readiness to change has allowed targeted education to improve A_1c levels.⁷¹ Continuity of care has also improved the quality of disease control by increasing adherence to recommended tests and exams.⁷²

Acknowlegments

The authors thank Marie Hamer, RN, for her continuous diabetes quality improvement efforts and Jean Camarata for her editorial and reference acquisition assistance.

Corresponding author
John E. Sutherland, MD, Northeast Iowa Family Practice Residency Program, University of Iowa College of Medicine, 2055 Kimball Avenue, Waterloo, Iowa 50702. E-mail: [email protected].

Glycemic control in diabetes begins with a patient’s adherence to several nonpharmacologic measures. Without such a commitment, success in controlling the disease will be difficult to achieve, and otherwise appropriate drug therapy will be hindered.

Most antidiabetic agents comparably reduce glycosylated hemoglobin (A_1c) levels. However, a particular agent may be preferred depending on a patient’s characteristics. And some circumstances call for combination therapy. This article reviews the advantages and disadvantages of the many pharmacologic treatments for glucose control and hyperglycemia in type 2 diabetes.

Benefits Of Diabetes Control

The benefits of diabetes control are detailed in this issue of THE JOURNAL OF FAMILY PRACTICE (“Strategies to reduce complications in type 2 diabetes,” pages 366–374). For every percentage-point reduction in hemoglobin A_1c, it is possible to achieve a 22% to 35% reduction in microvascular complications.^1,2 Cardiovascular disease can be reduced in patients with diabetes by treating hypertension^3,4 and hyperlipidemia, prescribing aspirin therapy, using angiotensin-converting enzyme (ACE) inhibitors, and with smoking cessation.^5,6

Targets For Glycemic Control

The American Diabetes Association’s (ADA) recommended targets for glycemic control are a preprandial blood glucose level of 80–120 mg/dL, a bedtime blood glucose level of 100–140 mg/dL, and a hemoglobin A_1c level of <7% (with a level of >8% requiring additional measures). Hemoglobin A_1c is the best determinant of glycemic exposure, and its mean value is a nationally recognized indicator of how well diabetes is being managed.⁷ The American College of Endocrinology has adopted a more aggressive approach by designating an A_1c level of 6.5% as both a target and action level.⁸

Self-monitoring of blood glucose

Self-monitoring of blood glucose (SMBG) is an integral component of diabetes therapy (strength of recommendation [SOR]: C) and should always be included in the management plan (SOR: C). The optimal frequency and timing of SMBG for type 2 diabetes is not known, but they should be sufficient to facilitate reaching glucose goals. The A_1c test should be performed at least semi-annually for patients with stable glycemic control, and quarterly for patients not meeting glycemic goals or those who are changing therapy. A_1c levels and mean plasma glucose levels can be approximately correlated (Table 1).⁷

TABLE 1
Correlation between hemoglobin A_1clevels and mean plasma glucose levels

Nonpharmacologic Therapy

Nonpharmacologic measures remain the cornerstone of managing type 2 diabetes. Hyperglycemia adversely and reversibly affects both insulin resistance and insulin secretion. Improvement in glycemic control can occur through dietary modification and regular exercise.

A recent meta-analysis of randomized controlled trials of diabetes patient education observed a net decrease in HbA_1c of 0.32% in intervention groups vs control.⁹ Interventions that included a face-to-face delivery, cognitive reframing teaching method, and exercise content were more likely to improve glycemic control.

Education

Lifestyle changes involving diet, exercise, and usually weight loss are key to effective management of diabetes. If patients are to change their behavior, they must be given detailed training.⁶ Self-management also necessitates that patients engage in problem solving. This requires that each aspect of the management plan is understood and agreed upon by the patient and providers, and that the goals and treatment plan are individualized and reasonable.

Diet: recommend soluble fiber, reduce calories

Medical nutrition therapy should be individualized and preferably provided by a registered dietitian familiar with diabetes (SOR: B). The goals of nutrition therapy, according to the ADA, are to attain recommended body weight and prevent or reverse obesity. The means of achieving these goals are nutrition assessment and modification of nutrient intake and lifestyle through healthy food choices and physical activity.⁷

A high intake of dietary fiber (particularly the soluble type) above the level recommended by the ADA improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations.¹⁰

Hypocaloric diets cause glucose plasma levels to fall, in some cases to a normal level with a weight loss of even 5 to 10 pounds.^7,11 Hypoglycemic medications are of course most effective in nonobese persons. But effectiveness is also improved if weight that is gained can be limited. Despite the clear benefit of weight loss, only a few patients are able to attain and maintain substantial weight loss. Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of body weight that is different from the usual weight.¹³ Part of the individualization of therapy is respect of personal and cultural preferences, lifestyles, and financial considerations.

Physical activity: a little goes a long way

A regular physical activity program is recommended for all patients with diabetes who are capable of participating (SOR: B).⁷ It improves blood glucose control, reduces cardiovascular risk factors, aids weight loss, and enhances well being.⁷ A recently published prospective cohort study showed that walking at least 2 hours a week was associated with a 39% lower all-cause mortality (hazard rate ratio [HRR], 0.61; 95% CI, 0.48–0.78) and a 34% lower cardiovascular mortality (HRR, 0.66; 95% CI, 0.45–0.96) across a diverse spectrum of adults with diabetes. The NNT (to prevent 1 death per year) is 61 for patients who walk at least 2 hours/week.¹⁴

In prescribing a physical activity plan for a patient, consider cardiovascular disease risk factors or complications to minimize the risk of untoward events. Micro- and macrovascular disease are of course prevalent among persons with diabetes, often resulting in functional limitations that make exercise more difficult.

Other priorities

Other recommended components of care include daily aspirin use, foot care exams, tobacco cessation, pneumococcal and influenza vaccinations, and an annual dilated retinal exam.

Pharmacologic Therapy

The coexisting defects in type 2 diabetes mellitus are as follows:

• resistance to insulin action in muscle
• defective pancreatic insulin secretion
• unrestrained hepatic glucose production, aggravated by increased lipolysis in adipose tissue.

Drug therapy is aimed at each of these defects, and also at reducing carbohydrate absorption in the small intestine (Figure 1). As far as antihyperglycemic effect is concerned, no one category of antidiabetic agent is favored over another.¹⁵ Except for nateglinide and α-glucosidase inhibitors (AGIs), each of the drug categories leads to a similar reduction in A_1c.¹⁶ However, patient characteristics may lead to selection of a particular agent. Table 2 summarizes oral treatment options, their relative advantages and costs.

FIGURE 1
Drug therapies for coexisting defects in type 2 diabetes

TABLE 2
Pharmacologic treatments for type 2 diabetes: monotherapies

Sulfonylureas

Sulfonylureas directly increase insulin secretion by binding to the sulfonylurea receptor on pancreatic beta cells; they provide a relatively quick onset of action. First-generation sulfonylureas (eg, tolbutamide, chlorpropamide) and second-generation sulfonylureas (eg, glyburide, glipizide, glimepiride) are equivalent in their maximum hypoglycemic effect.¹⁷

Second-generation agents are used more commonly than first-generation. They all contain the sulfonylurea moiety, but different chemical substitutions in the basic molecule change pharmacokinetics, resulting in different durations of action.¹⁷ Second-generation agents are probably safer than first-generation drugs, being less likely to cause hyponatremia, disulfiram-like reactions, or prolonged hypoglycemia.¹⁸

At maximal doses, sulfonylureas lower A_1c levels by 1–2 percentage points and fasting plasma glucose concentrations by 60–70 mg/dL;¹⁵ however, the glucose lowering effect typically plateaus after half the maximal recommended dose is reached. Sulfonylureas have no consistent effect on dyslipidemia. In UK Prospective Diabetes Study (UKPDS) 33, though improved glycemic control with sulfonylureas (or insulin) led to a 25% reduction in microvascular endpoints (mostly less retinal photocoagulation) (P<.01), sulfonylureas (or insulin) did not significantly reduce death or all-cause mortality compared with diet treatment.²

Adverse effects. The primary adverse effects of sulfonylureas are weight gain and hypoglycemia. In UKPDS 33, weight gain at 10 years was 2.6 kg (99% confidence interval [CI], 1.6–3.6) with chlorpropamide and 1.7 kg (99% CI, 0.7–2.7) with glyburide, compared with patients receiving diet therapy (each P<.001).² In the same study, the rate of major hypoglycemic episodes (third-party help or medical intervention necessary) while on therapy was 0.4%/year for chlorpropamide and 0.6%/year for glyburide, compared with 0.1%/year for diet.

Glyburide and chlorpropamide have active metabolites with renal elimination, and they should therefore be used with caution in patients with renal insufficiency. In 1971, the University Group Diabetes Project (UGDP) observed a twofold increase in the rate of cardiovascular death among patients receiving tolbutamide compared with those receiving insulin or placebo.¹⁸ This led to a decades long debate on the validity of this conclusion.¹⁹ More recently, UKPDS 33 did not demonstrate any increased cardiovascular mortality among patients receiving glyburide or chlorpropamide, and has largely negated this earlier concern.²

Cost. Sulfonylureas are the least expensive oral agents used to treat type 2 diabetes.

TABLE 3
Pharmacological treatments for type 2 diabetes: combination therapies

Non-sulfonylurea secretagogues

Like sulfonylureas, the non-sulfonylurea secretagogues (non-SU), repaglinide and nateglinide, stimulate beta cells to increase insulin secretion. However, the non-SU agents mediate their action through a different, adjacent site on the “sulfonylurea receptor.” Comparatively, the non-SU agents have a faster onset of action (20 minutes), shorter half-life (about 1.0–1.5 hours), and greater effects on postprandial glucose excursions than do sulfonylureas.²⁰ In contrast to the sulfonylureas, the extent of insulin release with non-SU agents is glucose dependent, and therefore they may have less risk of hypoglycemia several hours after meals.¹⁵

Repaglinide lowers the A_1c level by 1.7–1.9 percentage points, similar in efficacy to sulfonylureas. Nateglinide appears somewhat less efficacious and lowers A_1c by 0.6–1.0 percentage points.¹⁵ Nateglinide was significantly less effective than glyburide at lowering A_1c levels and the fasting plasma glucose in one 24-week study. Non-SUs added to sulfonylureas produce no additional benefit in glycemic control. The effect of non-SUs on microvascular or macrovascular endpoints is unknown.

Adverse effects. Hypoglycemia is the primary adverse effect of non-SUs. Confirmed hypoglycemia (plasma glucose <60 mg/dL) was observed in 2.4% of patients taking nateglinide compared with 0.4% of those receiving placebo. Mild or moderate hypoglycemia occurred in 16% of repaglinide patients, 20% of glyburide patients, and 19% of glipizide patients in one-year comparative studies. Further comparative studies are needed to determine if non-SUs produce significantly less hypoglycemia and weight gain than sulfonylureas.

Cost. Non-SUs must be dosed 3 times daily at the start of meals. One relative disadvantage is their increased cost compared with sulfonylureas.

Biguanides

The only biguanide marketed in the US is metformin. Its primary action is to inhibit hepatic glucose production and, to a much lesser extent, enhance insulin sensitivity in peripheral tissues.²¹ Metformin does not stimulate insulin secretion and does not cause hypoglycemia when used as monotherapy, but it can potentiate hypoglycemia in combination with insulin or insulin secretagogues.

