SECTION 2: Current and Emerging Antihyperglycemic Treatment Options for Type 2 Diabetes

Introduction

Type 2 diabetes is a complex disease and is often difficult to treat despite a broad array of treatment options, including 11 classes of medications. To this point, antihyperglycemic treatment concerns for patients with type 2 diabetes are discussed in this section.

After a brief review of treatment goals, nonpharmacologic and pharmacologic therapies are presented. This discussion includes challenges associated with some conventional glucose-lowering agents as well as the potential benefits of incretin-based therapies.

Treatment Goals

The American Diabetes Association (ADA) recommends an A1C goal of less than 7% for most nonpregnant adults with diabetes.¹ However, ADA guidelines stress the importance of individualization of goals. For some patients, including those with a short duration of diabetes, long life expectancy, or no significant cardiovascular disease, even lower A1C goals may be reasonable if they can be achieved without significant hypoglycemia or other adverse effects. On the other hand, less stringent goals may be appropriate for patients with limited life expectancy, advanced microvascular or macrovascular complications, severe comorbidities, history of severe hypoglycemia, and/or long-standing diabetes in which the general goal is difficult to achieve even with optimal therapy.²

The American Association of Clinical Endocrinologists/ American College of Endocrinology (AACE/ACE) guidelines and International Diabetes Federation guidelines recommend a lower general A1C goal of 6.5% or less, as long as it can be achieved without significant hypoglycemia or other adverse consequences.^3,4 The AACE/ACE guidelines also stress the importance of individualization of goals, stating that the "goal must be customized for the individual patient, with consideration of numerous factors such as comorbid conditions, duration of diabetes, history of hypoglycemia, hypoglycemia unawareness, patient education, motivation, adherence, age, limited life expectancy, and use of other medications."

Table 1

The guidelines recommend similar blood pressure and lipid goals for people with diabetes. The ADA and AACE/ACE glycemic and nonglycemic goals are summarized in .

Treatment Options

Nonpharmacologic Therapy

Lifestyle Modification

Lifestyle modification is an essential component of a diabetes treatment plan. The ADA and AACE/ACE guidelines stress the importance of a healthy diet, weight reduction, exercise, and smoking cessation.^2,3 Specific dietary recommendations from the ADA include limiting saturated fat to no more than 7% of total calories, reducing intake of trans fats, and monitoring carbohydrate intake.² The ADA also recommends at least 150 minutes/week of moderate-intensity aerobic physical activity (50%-70% of maximum heart rate). Patients with type 2 diabetes are also encouraged to perform resistance training 3 times per week.

Table 2

Lifestyle modifications can certainly improve glycemic control in patients with type 2 diabetes, with few adverse effects and low cost.⁵ In Look AHEAD (Action for Health in Diabetes), 5145 overweight or obese patients with type 2 diabetes were randomly assigned to either intensive lifestyle modification (ILM) or standard diabetes education/support. At 1 year, the ILM group had significant weight loss, as well as significant improvements in fasting glucose and A1C, compared with the usual-care group ().⁶ At 4 years