Metformin is similar in efficacy to the sulfonylureas. It lowers A_1c by 1.5–2.0 percentage points and fasting plasma glucose by 60–80 mg/dL. Its antihyperglycemic efficacy is independent of patient age, duration of diabetes, or BMI.²²

In the UKPDS 34 study, a subgroup of obese patients was randomized to receive intensive control (group 1, metformin; group 2, a sulfonylurea or insulin) or conventional diet therapy (group 3). Despite a similar reduction in the A_1c level between the 2 intensive-treatment groups, patients treated with metformin had a 32% reduction for any diabetes-related endpoint (95% CI, 13–47; P=.002), 43% fewer diabetes-related deaths (95% CI, 9–63; P=.017), and a 36% reduction in all cause mortality, compared with the diet therapy group (95% CI, 9–55; P=.011).²³

Metformin also showed significant benefit when compared with patients receiving sulfonylurea or insulin (group 2). The absolute risk of any diabetes endpoint was 29.8 vs. 40.1 (events per 1000 patient-years; P=.0034), all-cause mortality (13.5 vs 18.9; P=.021), and stroke (3.3 vs 6.2; P=.032), respectively, for metformin vs sulfonylurea or insulin (group 2). Thus, metformin is the only oral hypoglycemic agent proven to reduce macrovascular risk in overweight patients with type 2 diabetes. For perspective, in overweight patients, metformin significantly reduced all-cause mortality (NNT per year=141; 95% CI, 115–183; P=.011), and any diabetes-related outcome (NNT per year=74; 95% CI, 63–90; P=.0023), compared with diet alone.^23,24

Metformin induces weight loss (2–3 kg), preferentially involving adipose tissue in obese patients with type 2 diabetes over 4 to 6 months.^22,25 In UKPDS 34, weight gain was similar among those treated with metformin and diet (approximately 2 kg); weight gain over 10 years was less with metformin, however, than with sulfonylurea (approximately 4 kg) or insulin (approximately 6 kg).²³ Metformin also significantly improved levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides when compared with glyburide or placebo.²²

Risk of lactic acidosis. Lactic acidosis associated with metformin is a rare but serious adverse event, with an estimated prevalence of 3 cases per 100,000.²⁶ The product labeling notes most of these cases have occurred among patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion. Absolute contraindications include renal disease (serum creatinine ≥1.5 mg/dL [males] and ≥1.4 mg/dL [females]), congestive heart failure requiring pharmacological treatment, and acute or chronic metabolic acidosis. It should also be discontinued at the time of radiologic studies using intravascular iodinated contrast materials.

Additional “precautionary conditions” include age ≥80 years (unless measurement of creatinine clearance demonstrates that renal function is not reduced), hepatic disease, cationic drug use, conditions associated with hypoxia (eg, chronic obstructive pulmonary disease [COPD], acute myocardial infarction, dehydration, sepsis), excessive alcohol intake, and surgery, until patient’s oral intake is resumed.

Is the risk overstated? Despite these extensive precautions, published studies show that metformin is commonly prescribed to patients with absolute contraindications.^27,28 One recent study observed that 11.2% of Medicare beneficiaries hospitalized with congestive heart failure and concomitant diabetes were treated with metformin.²⁸ In the absence of advanced renal dysfunction, metformin rarely accumulates in the body,²⁹ and accumulation of metformin is rarely reported as a cause of lactic acidosis.^30,31 Rather, tissue hypoxia acts as a trigger in most cases. Metformin should therefore be discontinued whenever tissue hypoxia is suspected.³¹

A recent systematic review and meta analysis found no evidence that metformin was associated with an increased risk of lactic acidosis if the drug was prescribed under study conditions, taking into account contraindications.³² Refinement and clarification of the risk for lactic acidosis in these various populations is needed, to ensure optimal patient safety and to further assess this highly effective medication.

Common adverse effects associated with metformin are diarrhea and nausea, which can be minimized by administering the drug with meals and slowly titrating the dose, or perhaps by using the extended-release formulation.

Thiazolidinediones

Thiazolidinediones (TZDs) include rosiglitazone and pioglitazone. These agents, like metformin, do not increase insulin secretion but depend on the presence of insulin for their activity. TZDs are agonists at peroxisome-proliferator-activated receptor gamma (PPAR-γ) receptors in peripheral tissues such as skeletal muscle, where they increase glucose uptake.¹⁵ Thus, their predominant effect is to decrease insulin resistance.

TZDs have similar antihyperglycemic efficacy as sulfonylureas or metformin. They decrease A_1c levels by 0.6–1.9 percentage points and lower fasting plasma glucose levels by 50–80 mg/dL.¹⁵ They have a slower onset of action compared with other hypoglycemic drugs, and intervals of 3 to 4 weeks should be allowed between doses before increasing the dosage. TZDs also have favorable effects on lipid levels: HDL concentrations increase and triglyceride concentrations decrease with their use.³³ It is not known whether they decrease macrovascular or microvascular complications, although such studies are underway.

Adverse effects. TZDs are typically well tolerated, though weight gain of 1–3 kg, edema (4%–5%) and anemia (1%–2%) can occur. Weight gain and edema are more pronounced when TZDs are used in combination with insulin. Anemia is likely due to increased plasma volume rather than any significant hematological effect.

Due to adverse events related to volume expansion, TZDs are not recommended for patients with New York Heart Association class III or IV heart failure. A recent consensus statement from the American Heart Association and the ADA stresses that before administering TZD treatment, the physician should explore the possible presence of cardiac disease, use of other drugs that cause fluid retention, and the pathogenesis of any existing edema or dyspnea.³⁴

Although troglitazone was removed from the market due to its association with hepatocellular injury, pioglitazone and rosiglitazone are not as convincingly associated with liver injury.¹⁵ In preapproval clinical studies, less than 0.5% of patients treated with rosiglitzone and pioglitazone had elevations in alanine transaminase (ALT) >3 times the upper limit of normal.

The incidence of hepatitis or acute liver failure from troglitazone was compared with rosiglitazone, pioglitazone, metformin, and glyburide, by analysis of spontaneously reported adverse events to the Food and Drug Administration (FDA) MEDWATCH database during the first 15 months of marketing of each drug.^35,36 The incidence of hepatitis per million prescriptions was 21.5, 14.7, 9.4, 2.9, and 4.1, respectively, while the incidence of acute liver failure per 100,000 prescriptions was 4.6, 0.9, 0.8, 0.2, and 0. It appears that postmarketing data support preclinical studies, in that the incidence of acute liver failure is an order of magnitude higher for troglitazone vs. other TZDs.³⁵ However, the FDA recommends avoiding their use in patients with baseline ALT levels >2.5 times the upper limit of normal. The FDA recently reduced the recommended frequency for ALT monitoring for pioglitazone (and is currently considering the same for rosiglitazone). Serum ALT is recommended prior to initiation and then periodically thereafter.

Cost. TZDs are expensive relative to other hypoglycemic agents.

α-glucosidase inhibitors

The α-glucosidase inhibitors (AGIs), acarbose and miglitol, act through competitive, reversible inhibition of membrane-bound intestinal α-glucosidase, which hydrolyzes complex carbohydrates to glucose and other monosaccharides. This inhibition delays glucose absorption and decreases postprandial hyperglycemia.³⁷ Thus, they have a nonsystemic mechanism of action.

These agents cause a modest reduction in the A_1c level (0.5–1.0 percentage points) and are thus less effective than sulfonylureas, metformin, or TZDs. They do not reduce fasting plasma glucose levels, but reduce postprandial hyperglycemia by 50 mg/dL.³⁸ No long-term studies have evaluated whether AGIs reduce diabetes-related macrovascular or microvascular outcomes.

Adverse effects. While AGIs are virtually free of serious toxicities, patient tolerability can be a problem due to adverse gastrointestinal effects. In indirect comparisons from placebo-controlled trials, patients treated with miglitol and acarbose commonly reported abdominal pain (11.7%, 19%), diarrhea (28.7%, 31%), and flatulence (41.5%, 74%), respectively. Systemic accumulation of AGIs has been shown to increase in proportion to the degree of renal insufficiency, and their use is not recommended for patients with serum creatinine >2.0 mg/dL. However, whether such patients are at greater risk of any toxicity is unknown. Acarbose at doses above 100 mg 3 times daily has been associated with elevated serum transaminase levels; however, this risk appears negligible at standard doses.

Insulin

Insulin is the oldest therapy for diabetes, and it has no upper dose limit.³⁹ It increases insulin levels and can reduce A_1c levels by 1.5 to 2.5 percentage points. Though half of diabetes patients need insulin eventually for optimal control, historically it has been introduced late in the disease process unless patients have severe hyperglycemia (fasting blood sugar >350 mg/dL) or ketonuria.³⁸ However, it is effective in gaining initial control, decreasing gluconeogenesis and increasing glucose uptake. Disadvantages are weight gain, hypoglycemia, and patient reluctance to give injections.

When insulin is indicated. Patients who exhibit persistent hyperglycemia despite oral hypoglycemic therapy may stop the oral drug(s) and begin insulin. By combining insulin with oral therapy, lower insulin doses may be used to achieve desired control vs using insulin alone.⁴⁰ For some patients a basal supplement of insulin may be sufficient and can be given as a single dose at bedtime, without an oral hypoglycemic drug.⁴¹

Insulin regimens. Various insulin regimens are available: very rapid acting (lispro and aspart), rapid acting (regular), intermediate acting (isophane insulin [NPH] and lente) and very long acting (ultralente and glargine). Glargine insulin (Lantus) has more predictable absorption than NPH, lente, and ultralente. Lantus, compared with NPH, has been associated with less nocturnal and postprandial hypoglycemia.^38,42,43 This is consistent with the peakless and longer duration of glargine compared with NPH.⁴⁴ A recent randomized controlled trial demonstrated that morning insulin glargine lowered A_1c levels more than a bedtime dose of NPH (–1.24 vs –0.84; 95% CI, 0.23%–0.58%) or a bedtime dose of glargine (–1.24 vs –0.96%; 95% CI, 0.11%–0.46%).⁴⁵ Glargine’s only relative disadvantage is increased cost.

Combination products. Combination insulin options are 70 NPH/30 regular, 50 NPH/50 regular, and 75 lispro protamine/25 lispro. Many combinations of insulin regimens have been used successfully. The typical range of insulin needed for monotherapy is 0.4–1 U/kg/d. Once-daily injection of intermediate acting or long acting insulins at bedtime or before breakfast, once-daily or twice-daily combinations of intermediate and rapid acting insulins, and more complex regimens have been used to good effect.

Using prandial insulin at each meal with separate basal insulin adds flexibility to meal times and doses administered.⁴³ With multiple-dose intensive insulin therapy, a basal dose suppresses hepatic glucose output and the bolus doses enhance postprandial glucose uptake. This intensive insulin treatment reduces mortality among critically ill patients in surgical intensive care units and for those with acute myocardial infarction.^46,47 An algorithm for using progressive therapy in diabetes mellitus is shown in Figure 2.⁴⁸

FIGURE 2
ADA recommendations for the treatment of type 2 diabetes

Combination Therapy

Over time glycemic control becomes more difficult, even with maximum monotherapy for patients with healthy lifestyles. It was shown in UKPDS 49 that monotherapy with sulfonylurea, metformin, or insulin eventually fails in most cases—by 3 years after diagnosis, about 50% of patients need more than monotherapy; 75% by 9 years.⁴⁹ In UKPDS 33, the median A_1c level increased steadily over 10 years with both conventional therapy and intensive therapy (Figure 3).²

Several options are available when monotherapy fails. Based on expert opinion, the principle is to combine drugs with different mechanisms of action to achieve an additive effect for glycemic control. Combination products may simplify the treatment regimen and improve adherence. In many instances, they may also cost less.⁵⁰

Successful combinations. The combination of sulfonylurea and metformin has proven effective in many studies.^22,51,52 One study showed that initial treatment with glyburide/metformin improved glycemic control better than either glyburide or metformin monotherapy (SOR: A).^53,54 The addition of the non-SU secretagogues repaglinide and nateglinide to metformin significantly improved glycemic control, with repaglinide showing superiority over nateglinide.⁵⁵ A TZD added to a sulfonylurea has also significantly improved A_1c and fasting blood sugar results.⁵⁶ Patients whose diabetes was inadequately controlled with diet alone or diet plus a sulfonylurea showed improvement with the addition of the AGI miglitol, compared with addition of placebo.⁵⁷ The AGI acarbose has shown to be an effective addition to diet, metformin, sulfonylurea, and insulin.⁵⁸ A TZD added to metformin has also been shown to improve glycemic control.⁵⁹ A non-SU added to patients inadequately controlled with a TZD has also been effective.⁶⁰

The early addition of insulin when maximal sulfonylurea therapy is inadequate has been effective.^61-63 When introducing insulin, a nighttime regimen of NPH or glargine, 10 units at bedtime, is an appropriate dose (SOR: C). This is easier and less costly than often assumed, and helps improve glycemic control.⁶⁴ Most patients require combination therapy as their disease progresses.³⁹

FIGURE 3
Glycemic control in type 2 DM

Improving Outcomes

Cumulative survey data reveal a wide gap between guideline recommendations and the care patients receive.⁶⁵ One study showed that physicians initiated treatment changes only after the A_1c level had reached 9.0% or higher instead of the 8.0% level recommended by ADA.⁶⁶ How can the quality of management be improved?

In private practices and institutions, many interventions have been shown to improve outcomes in diabetes mellitus. Education measures work, and they include chart audits, reminder cards, pharmacist collaboration, flow sheets, and nursing initiatives.^67,68 Effective disease-management programs have also used clinical guidelines, outcomes reporting, coverage of glucose meters and strips, and the support of clinical leadership.⁶⁹

Computerized systems that track patients and recommended laboratory tests have improved screening rates and glycemic and blood pressure control.⁷⁰ Monitoring patients’ readiness to change has allowed targeted education to improve A_1c levels.⁷¹ Continuity of care has also improved the quality of disease control by increasing adherence to recommended tests and exams.⁷²

Acknowlegments

The authors thank Marie Hamer, RN, for her continuous diabetes quality improvement efforts and Jean Camarata for her editorial and reference acquisition assistance.

Corresponding author
John E. Sutherland, MD, Northeast Iowa Family Practice Residency Program, University of Iowa College of Medicine, 2055 Kimball Avenue, Waterloo, Iowa 50702. E-mail: [email protected].

Glycemic control in diabetes begins with a patient’s adherence to several nonpharmacologic measures. Without such a commitment, success in controlling the disease will be difficult to achieve, and otherwise appropriate drug therapy will be hindered.

Most antidiabetic agents comparably reduce glycosylated hemoglobin (A_1c) levels. However, a particular agent may be preferred depending on a patient’s characteristics. And some circumstances call for combination therapy. This article reviews the advantages and disadvantages of the many pharmacologic treatments for glucose control and hyperglycemia in type 2 diabetes.

Benefits Of Diabetes Control

The benefits of diabetes control are detailed in this issue of THE JOURNAL OF FAMILY PRACTICE (“Strategies to reduce complications in type 2 diabetes,” pages 366–374). For every percentage-point reduction in hemoglobin A_1c, it is possible to achieve a 22% to 35% reduction in microvascular complications.^1,2 Cardiovascular disease can be reduced in patients with diabetes by treating hypertension^3,4 and hyperlipidemia, prescribing aspirin therapy, using angiotensin-converting enzyme (ACE) inhibitors, and with smoking cessation.^5,6

Targets For Glycemic Control

The American Diabetes Association’s (ADA) recommended targets for glycemic control are a preprandial blood glucose level of 80–120 mg/dL, a bedtime blood glucose level of 100–140 mg/dL, and a hemoglobin A_1c level of <7% (with a level of >8% requiring additional measures). Hemoglobin A_1c is the best determinant of glycemic exposure, and its mean value is a nationally recognized indicator of how well diabetes is being managed.⁷ The American College of Endocrinology has adopted a more aggressive approach by designating an A_1c level of 6.5% as both a target and action level.⁸

Self-monitoring of blood glucose

Self-monitoring of blood glucose (SMBG) is an integral component of diabetes therapy (strength of recommendation [SOR]: C) and should always be included in the management plan (SOR: C). The optimal frequency and timing of SMBG for type 2 diabetes is not known, but they should be sufficient to facilitate reaching glucose goals. The A_1c test should be performed at least semi-annually for patients with stable glycemic control, and quarterly for patients not meeting glycemic goals or those who are changing therapy. A_1c levels and mean plasma glucose levels can be approximately correlated (Table 1).⁷

TABLE 1
Correlation between hemoglobin A_1clevels and mean plasma glucose levels

Nonpharmacologic Therapy

Nonpharmacologic measures remain the cornerstone of managing type 2 diabetes. Hyperglycemia adversely and reversibly affects both insulin resistance and insulin secretion. Improvement in glycemic control can occur through dietary modification and regular exercise.

A recent meta-analysis of randomized controlled trials of diabetes patient education observed a net decrease in HbA_1c of 0.32% in intervention groups vs control.⁹ Interventions that included a face-to-face delivery, cognitive reframing teaching method, and exercise content were more likely to improve glycemic control.

Education

Lifestyle changes involving diet, exercise, and usually weight loss are key to effective management of diabetes. If patients are to change their behavior, they must be given detailed training.⁶ Self-management also necessitates that patients engage in problem solving. This requires that each aspect of the management plan is understood and agreed upon by the patient and providers, and that the goals and treatment plan are individualized and reasonable.

Diet: recommend soluble fiber, reduce calories

Medical nutrition therapy should be individualized and preferably provided by a registered dietitian familiar with diabetes (SOR: B). The goals of nutrition therapy, according to the ADA, are to attain recommended body weight and prevent or reverse obesity. The means of achieving these goals are nutrition assessment and modification of nutrient intake and lifestyle through healthy food choices and physical activity.⁷

A high intake of dietary fiber (particularly the soluble type) above the level recommended by the ADA improves glycemic control, decreases hyperinsulinemia, and lowers plasma lipid concentrations.¹⁰

Hypocaloric diets cause glucose plasma levels to fall, in some cases to a normal level with a weight loss of even 5 to 10 pounds.^7,11 Hypoglycemic medications are of course most effective in nonobese persons. But effectiveness is also improved if weight that is gained can be limited. Despite the clear benefit of weight loss, only a few patients are able to attain and maintain substantial weight loss. Maintenance of a reduced or elevated body weight is associated with compensatory changes in energy expenditure, which oppose the maintenance of body weight that is different from the usual weight.¹³ Part of the individualization of therapy is respect of personal and cultural preferences, lifestyles, and financial considerations.

Physical activity: a little goes a long way

A regular physical activity program is recommended for all patients with diabetes who are capable of participating (SOR: B).⁷ It improves blood glucose control, reduces cardiovascular risk factors, aids weight loss, and enhances well being.⁷ A recently published prospective cohort study showed that walking at least 2 hours a week was associated with a 39% lower all-cause mortality (hazard rate ratio [HRR], 0.61; 95% CI, 0.48–0.78) and a 34% lower cardiovascular mortality (HRR, 0.66; 95% CI, 0.45–0.96) across a diverse spectrum of adults with diabetes. The NNT (to prevent 1 death per year) is 61 for patients who walk at least 2 hours/week.¹⁴

In prescribing a physical activity plan for a patient, consider cardiovascular disease risk factors or complications to minimize the risk of untoward events. Micro- and macrovascular disease are of course prevalent among persons with diabetes, often resulting in functional limitations that make exercise more difficult.

Other priorities

Other recommended components of care include daily aspirin use, foot care exams, tobacco cessation, pneumococcal and influenza vaccinations, and an annual dilated retinal exam.

Pharmacologic Therapy

The coexisting defects in type 2 diabetes mellitus are as follows:

• resistance to insulin action in muscle
• defective pancreatic insulin secretion
• unrestrained hepatic glucose production, aggravated by increased lipolysis in adipose tissue.

Drug therapy is aimed at each of these defects, and also at reducing carbohydrate absorption in the small intestine (Figure 1). As far as antihyperglycemic effect is concerned, no one category of antidiabetic agent is favored over another.¹⁵ Except for nateglinide and α-glucosidase inhibitors (AGIs), each of the drug categories leads to a similar reduction in A_1c.¹⁶ However, patient characteristics may lead to selection of a particular agent. Table 2 summarizes oral treatment options, their relative advantages and costs.

FIGURE 1
Drug therapies for coexisting defects in type 2 diabetes

TABLE 2
Pharmacologic treatments for type 2 diabetes: monotherapies

Sulfonylureas

Sulfonylureas directly increase insulin secretion by binding to the sulfonylurea receptor on pancreatic beta cells; they provide a relatively quick onset of action. First-generation sulfonylureas (eg, tolbutamide, chlorpropamide) and second-generation sulfonylureas (eg, glyburide, glipizide, glimepiride) are equivalent in their maximum hypoglycemic effect.¹⁷

Second-generation agents are used more commonly than first-generation. They all contain the sulfonylurea moiety, but different chemical substitutions in the basic molecule change pharmacokinetics, resulting in different durations of action.¹⁷ Second-generation agents are probably safer than first-generation drugs, being less likely to cause hyponatremia, disulfiram-like reactions, or prolonged hypoglycemia.¹⁸

At maximal doses, sulfonylureas lower A_1c levels by 1–2 percentage points and fasting plasma glucose concentrations by 60–70 mg/dL;¹⁵ however, the glucose lowering effect typically plateaus after half the maximal recommended dose is reached. Sulfonylureas have no consistent effect on dyslipidemia. In UK Prospective Diabetes Study (UKPDS) 33, though improved glycemic control with sulfonylureas (or insulin) led to a 25% reduction in microvascular endpoints (mostly less retinal photocoagulation) (P<.01), sulfonylureas (or insulin) did not significantly reduce death or all-cause mortality compared with diet treatment.²

Adverse effects. The primary adverse effects of sulfonylureas are weight gain and hypoglycemia. In UKPDS 33, weight gain at 10 years was 2.6 kg (99% confidence interval [CI], 1.6–3.6) with chlorpropamide and 1.7 kg (99% CI, 0.7–2.7) with glyburide, compared with patients receiving diet therapy (each P<.001).² In the same study, the rate of major hypoglycemic episodes (third-party help or medical intervention necessary) while on therapy was 0.4%/year for chlorpropamide and 0.6%/year for glyburide, compared with 0.1%/year for diet.

Glyburide and chlorpropamide have active metabolites with renal elimination, and they should therefore be used with caution in patients with renal insufficiency. In 1971, the University Group Diabetes Project (UGDP) observed a twofold increase in the rate of cardiovascular death among patients receiving tolbutamide compared with those receiving insulin or placebo.¹⁸ This led to a decades long debate on the validity of this conclusion.¹⁹ More recently, UKPDS 33 did not demonstrate any increased cardiovascular mortality among patients receiving glyburide or chlorpropamide, and has largely negated this earlier concern.²

Cost. Sulfonylureas are the least expensive oral agents used to treat type 2 diabetes.

TABLE 3
Pharmacological treatments for type 2 diabetes: combination therapies

Non-sulfonylurea secretagogues

Like sulfonylureas, the non-sulfonylurea secretagogues (non-SU), repaglinide and nateglinide, stimulate beta cells to increase insulin secretion. However, the non-SU agents mediate their action through a different, adjacent site on the “sulfonylurea receptor.” Comparatively, the non-SU agents have a faster onset of action (20 minutes), shorter half-life (about 1.0–1.5 hours), and greater effects on postprandial glucose excursions than do sulfonylureas.²⁰ In contrast to the sulfonylureas, the extent of insulin release with non-SU agents is glucose dependent, and therefore they may have less risk of hypoglycemia several hours after meals.¹⁵

Repaglinide lowers the A_1c level by 1.7–1.9 percentage points, similar in efficacy to sulfonylureas. Nateglinide appears somewhat less efficacious and lowers A_1c by 0.6–1.0 percentage points.¹⁵ Nateglinide was significantly less effective than glyburide at lowering A_1c levels and the fasting plasma glucose in one 24-week study. Non-SUs added to sulfonylureas produce no additional benefit in glycemic control. The effect of non-SUs on microvascular or macrovascular endpoints is unknown.

Adverse effects. Hypoglycemia is the primary adverse effect of non-SUs. Confirmed hypoglycemia (plasma glucose <60 mg/dL) was observed in 2.4% of patients taking nateglinide compared with 0.4% of those receiving placebo. Mild or moderate hypoglycemia occurred in 16% of repaglinide patients, 20% of glyburide patients, and 19% of glipizide patients in one-year comparative studies. Further comparative studies are needed to determine if non-SUs produce significantly less hypoglycemia and weight gain than sulfonylureas.

Cost. Non-SUs must be dosed 3 times daily at the start of meals. One relative disadvantage is their increased cost compared with sulfonylureas.

Biguanides

The only biguanide marketed in the US is metformin. Its primary action is to inhibit hepatic glucose production and, to a much lesser extent, enhance insulin sensitivity in peripheral tissues.²¹ Metformin does not stimulate insulin secretion and does not cause hypoglycemia when used as monotherapy, but it can potentiate hypoglycemia in combination with insulin or insulin secretagogues.

Metformin is similar in efficacy to the sulfonylureas. It lowers A_1c by 1.5–2.0 percentage points and fasting plasma glucose by 60–80 mg/dL. Its antihyperglycemic efficacy is independent of patient age, duration of diabetes, or BMI.²²

In the UKPDS 34 study, a subgroup of obese patients was randomized to receive intensive control (group 1, metformin; group 2, a sulfonylurea or insulin) or conventional diet therapy (group 3). Despite a similar reduction in the A_1c level between the 2 intensive-treatment groups, patients treated with metformin had a 32% reduction for any diabetes-related endpoint (95% CI, 13–47; P=.002), 43% fewer diabetes-related deaths (95% CI, 9–63; P=.017), and a 36% reduction in all cause mortality, compared with the diet therapy group (95% CI, 9–55; P=.011).²³

Metformin also showed significant benefit when compared with patients receiving sulfonylurea or insulin (group 2). The absolute risk of any diabetes endpoint was 29.8 vs. 40.1 (events per 1000 patient-years; P=.0034), all-cause mortality (13.5 vs 18.9; P=.021), and stroke (3.3 vs 6.2; P=.032), respectively, for metformin vs sulfonylurea or insulin (group 2). Thus, metformin is the only oral hypoglycemic agent proven to reduce macrovascular risk in overweight patients with type 2 diabetes. For perspective, in overweight patients, metformin significantly reduced all-cause mortality (NNT per year=141; 95% CI, 115–183; P=.011), and any diabetes-related outcome (NNT per year=74; 95% CI, 63–90; P=.0023), compared with diet alone.^23,24

Metformin induces weight loss (2–3 kg), preferentially involving adipose tissue in obese patients with type 2 diabetes over 4 to 6 months.^22,25 In UKPDS 34, weight gain was similar among those treated with metformin and diet (approximately 2 kg); weight gain over 10 years was less with metformin, however, than with sulfonylurea (approximately 4 kg) or insulin (approximately 6 kg).²³ Metformin also significantly improved levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides when compared with glyburide or placebo.²²

Risk of lactic acidosis. Lactic acidosis associated with metformin is a rare but serious adverse event, with an estimated prevalence of 3 cases per 100,000.²⁶ The product labeling notes most of these cases have occurred among patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion. Absolute contraindications include renal disease (serum creatinine ≥1.5 mg/dL [males] and ≥1.4 mg/dL [females]), congestive heart failure requiring pharmacological treatment, and acute or chronic metabolic acidosis. It should also be discontinued at the time of radiologic studies using intravascular iodinated contrast materials.

Additional “precautionary conditions” include age ≥80 years (unless measurement of creatinine clearance demonstrates that renal function is not reduced), hepatic disease, cationic drug use, conditions associated with hypoxia (eg, chronic obstructive pulmonary disease [COPD], acute myocardial infarction, dehydration, sepsis), excessive alcohol intake, and surgery, until patient’s oral intake is resumed.

Is the risk overstated? Despite these extensive precautions, published studies show that metformin is commonly prescribed to patients with absolute contraindications.^27,28 One recent study observed that 11.2% of Medicare beneficiaries hospitalized with congestive heart failure and concomitant diabetes were treated with metformin.²⁸ In the absence of advanced renal dysfunction, metformin rarely accumulates in the body,²⁹ and accumulation of metformin is rarely reported as a cause of lactic acidosis.^30,31 Rather, tissue hypoxia acts as a trigger in most cases. Metformin should therefore be discontinued whenever tissue hypoxia is suspected.³¹

A recent systematic review and meta analysis found no evidence that metformin was associated with an increased risk of lactic acidosis if the drug was prescribed under study conditions, taking into account contraindications.³² Refinement and clarification of the risk for lactic acidosis in these various populations is needed, to ensure optimal patient safety and to further assess this highly effective medication.

Common adverse effects associated with metformin are diarrhea and nausea, which can be minimized by administering the drug with meals and slowly titrating the dose, or perhaps by using the extended-release formulation.

Thiazolidinediones

Thiazolidinediones (TZDs) include rosiglitazone and pioglitazone. These agents, like metformin, do not increase insulin secretion but depend on the presence of insulin for their activity. TZDs are agonists at peroxisome-proliferator-activated receptor gamma (PPAR-γ) receptors in peripheral tissues such as skeletal muscle, where they increase glucose uptake.¹⁵ Thus, their predominant effect is to decrease insulin resistance.

TZDs have similar antihyperglycemic efficacy as sulfonylureas or metformin. They decrease A_1c levels by 0.6–1.9 percentage points and lower fasting plasma glucose levels by 50–80 mg/dL.¹⁵ They have a slower onset of action compared with other hypoglycemic drugs, and intervals of 3 to 4 weeks should be allowed between doses before increasing the dosage. TZDs also have favorable effects on lipid levels: HDL concentrations increase and triglyceride concentrations decrease with their use.³³ It is not known whether they decrease macrovascular or microvascular complications, although such studies are underway.

Adverse effects. TZDs are typically well tolerated, though weight gain of 1–3 kg, edema (4%–5%) and anemia (1%–2%) can occur. Weight gain and edema are more pronounced when TZDs are used in combination with insulin. Anemia is likely due to increased plasma volume rather than any significant hematological effect.

Due to adverse events related to volume expansion, TZDs are not recommended for patients with New York Heart Association class III or IV heart failure. A recent consensus statement from the American Heart Association and the ADA stresses that before administering TZD treatment, the physician should explore the possible presence of cardiac disease, use of other drugs that cause fluid retention, and the pathogenesis of any existing edema or dyspnea.³⁴

Although troglitazone was removed from the market due to its association with hepatocellular injury, pioglitazone and rosiglitazone are not as convincingly associated with liver injury.¹⁵ In preapproval clinical studies, less than 0.5% of patients treated with rosiglitzone and pioglitazone had elevations in alanine transaminase (ALT) >3 times the upper limit of normal.

The incidence of hepatitis or acute liver failure from troglitazone was compared with rosiglitazone, pioglitazone, metformin, and glyburide, by analysis of spontaneously reported adverse events to the Food and Drug Administration (FDA) MEDWATCH database during the first 15 months of marketing of each drug.^35,36 The incidence of hepatitis per million prescriptions was 21.5, 14.7, 9.4, 2.9, and 4.1, respectively, while the incidence of acute liver failure per 100,000 prescriptions was 4.6, 0.9, 0.8, 0.2, and 0. It appears that postmarketing data support preclinical studies, in that the incidence of acute liver failure is an order of magnitude higher for troglitazone vs. other TZDs.³⁵ However, the FDA recommends avoiding their use in patients with baseline ALT levels >2.5 times the upper limit of normal. The FDA recently reduced the recommended frequency for ALT monitoring for pioglitazone (and is currently considering the same for rosiglitazone). Serum ALT is recommended prior to initiation and then periodically thereafter.

Cost. TZDs are expensive relative to other hypoglycemic agents.

α-glucosidase inhibitors

The α-glucosidase inhibitors (AGIs), acarbose and miglitol, act through competitive, reversible inhibition of membrane-bound intestinal α-glucosidase, which hydrolyzes complex carbohydrates to glucose and other monosaccharides. This inhibition delays glucose absorption and decreases postprandial hyperglycemia.³⁷ Thus, they have a nonsystemic mechanism of action.

These agents cause a modest reduction in the A_1c level (0.5–1.0 percentage points) and are thus less effective than sulfonylureas, metformin, or TZDs. They do not reduce fasting plasma glucose levels, but reduce postprandial hyperglycemia by 50 mg/dL.³⁸ No long-term studies have evaluated whether AGIs reduce diabetes-related macrovascular or microvascular outcomes.

Adverse effects. While AGIs are virtually free of serious toxicities, patient tolerability can be a problem due to adverse gastrointestinal effects. In indirect comparisons from placebo-controlled trials, patients treated with miglitol and acarbose commonly reported abdominal pain (11.7%, 19%), diarrhea (28.7%, 31%), and flatulence (41.5%, 74%), respectively. Systemic accumulation of AGIs has been shown to increase in proportion to the degree of renal insufficiency, and their use is not recommended for patients with serum creatinine >2.0 mg/dL. However, whether such patients are at greater risk of any toxicity is unknown. Acarbose at doses above 100 mg 3 times daily has been associated with elevated serum transaminase levels; however, this risk appears negligible at standard doses.

Insulin

Insulin is the oldest therapy for diabetes, and it has no upper dose limit.³⁹ It increases insulin levels and can reduce A_1c levels by 1.5 to 2.5 percentage points. Though half of diabetes patients need insulin eventually for optimal control, historically it has been introduced late in the disease process unless patients have severe hyperglycemia (fasting blood sugar >350 mg/dL) or ketonuria.³⁸ However, it is effective in gaining initial control, decreasing gluconeogenesis and increasing glucose uptake. Disadvantages are weight gain, hypoglycemia, and patient reluctance to give injections.

When insulin is indicated. Patients who exhibit persistent hyperglycemia despite oral hypoglycemic therapy may stop the oral drug(s) and begin insulin. By combining insulin with oral therapy, lower insulin doses may be used to achieve desired control vs using insulin alone.⁴⁰ For some patients a basal supplement of insulin may be sufficient and can be given as a single dose at bedtime, without an oral hypoglycemic drug.⁴¹

Insulin regimens. Various insulin regimens are available: very rapid acting (lispro and aspart), rapid acting (regular), intermediate acting (isophane insulin [NPH] and lente) and very long acting (ultralente and glargine). Glargine insulin (Lantus) has more predictable absorption than NPH, lente, and ultralente. Lantus, compared with NPH, has been associated with less nocturnal and postprandial hypoglycemia.^38,42,43 This is consistent with the peakless and longer duration of glargine compared with NPH.⁴⁴ A recent randomized controlled trial demonstrated that morning insulin glargine lowered A_1c levels more than a bedtime dose of NPH (–1.24 vs –0.84; 95% CI, 0.23%–0.58%) or a bedtime dose of glargine (–1.24 vs –0.96%; 95% CI, 0.11%–0.46%).⁴⁵ Glargine’s only relative disadvantage is increased cost.

Combination products. Combination insulin options are 70 NPH/30 regular, 50 NPH/50 regular, and 75 lispro protamine/25 lispro. Many combinations of insulin regimens have been used successfully. The typical range of insulin needed for monotherapy is 0.4–1 U/kg/d. Once-daily injection of intermediate acting or long acting insulins at bedtime or before breakfast, once-daily or twice-daily combinations of intermediate and rapid acting insulins, and more complex regimens have been used to good effect.

Using prandial insulin at each meal with separate basal insulin adds flexibility to meal times and doses administered.⁴³ With multiple-dose intensive insulin therapy, a basal dose suppresses hepatic glucose output and the bolus doses enhance postprandial glucose uptake. This intensive insulin treatment reduces mortality among critically ill patients in surgical intensive care units and for those with acute myocardial infarction.^46,47 An algorithm for using progressive therapy in diabetes mellitus is shown in Figure 2.⁴⁸

FIGURE 2
ADA recommendations for the treatment of type 2 diabetes

Combination Therapy

Over time glycemic control becomes more difficult, even with maximum monotherapy for patients with healthy lifestyles. It was shown in UKPDS 49 that monotherapy with sulfonylurea, metformin, or insulin eventually fails in most cases—by 3 years after diagnosis, about 50% of patients need more than monotherapy; 75% by 9 years.⁴⁹ In UKPDS 33, the median A_1c level increased steadily over 10 years with both conventional therapy and intensive therapy (Figure 3).²

Several options are available when monotherapy fails. Based on expert opinion, the principle is to combine drugs with different mechanisms of action to achieve an additive effect for glycemic control. Combination products may simplify the treatment regimen and improve adherence. In many instances, they may also cost less.⁵⁰

Successful combinations. The combination of sulfonylurea and metformin has proven effective in many studies.^22,51,52 One study showed that initial treatment with glyburide/metformin improved glycemic control better than either glyburide or metformin monotherapy (SOR: A).^53,54 The addition of the non-SU secretagogues repaglinide and nateglinide to metformin significantly improved glycemic control, with repaglinide showing superiority over nateglinide.⁵⁵ A TZD added to a sulfonylurea has also significantly improved A_1c and fasting blood sugar results.⁵⁶ Patients whose diabetes was inadequately controlled with diet alone or diet plus a sulfonylurea showed improvement with the addition of the AGI miglitol, compared with addition of placebo.⁵⁷ The AGI acarbose has shown to be an effective addition to diet, metformin, sulfonylurea, and insulin.⁵⁸ A TZD added to metformin has also been shown to improve glycemic control.⁵⁹ A non-SU added to patients inadequately controlled with a TZD has also been effective.⁶⁰

The early addition of insulin when maximal sulfonylurea therapy is inadequate has been effective.^61-63 When introducing insulin, a nighttime regimen of NPH or glargine, 10 units at bedtime, is an appropriate dose (SOR: C). This is easier and less costly than often assumed, and helps improve glycemic control.⁶⁴ Most patients require combination therapy as their disease progresses.³⁹

FIGURE 3
Glycemic control in type 2 DM

Improving Outcomes

Cumulative survey data reveal a wide gap between guideline recommendations and the care patients receive.⁶⁵ One study showed that physicians initiated treatment changes only after the A_1c level had reached 9.0% or higher instead of the 8.0% level recommended by ADA.⁶⁶ How can the quality of management be improved?

In private practices and institutions, many interventions have been shown to improve outcomes in diabetes mellitus. Education measures work, and they include chart audits, reminder cards, pharmacist collaboration, flow sheets, and nursing initiatives.^67,68 Effective disease-management programs have also used clinical guidelines, outcomes reporting, coverage of glucose meters and strips, and the support of clinical leadership.⁶⁹

Computerized systems that track patients and recommended laboratory tests have improved screening rates and glycemic and blood pressure control.⁷⁰ Monitoring patients’ readiness to change has allowed targeted education to improve A_1c levels.⁷¹ Continuity of care has also improved the quality of disease control by increasing adherence to recommended tests and exams.⁷²

Acknowlegments

The authors thank Marie Hamer, RN, for her continuous diabetes quality improvement efforts and Jean Camarata for her editorial and reference acquisition assistance.

Corresponding author
John E. Sutherland, MD, Northeast Iowa Family Practice Residency Program, University of Iowa College of Medicine, 2055 Kimball Avenue, Waterloo, Iowa 50702. E-mail: [email protected].

You are more likely to see depression in your practice than any other disorder except hypertension.¹ Given the prevalence of depression* and the variability of its clinical symptoms and comorbidities, how do you determine the optimal therapy for a given patient?

A sobering thought: nearly half of all patients stop taking their antidepressant prescription medication within the first month of treatment.¹ We discuss the critical factors you can address to help patients stick with treatment and achieve the best outcome.

Therapeutic Options

Pharmacotherapy

Antidepressants are thought to exert their therapeutic and adverse effects through 3 chemical monamine neurotransmission systems; by increasing levels of norepinephrine, serotonin, or dopamine in the synapse; and by resultant secondary changes in presynaptic and postsynaptic receptor physiology.^3,8,9 Newer medications—such as selective serotonin reuptake inhibitors (SSRIs)—have simpler dose schedules, different (and for some patients more favorable) adverse effect profiles, and less likelihood of causing death from overdose compared with older tricyclic antidepressants (TCAs) and monamine oxidase inhibitors (MAOIs).

Patients are less likely to discontinue treatment with SSRIs than with TCAs (odds ratio=1.21; 95% confidence interval [CI], 1.12–1.30).¹⁰

However, there are no clinically significant differences in effectiveness between SSRIs and TCAs (strength of recommendation [SOR]: A).¹¹ Importantly, although practice patterns in the use of antidepressants have changed, some reasons for the preference of newer effective agents have not been substantiated. For instance, we do not know whether the patient population taking newer agents has a lower rate of suicide, despite the difference in fatality risk mentioned earlier.

Combined pharmacotherapy and psychiatric consultation

Combining pharmacotherapy and psychotherapy can be more effective than either modality alone. In one study, 73% of patients with chronic depression treated with combination therapy showed a reduction of 50% or more on the Hamilton Rating Scale for Depression (HRSD), compared with just 48% in the nefazodone-only and psychotherapy-only groups (SOR: A). Among those who completed the study, the rates of response were 85%, 55%, and 52%, respectively (although the results considered compliant patients only, which biases the results in favor of treatment).²

Among elderly depressed patients who received home care, 58% of those who underwent intervention by a psychogeriatric team recovered, compared with just 25% in the control group (SOR: A).¹² The intervention group received a multidisciplinary team evaluation and an individualized management plan, which could include any combination of physical, psychological, or social interventions. The control group received usual care from their general practitioner.

Studies of combination therapy have yielded mixed results, but guidelines from the psychiatric literature based on clinical experience advocate concomitant psychotherapy and medication (SOR: A).¹³ For patients with persistent symptoms after 6 to 8 weeks of taking antidepressant medication, concomitant psychotherapy improved compliance, satisfaction, and outcomes when compared with usual care.¹⁴

The concomitant therapy group participated in a multifaceted program including education, psychiatric referral, pharmacy utilization records, and primary physician feedback. The usual care group received standard antidepressants and follow-up visits from their family physician, with optional referral to a mental health provider.

Psychotherapy has also been shown to decrease the risk of relapse once symptoms have remitted.¹⁵ Primary care physicians can also incorporate counseling as adjunctive therapy.

Herbal and nutritional products

St. John’s wort. St. John’s wort (Hypericum perforatum L.) has been used as an herbal medication for more than 2000 years. Its efficacy in the treatment of depression has been studied extensively. Some studies demonstrated that these extracts are more effective than placebo for the short-term treatment of mild and moderate depression.^16,17,18 Two randomized controlled trials demonstrated minimal efficacy of St. John’s wort in moderately severe major depression.^19,20 The National Institutes of Health is sponsoring a placebo-controlled, double-blinded trial comparing St. John’s wort with SSRIs.²¹

Omega-3 fatty acids. Chronic deficiencies of essential fatty acids may adversely affect central nervous system function. In a small, 4-week double-blind study, outpatients receiving antidepressant therapy who were also given eicosapentaenoic acid exhibited improvement in core depressive symptoms (eg, worthlessness, guilt, insomnia) compared with the antidepressantplus-placebo group. Larger, long-term prospective trials are needed to confirm an antidepressant effect with omega-3 fatty acids.²²

S-adenosyl-L-methionine. S-adenosyl-L-methionine is possibly effective for short-term treatment of major depression. Data for other herbal or nutritional remedies are negligible.²³

Exercise

Physical activity may play an important role in relieving depression. One randomized controlled trial showed that an aerobic exercise program, sertraline therapy, or a combination of both were equally effective in the treatment of depression, although there was a more rapid initial response with sertraline.²⁴

A systematic review and meta-analysis concluded that exercise may reduce depression symptoms short term, but much of the evidence is of poor quality.²⁵ Well-controlled studies are needed to clarify the role of exercise in the treatment of depression. However, exercise is promising enough to consider implementation in clinical practice at this time.

Treatment strategy

Guidelines for medicating patients and setting expectations

Start antidepressant therapy promptly when depression is diagnosed. Maintain the initial dosage for at least 3 to 4 weeks before increasing it. A trial of 6 to 8 weeks at maximum dosage (or the maximum tolerated dosage) is necessary to confirm treatment success or failure.^26,27,28

An improvement in symptoms will usually not be noted until after 2 to 6 weeks of therapy. Depending on depression severity, schedule weekly or monthly visits for patients during the initial treatment phase. The response rate to initial treatment is only 50% to 60%, but more than 80% of depressed patients will respond to at least 1 medication.¹

Response to placebo is highly variable. It is often substantial and has increased in recent years. In an analysis of 75 trials between 1981 and 2001, the mean proportion of patients in the placebo group who responded (50% improvement on the HRSD) was 29.7%, compared with 50.1% in the active medication group.²⁹ The placebo effect may reflect some combination of patient expectations, the natural history of depression with possible spontaneous remission, and limitations of study methods.

Antidepressant therapy is effective compared with placebo for depression secondary to medical illness (number needed to treat [NNT], 4.2; 95% CI, 3.2–6.4), with minimal treatment dropout (number needed to harm, 9.8; 95% CI, 5.4–42.9).³⁰ Although many patients settle for partial improvement of their symptoms, the treatment goal should be complete remission.

Factors in drug selection

Selecting an antidepressant can be challenging: more than 24 drugs are on the market, each working through 1 or more of 7 pharmacologic mechanisms. Theoretically, choosing a drug is made easier by matching patient symptoms to likely medication side effects or by knowing that the patient or a family member responded favorably to a particular antidepressant in the past.

This intuitive model has not been proven superior to any other model of selecting antidepres-sants, but it is clinically sound, pharmacodynamically appealing, and supported by case reports. Its strength may lie in enhancing patient adherence during the critical initial phase of treatment.

A recent randomized, prospective comparison of the SSRIs paroxetine, fluoxetine, and sertraline showed similar effectiveness and tolerability (SOR: A).³¹ This suggests that efforts to individualize therapy based on comorbidities or likely side effects may not be as useful when choosing from among analogous SSRIs.

Nevertheless, choosing a drug that is effective, convenient, and well tolerated will improve the likelihood of achieving and maintaining a full remission. The data on adverse effects of antidepressants are widely available and well understood. Also consider cost (Table).

Preferences based on characteristics. For a patient whose depression is not complicated by other clinical conditions, the initial choice of antidepressant would usually be an SSRI. But nefazodone, mirtazapine, bupropion, or low-dose venlafaxine may be equally appropriate.

For a patient whose depression has other specific components, use your knowledge of drugs’ common side effects to fit the patient’s clinical profile.

• If there is generalized anxiety, agitation, and insomnia, both nefazodone⁸ and mirtazapine³² are excellent choices. Trazodone at low doses is often used as a sedative with nonsedating antidepressants.⁸
• If weight gain is desired, mirtazapine is indicated.³²
• If tobacco cessation is a secondary goal, bupropion is preferred.³¹
• Those suffering from hypersomnia, retarded depression, cognitive slowing, and pseudodementia would benefit from bupropion or venlafaxine.⁹
• For more severely depressed patients, venlafaxine may be advantageous due to its dual serotonergic and noradrenergic activity at moderate to high doses.^34,35,36 Mirtazapine and TCAs are also useful in severe depression, as well as for coexisting chronic pain syndromes.⁸ For refractory or atypical depression in motivated and compliant patients, MAOIs my be useful.⁸

When to avoid specific drugs.

• Patients with hypersomnia and motor retardation should avoid nefazodone and mirtazapine.^8,32
• With obesity, mirtazapine and TCAs are least preferred.^8,32
• If sexual dysfunction preceded depression, avoid giving SSRIs and venlafaxine.³
• Those experiencing agitation and insomnia should avoid bupropion and venlafaxine.³
• Seizure disorder is a contraindication to bupropion.³
• Hypertension is a relative contraindication to venlafaxine.³
• Liver disease is a contraindication to nefazodone.³⁷
• Preexisting heart disease and increased suicide risk are both relative contraindications to TCAs.⁸

TABLE
Comparative dosages and costs of antidepressant drugs

Helping nonresponders

Patients whose symptoms do not improve with therapy could be switched to a different monotherapy or to multiple drugs. Drug choices for treatment-refractory and nonresponding patients have evolved more by anecdote than by systematic study.⁹

Switch drugs. The benefit of switching patients to another category of antidepressant was recently demonstrated in a study where nearly half of patients who did not respond to an initial antidepressant, whether SSRI or TCA, responded when switched to the alternate agent (SOR: A).³⁸ It is also beneficial to switch medications within a category (SOR: B).^27,39,40

Add a drug. Adding a second antidepressant from a category with a different mechanism of action often enhances clinical efficacy. This has been demonstrated in combining an SSRI with a TCA (SOR: B).⁴¹ Though response rates are very similar for various antidepressants, complete remission and rates of response in severely depressed patients may be higher in dual-action antidepressants (SOR: A).^34,35,36

Add lithium. A great deal of evidence supports the use of lithium augmentation (SOR: A).^42,43 This agent should be used more in primary care and not only by psychiatrists. A recent meta-analysis of double-blind, placebo-controlled studies of lithium (given at a dosage of at least 800 mg/d or at a level high enough to achieve a serum drug concentration of 0.5 mEq/L for at least 2 weeks) found a summary pooled odds ratio of response to lithium of 3.31 (95% CI, 1.46–7.53) with a NNT of 3.7.⁴⁴ Other studies have been less clear on the optimal dose or blood level, so a starting dose of 300 mg twice daily with a serum drug concentration of 0.4 mEq/L has been recommended.

If renal function is normal, the concentration of lithium can be checked 5 days after a patient has received a stable dosage, at least 8 hours fol-lowing the last dose. Lithium may cause thyroid abnormalities; monitoring should include a measurement of thyroid-stimulating hormone, repeated at 6 months and 1 year.

Other augmentation options. Augmentation of antidepressants with buspirone has been proven useful in major depression (SOR: B).⁴⁵ Thyroid supplementation may also increase the effectiveness of antidepressant therapy using triiodothyronine (T₃), at doses not to exceed 50 mcg per day (SOR: B).^46,47 Electroconvulsive therapy (ECT) has a high rate of therapeutic success, including speed and safety, but it is not administered as first-line treatment by psychiatrists except in severe cases (SOR: A).^48,49 Augmentation with antipsychotic or anticonvulsants is another strategy that shows some benefit for select patients.⁵⁰

Texas medication algorithm project

The process of drug selection just described can avoid treatment-threatening side effects, enable patient adherence to treatment, and maximize the potential for therapeutic response. However, the model can become disorienting for the clinician and the patient if 1 or 2 initial selections for treatment do not succeed. A useful synergy may be achieved by adapting the intuitive model to an algorithmic model—the Texas Medication Algorithm Project (TMAP). TMAP is an evolving model that reflects ongoing clinical research in the treatment of depression.²⁷

Developed in 1995 from a review of existing antidepressant research and several consensus conferences, the TMAP (continually updated with new research findings) has developed algorithms for treatment of schizophrenia and bipolar disorder in addition to major depression. At each stage in the depression algorithm, treatment plans similar in efficacy and safety are grouped together, and the clinician is given a limited number of options. The later stages in the algorithm are more complex, admittedly with a greater potential for medical complications (Figure).⁵¹

The algorithm represents a tentative foundation for a sequenced medication plan. Research pertaining to the selection of antidepressant medicationis underway, sponsored by the National Institute of Mental Health. Unlike most antide-pressant trials, this study includes subjects with significant concomitant medical illnesses.

FIGURE
Treatment of chronic major depression*

When to refer

Patients requiring referral to a psychiatrist include those with suicidal ideation or severe depression, aggressive ideation, bipolar disorder, atypical depression, psychotic depression, substance abuse, or treatment resistance.⁵² Referral to a licensed counselor should be offered to most patients with depression, with or without psychiatric involvement, though many factors (eg, patient motivation, capacity for insight, patient perceptions of therapist) will affect follow-through and outcome.

Maintenance therapy

Once full remission has been achieved, 6 to 12 months of continued pharmacotherapy at the same dose is recommended, as it decreases the risk of relapse by 70%.^5,21,26 More than half of patients will have a recurrence of depression in their lifetime, and they should be advised about this risk.¹

A second episode of major depression confers an 80% chance of additional recurrences, and patients should therefore be maintained on medication for 1 to 2 years.

A third episode requires indefinite maintenance treatment because of a 90% recurrence rate.^3,26

Follow-up visits after remission can be tapered gradually to once every 3 months. Discontinuation of therapy should be done gradually to minimize withdrawal reactions; it also necessitates follow-up visits or phone calls.

* For a review of screening for depression, see Nease DE, Malouin JM. Depression screening: A practical strategy. J Fam Pract 2003; 52(2):118–126.

You are more likely to see depression in your practice than any other disorder except hypertension.¹ Given the prevalence of depression* and the variability of its clinical symptoms and comorbidities, how do you determine the optimal therapy for a given patient?

A sobering thought: nearly half of all patients stop taking their antidepressant prescription medication within the first month of treatment.¹ We discuss the critical factors you can address to help patients stick with treatment and achieve the best outcome.

Therapeutic Options

Pharmacotherapy

Antidepressants are thought to exert their therapeutic and adverse effects through 3 chemical monamine neurotransmission systems; by increasing levels of norepinephrine, serotonin, or dopamine in the synapse; and by resultant secondary changes in presynaptic and postsynaptic receptor physiology.^3,8,9 Newer medications—such as selective serotonin reuptake inhibitors (SSRIs)—have simpler dose schedules, different (and for some patients more favorable) adverse effect profiles, and less likelihood of causing death from overdose compared with older tricyclic antidepressants (TCAs) and monamine oxidase inhibitors (MAOIs).

Patients are less likely to discontinue treatment with SSRIs than with TCAs (odds ratio=1.21; 95% confidence interval [CI], 1.12–1.30).¹⁰

However, there are no clinically significant differences in effectiveness between SSRIs and TCAs (strength of recommendation [SOR]: A).¹¹ Importantly, although practice patterns in the use of antidepressants have changed, some reasons for the preference of newer effective agents have not been substantiated. For instance, we do not know whether the patient population taking newer agents has a lower rate of suicide, despite the difference in fatality risk mentioned earlier.

Combined pharmacotherapy and psychiatric consultation

Combining pharmacotherapy and psychotherapy can be more effective than either modality alone. In one study, 73% of patients with chronic depression treated with combination therapy showed a reduction of 50% or more on the Hamilton Rating Scale for Depression (HRSD), compared with just 48% in the nefazodone-only and psychotherapy-only groups (SOR: A). Among those who completed the study, the rates of response were 85%, 55%, and 52%, respectively (although the results considered compliant patients only, which biases the results in favor of treatment).²

Among elderly depressed patients who received home care, 58% of those who underwent intervention by a psychogeriatric team recovered, compared with just 25% in the control group (SOR: A).¹² The intervention group received a multidisciplinary team evaluation and an individualized management plan, which could include any combination of physical, psychological, or social interventions. The control group received usual care from their general practitioner.

Studies of combination therapy have yielded mixed results, but guidelines from the psychiatric literature based on clinical experience advocate concomitant psychotherapy and medication (SOR: A).¹³ For patients with persistent symptoms after 6 to 8 weeks of taking antidepressant medication, concomitant psychotherapy improved compliance, satisfaction, and outcomes when compared with usual care.¹⁴

The concomitant therapy group participated in a multifaceted program including education, psychiatric referral, pharmacy utilization records, and primary physician feedback. The usual care group received standard antidepressants and follow-up visits from their family physician, with optional referral to a mental health provider.

Psychotherapy has also been shown to decrease the risk of relapse once symptoms have remitted.¹⁵ Primary care physicians can also incorporate counseling as adjunctive therapy.

Herbal and nutritional products

St. John’s wort. St. John’s wort (Hypericum perforatum L.) has been used as an herbal medication for more than 2000 years. Its efficacy in the treatment of depression has been studied extensively. Some studies demonstrated that these extracts are more effective than placebo for the short-term treatment of mild and moderate depression.^16,17,18 Two randomized controlled trials demonstrated minimal efficacy of St. John’s wort in moderately severe major depression.^19,20 The National Institutes of Health is sponsoring a placebo-controlled, double-blinded trial comparing St. John’s wort with SSRIs.²¹

Omega-3 fatty acids. Chronic deficiencies of essential fatty acids may adversely affect central nervous system function. In a small, 4-week double-blind study, outpatients receiving antidepressant therapy who were also given eicosapentaenoic acid exhibited improvement in core depressive symptoms (eg, worthlessness, guilt, insomnia) compared with the antidepressantplus-placebo group. Larger, long-term prospective trials are needed to confirm an antidepressant effect with omega-3 fatty acids.²²

S-adenosyl-L-methionine. S-adenosyl-L-methionine is possibly effective for short-term treatment of major depression. Data for other herbal or nutritional remedies are negligible.²³

Exercise

Physical activity may play an important role in relieving depression. One randomized controlled trial showed that an aerobic exercise program, sertraline therapy, or a combination of both were equally effective in the treatment of depression, although there was a more rapid initial response with sertraline.²⁴

A systematic review and meta-analysis concluded that exercise may reduce depression symptoms short term, but much of the evidence is of poor quality.²⁵ Well-controlled studies are needed to clarify the role of exercise in the treatment of depression. However, exercise is promising enough to consider implementation in clinical practice at this time.

Treatment strategy

Guidelines for medicating patients and setting expectations

Start antidepressant therapy promptly when depression is diagnosed. Maintain the initial dosage for at least 3 to 4 weeks before increasing it. A trial of 6 to 8 weeks at maximum dosage (or the maximum tolerated dosage) is necessary to confirm treatment success or failure.^26,27,28

An improvement in symptoms will usually not be noted until after 2 to 6 weeks of therapy. Depending on depression severity, schedule weekly or monthly visits for patients during the initial treatment phase. The response rate to initial treatment is only 50% to 60%, but more than 80% of depressed patients will respond to at least 1 medication.¹

Response to placebo is highly variable. It is often substantial and has increased in recent years. In an analysis of 75 trials between 1981 and 2001, the mean proportion of patients in the placebo group who responded (50% improvement on the HRSD) was 29.7%, compared with 50.1% in the active medication group.²⁹ The placebo effect may reflect some combination of patient expectations, the natural history of depression with possible spontaneous remission, and limitations of study methods.

Antidepressant therapy is effective compared with placebo for depression secondary to medical illness (number needed to treat [NNT], 4.2; 95% CI, 3.2–6.4), with minimal treatment dropout (number needed to harm, 9.8; 95% CI, 5.4–42.9).³⁰ Although many patients settle for partial improvement of their symptoms, the treatment goal should be complete remission.

Factors in drug selection

Selecting an antidepressant can be challenging: more than 24 drugs are on the market, each working through 1 or more of 7 pharmacologic mechanisms. Theoretically, choosing a drug is made easier by matching patient symptoms to likely medication side effects or by knowing that the patient or a family member responded favorably to a particular antidepressant in the past.

This intuitive model has not been proven superior to any other model of selecting antidepres-sants, but it is clinically sound, pharmacodynamically appealing, and supported by case reports. Its strength may lie in enhancing patient adherence during the critical initial phase of treatment.

A recent randomized, prospective comparison of the SSRIs paroxetine, fluoxetine, and sertraline showed similar effectiveness and tolerability (SOR: A).³¹ This suggests that efforts to individualize therapy based on comorbidities or likely side effects may not be as useful when choosing from among analogous SSRIs.

Nevertheless, choosing a drug that is effective, convenient, and well tolerated will improve the likelihood of achieving and maintaining a full remission. The data on adverse effects of antidepressants are widely available and well understood. Also consider cost (Table).

Preferences based on characteristics. For a patient whose depression is not complicated by other clinical conditions, the initial choice of antidepressant would usually be an SSRI. But nefazodone, mirtazapine, bupropion, or low-dose venlafaxine may be equally appropriate.

For a patient whose depression has other specific components, use your knowledge of drugs’ common side effects to fit the patient’s clinical profile.

• If there is generalized anxiety, agitation, and insomnia, both nefazodone⁸ and mirtazapine³² are excellent choices. Trazodone at low doses is often used as a sedative with nonsedating antidepressants.⁸
• If weight gain is desired, mirtazapine is indicated.³²
• If tobacco cessation is a secondary goal, bupropion is preferred.³¹
• Those suffering from hypersomnia, retarded depression, cognitive slowing, and pseudodementia would benefit from bupropion or venlafaxine.⁹
• For more severely depressed patients, venlafaxine may be advantageous due to its dual serotonergic and noradrenergic activity at moderate to high doses.^34,35,36 Mirtazapine and TCAs are also useful in severe depression, as well as for coexisting chronic pain syndromes.⁸ For refractory or atypical depression in motivated and compliant patients, MAOIs my be useful.⁸

When to avoid specific drugs.

• Patients with hypersomnia and motor retardation should avoid nefazodone and mirtazapine.^8,32
• With obesity, mirtazapine and TCAs are least preferred.^8,32
• If sexual dysfunction preceded depression, avoid giving SSRIs and venlafaxine.³
• Those experiencing agitation and insomnia should avoid bupropion and venlafaxine.³
• Seizure disorder is a contraindication to bupropion.³
• Hypertension is a relative contraindication to venlafaxine.³
• Liver disease is a contraindication to nefazodone.³⁷
• Preexisting heart disease and increased suicide risk are both relative contraindications to TCAs.⁸

TABLE
Comparative dosages and costs of antidepressant drugs

Helping nonresponders

Patients whose symptoms do not improve with therapy could be switched to a different monotherapy or to multiple drugs. Drug choices for treatment-refractory and nonresponding patients have evolved more by anecdote than by systematic study.⁹

Switch drugs. The benefit of switching patients to another category of antidepressant was recently demonstrated in a study where nearly half of patients who did not respond to an initial antidepressant, whether SSRI or TCA, responded when switched to the alternate agent (SOR: A).³⁸ It is also beneficial to switch medications within a category (SOR: B).^27,39,40

Add a drug. Adding a second antidepressant from a category with a different mechanism of action often enhances clinical efficacy. This has been demonstrated in combining an SSRI with a TCA (SOR: B).⁴¹ Though response rates are very similar for various antidepressants, complete remission and rates of response in severely depressed patients may be higher in dual-action antidepressants (SOR: A).^34,35,36

Add lithium. A great deal of evidence supports the use of lithium augmentation (SOR: A).^42,43 This agent should be used more in primary care and not only by psychiatrists. A recent meta-analysis of double-blind, placebo-controlled studies of lithium (given at a dosage of at least 800 mg/d or at a level high enough to achieve a serum drug concentration of 0.5 mEq/L for at least 2 weeks) found a summary pooled odds ratio of response to lithium of 3.31 (95% CI, 1.46–7.53) with a NNT of 3.7.⁴⁴ Other studies have been less clear on the optimal dose or blood level, so a starting dose of 300 mg twice daily with a serum drug concentration of 0.4 mEq/L has been recommended.

If renal function is normal, the concentration of lithium can be checked 5 days after a patient has received a stable dosage, at least 8 hours fol-lowing the last dose. Lithium may cause thyroid abnormalities; monitoring should include a measurement of thyroid-stimulating hormone, repeated at 6 months and 1 year.

Other augmentation options. Augmentation of antidepressants with buspirone has been proven useful in major depression (SOR: B).⁴⁵ Thyroid supplementation may also increase the effectiveness of antidepressant therapy using triiodothyronine (T₃), at doses not to exceed 50 mcg per day (SOR: B).^46,47 Electroconvulsive therapy (ECT) has a high rate of therapeutic success, including speed and safety, but it is not administered as first-line treatment by psychiatrists except in severe cases (SOR: A).^48,49 Augmentation with antipsychotic or anticonvulsants is another strategy that shows some benefit for select patients.⁵⁰

Texas medication algorithm project

The process of drug selection just described can avoid treatment-threatening side effects, enable patient adherence to treatment, and maximize the potential for therapeutic response. However, the model can become disorienting for the clinician and the patient if 1 or 2 initial selections for treatment do not succeed. A useful synergy may be achieved by adapting the intuitive model to an algorithmic model—the Texas Medication Algorithm Project (TMAP). TMAP is an evolving model that reflects ongoing clinical research in the treatment of depression.²⁷

Developed in 1995 from a review of existing antidepressant research and several consensus conferences, the TMAP (continually updated with new research findings) has developed algorithms for treatment of schizophrenia and bipolar disorder in addition to major depression. At each stage in the depression algorithm, treatment plans similar in efficacy and safety are grouped together, and the clinician is given a limited number of options. The later stages in the algorithm are more complex, admittedly with a greater potential for medical complications (Figure).⁵¹

The algorithm represents a tentative foundation for a sequenced medication plan. Research pertaining to the selection of antidepressant medicationis underway, sponsored by the National Institute of Mental Health. Unlike most antide-pressant trials, this study includes subjects with significant concomitant medical illnesses.

FIGURE
Treatment of chronic major depression*

When to refer

Patients requiring referral to a psychiatrist include those with suicidal ideation or severe depression, aggressive ideation, bipolar disorder, atypical depression, psychotic depression, substance abuse, or treatment resistance.⁵² Referral to a licensed counselor should be offered to most patients with depression, with or without psychiatric involvement, though many factors (eg, patient motivation, capacity for insight, patient perceptions of therapist) will affect follow-through and outcome.

Maintenance therapy

Once full remission has been achieved, 6 to 12 months of continued pharmacotherapy at the same dose is recommended, as it decreases the risk of relapse by 70%.^5,21,26 More than half of patients will have a recurrence of depression in their lifetime, and they should be advised about this risk.¹

A second episode of major depression confers an 80% chance of additional recurrences, and patients should therefore be maintained on medication for 1 to 2 years.

A third episode requires indefinite maintenance treatment because of a 90% recurrence rate.^3,26

Follow-up visits after remission can be tapered gradually to once every 3 months. Discontinuation of therapy should be done gradually to minimize withdrawal reactions; it also necessitates follow-up visits or phone calls.

* For a review of screening for depression, see Nease DE, Malouin JM. Depression screening: A practical strategy. J Fam Pract 2003; 52(2):118–126.

You are more likely to see depression in your practice than any other disorder except hypertension.¹ Given the prevalence of depression* and the variability of its clinical symptoms and comorbidities, how do you determine the optimal therapy for a given patient?

A sobering thought: nearly half of all patients stop taking their antidepressant prescription medication within the first month of treatment.¹ We discuss the critical factors you can address to help patients stick with treatment and achieve the best outcome.

Therapeutic Options

Pharmacotherapy

Antidepressants are thought to exert their therapeutic and adverse effects through 3 chemical monamine neurotransmission systems; by increasing levels of norepinephrine, serotonin, or dopamine in the synapse; and by resultant secondary changes in presynaptic and postsynaptic receptor physiology.^3,8,9 Newer medications—such as selective serotonin reuptake inhibitors (SSRIs)—have simpler dose schedules, different (and for some patients more favorable) adverse effect profiles, and less likelihood of causing death from overdose compared with older tricyclic antidepressants (TCAs) and monamine oxidase inhibitors (MAOIs).

Patients are less likely to discontinue treatment with SSRIs than with TCAs (odds ratio=1.21; 95% confidence interval [CI], 1.12–1.30).¹⁰

However, there are no clinically significant differences in effectiveness between SSRIs and TCAs (strength of recommendation [SOR]: A).¹¹ Importantly, although practice patterns in the use of antidepressants have changed, some reasons for the preference of newer effective agents have not been substantiated. For instance, we do not know whether the patient population taking newer agents has a lower rate of suicide, despite the difference in fatality risk mentioned earlier.

Combined pharmacotherapy and psychiatric consultation

Combining pharmacotherapy and psychotherapy can be more effective than either modality alone. In one study, 73% of patients with chronic depression treated with combination therapy showed a reduction of 50% or more on the Hamilton Rating Scale for Depression (HRSD), compared with just 48% in the nefazodone-only and psychotherapy-only groups (SOR: A). Among those who completed the study, the rates of response were 85%, 55%, and 52%, respectively (although the results considered compliant patients only, which biases the results in favor of treatment).²

Among elderly depressed patients who received home care, 58% of those who underwent intervention by a psychogeriatric team recovered, compared with just 25% in the control group (SOR: A).¹² The intervention group received a multidisciplinary team evaluation and an individualized management plan, which could include any combination of physical, psychological, or social interventions. The control group received usual care from their general practitioner.

Studies of combination therapy have yielded mixed results, but guidelines from the psychiatric literature based on clinical experience advocate concomitant psychotherapy and medication (SOR: A).¹³ For patients with persistent symptoms after 6 to 8 weeks of taking antidepressant medication, concomitant psychotherapy improved compliance, satisfaction, and outcomes when compared with usual care.¹⁴

The concomitant therapy group participated in a multifaceted program including education, psychiatric referral, pharmacy utilization records, and primary physician feedback. The usual care group received standard antidepressants and follow-up visits from their family physician, with optional referral to a mental health provider.

Psychotherapy has also been shown to decrease the risk of relapse once symptoms have remitted.¹⁵ Primary care physicians can also incorporate counseling as adjunctive therapy.

Herbal and nutritional products

St. John’s wort. St. John’s wort (Hypericum perforatum L.) has been used as an herbal medication for more than 2000 years. Its efficacy in the treatment of depression has been studied extensively. Some studies demonstrated that these extracts are more effective than placebo for the short-term treatment of mild and moderate depression.^16,17,18 Two randomized controlled trials demonstrated minimal efficacy of St. John’s wort in moderately severe major depression.^19,20 The National Institutes of Health is sponsoring a placebo-controlled, double-blinded trial comparing St. John’s wort with SSRIs.²¹

Omega-3 fatty acids. Chronic deficiencies of essential fatty acids may adversely affect central nervous system function. In a small, 4-week double-blind study, outpatients receiving antidepressant therapy who were also given eicosapentaenoic acid exhibited improvement in core depressive symptoms (eg, worthlessness, guilt, insomnia) compared with the antidepressantplus-placebo group. Larger, long-term prospective trials are needed to confirm an antidepressant effect with omega-3 fatty acids.²²

S-adenosyl-L-methionine. S-adenosyl-L-methionine is possibly effective for short-term treatment of major depression. Data for other herbal or nutritional remedies are negligible.²³

Exercise

Physical activity may play an important role in relieving depression. One randomized controlled trial showed that an aerobic exercise program, sertraline therapy, or a combination of both were equally effective in the treatment of depression, although there was a more rapid initial response with sertraline.²⁴

A systematic review and meta-analysis concluded that exercise may reduce depression symptoms short term, but much of the evidence is of poor quality.²⁵ Well-controlled studies are needed to clarify the role of exercise in the treatment of depression. However, exercise is promising enough to consider implementation in clinical practice at this time.

Treatment strategy

Guidelines for medicating patients and setting expectations

Start antidepressant therapy promptly when depression is diagnosed. Maintain the initial dosage for at least 3 to 4 weeks before increasing it. A trial of 6 to 8 weeks at maximum dosage (or the maximum tolerated dosage) is necessary to confirm treatment success or failure.^26,27,28

An improvement in symptoms will usually not be noted until after 2 to 6 weeks of therapy. Depending on depression severity, schedule weekly or monthly visits for patients during the initial treatment phase. The response rate to initial treatment is only 50% to 60%, but more than 80% of depressed patients will respond to at least 1 medication.¹

Response to placebo is highly variable. It is often substantial and has increased in recent years. In an analysis of 75 trials between 1981 and 2001, the mean proportion of patients in the placebo group who responded (50% improvement on the HRSD) was 29.7%, compared with 50.1% in the active medication group.²⁹ The placebo effect may reflect some combination of patient expectations, the natural history of depression with possible spontaneous remission, and limitations of study methods.

Antidepressant therapy is effective compared with placebo for depression secondary to medical illness (number needed to treat [NNT], 4.2; 95% CI, 3.2–6.4), with minimal treatment dropout (number needed to harm, 9.8; 95% CI, 5.4–42.9).³⁰ Although many patients settle for partial improvement of their symptoms, the treatment goal should be complete remission.

Factors in drug selection

Selecting an antidepressant can be challenging: more than 24 drugs are on the market, each working through 1 or more of 7 pharmacologic mechanisms. Theoretically, choosing a drug is made easier by matching patient symptoms to likely medication side effects or by knowing that the patient or a family member responded favorably to a particular antidepressant in the past.

This intuitive model has not been proven superior to any other model of selecting antidepres-sants, but it is clinically sound, pharmacodynamically appealing, and supported by case reports. Its strength may lie in enhancing patient adherence during the critical initial phase of treatment.

A recent randomized, prospective comparison of the SSRIs paroxetine, fluoxetine, and sertraline showed similar effectiveness and tolerability (SOR: A).³¹ This suggests that efforts to individualize therapy based on comorbidities or likely side effects may not be as useful when choosing from among analogous SSRIs.

Nevertheless, choosing a drug that is effective, convenient, and well tolerated will improve the likelihood of achieving and maintaining a full remission. The data on adverse effects of antidepressants are widely available and well understood. Also consider cost (Table).

Preferences based on characteristics. For a patient whose depression is not complicated by other clinical conditions, the initial choice of antidepressant would usually be an SSRI. But nefazodone, mirtazapine, bupropion, or low-dose venlafaxine may be equally appropriate.

For a patient whose depression has other specific components, use your knowledge of drugs’ common side effects to fit the patient’s clinical profile.

• If there is generalized anxiety, agitation, and insomnia, both nefazodone⁸ and mirtazapine³² are excellent choices. Trazodone at low doses is often used as a sedative with nonsedating antidepressants.⁸
• If weight gain is desired, mirtazapine is indicated.³²
• If tobacco cessation is a secondary goal, bupropion is preferred.³¹
• Those suffering from hypersomnia, retarded depression, cognitive slowing, and pseudodementia would benefit from bupropion or venlafaxine.⁹
• For more severely depressed patients, venlafaxine may be advantageous due to its dual serotonergic and noradrenergic activity at moderate to high doses.^34,35,36 Mirtazapine and TCAs are also useful in severe depression, as well as for coexisting chronic pain syndromes.⁸ For refractory or atypical depression in motivated and compliant patients, MAOIs my be useful.⁸

When to avoid specific drugs.

• Patients with hypersomnia and motor retardation should avoid nefazodone and mirtazapine.^8,32
• With obesity, mirtazapine and TCAs are least preferred.^8,32
• If sexual dysfunction preceded depression, avoid giving SSRIs and venlafaxine.³
• Those experiencing agitation and insomnia should avoid bupropion and venlafaxine.³
• Seizure disorder is a contraindication to bupropion.³
• Hypertension is a relative contraindication to venlafaxine.³
• Liver disease is a contraindication to nefazodone.³⁷
• Preexisting heart disease and increased suicide risk are both relative contraindications to TCAs.⁸

TABLE
Comparative dosages and costs of antidepressant drugs

Helping nonresponders

Patients whose symptoms do not improve with therapy could be switched to a different monotherapy or to multiple drugs. Drug choices for treatment-refractory and nonresponding patients have evolved more by anecdote than by systematic study.⁹

Switch drugs. The benefit of switching patients to another category of antidepressant was recently demonstrated in a study where nearly half of patients who did not respond to an initial antidepressant, whether SSRI or TCA, responded when switched to the alternate agent (SOR: A).³⁸ It is also beneficial to switch medications within a category (SOR: B).^27,39,40

Add a drug. Adding a second antidepressant from a category with a different mechanism of action often enhances clinical efficacy. This has been demonstrated in combining an SSRI with a TCA (SOR: B).⁴¹ Though response rates are very similar for various antidepressants, complete remission and rates of response in severely depressed patients may be higher in dual-action antidepressants (SOR: A).^34,35,36

Add lithium. A great deal of evidence supports the use of lithium augmentation (SOR: A).^42,43 This agent should be used more in primary care and not only by psychiatrists. A recent meta-analysis of double-blind, placebo-controlled studies of lithium (given at a dosage of at least 800 mg/d or at a level high enough to achieve a serum drug concentration of 0.5 mEq/L for at least 2 weeks) found a summary pooled odds ratio of response to lithium of 3.31 (95% CI, 1.46–7.53) with a NNT of 3.7.⁴⁴ Other studies have been less clear on the optimal dose or blood level, so a starting dose of 300 mg twice daily with a serum drug concentration of 0.4 mEq/L has been recommended.

If renal function is normal, the concentration of lithium can be checked 5 days after a patient has received a stable dosage, at least 8 hours fol-lowing the last dose. Lithium may cause thyroid abnormalities; monitoring should include a measurement of thyroid-stimulating hormone, repeated at 6 months and 1 year.

Other augmentation options. Augmentation of antidepressants with buspirone has been proven useful in major depression (SOR: B).⁴⁵ Thyroid supplementation may also increase the effectiveness of antidepressant therapy using triiodothyronine (T₃), at doses not to exceed 50 mcg per day (SOR: B).^46,47 Electroconvulsive therapy (ECT) has a high rate of therapeutic success, including speed and safety, but it is not administered as first-line treatment by psychiatrists except in severe cases (SOR: A).^48,49 Augmentation with antipsychotic or anticonvulsants is another strategy that shows some benefit for select patients.⁵⁰

Texas medication algorithm project

The process of drug selection just described can avoid treatment-threatening side effects, enable patient adherence to treatment, and maximize the potential for therapeutic response. However, the model can become disorienting for the clinician and the patient if 1 or 2 initial selections for treatment do not succeed. A useful synergy may be achieved by adapting the intuitive model to an algorithmic model—the Texas Medication Algorithm Project (TMAP). TMAP is an evolving model that reflects ongoing clinical research in the treatment of depression.²⁷

Developed in 1995 from a review of existing antidepressant research and several consensus conferences, the TMAP (continually updated with new research findings) has developed algorithms for treatment of schizophrenia and bipolar disorder in addition to major depression. At each stage in the depression algorithm, treatment plans similar in efficacy and safety are grouped together, and the clinician is given a limited number of options. The later stages in the algorithm are more complex, admittedly with a greater potential for medical complications (Figure).⁵¹

The algorithm represents a tentative foundation for a sequenced medication plan. Research pertaining to the selection of antidepressant medicationis underway, sponsored by the National Institute of Mental Health. Unlike most antide-pressant trials, this study includes subjects with significant concomitant medical illnesses.

FIGURE
Treatment of chronic major depression*

When to refer

Patients requiring referral to a psychiatrist include those with suicidal ideation or severe depression, aggressive ideation, bipolar disorder, atypical depression, psychotic depression, substance abuse, or treatment resistance.⁵² Referral to a licensed counselor should be offered to most patients with depression, with or without psychiatric involvement, though many factors (eg, patient motivation, capacity for insight, patient perceptions of therapist) will affect follow-through and outcome.

Maintenance therapy

Once full remission has been achieved, 6 to 12 months of continued pharmacotherapy at the same dose is recommended, as it decreases the risk of relapse by 70%.^5,21,26 More than half of patients will have a recurrence of depression in their lifetime, and they should be advised about this risk.¹

A second episode of major depression confers an 80% chance of additional recurrences, and patients should therefore be maintained on medication for 1 to 2 years.

A third episode requires indefinite maintenance treatment because of a 90% recurrence rate.^3,26

Follow-up visits after remission can be tapered gradually to once every 3 months. Discontinuation of therapy should be done gradually to minimize withdrawal reactions; it also necessitates follow-up visits or phone calls.

* For a review of screening for depression, see Nease DE, Malouin JM. Depression screening: A practical strategy. J Fam Pract 2003; 52(2):118–126.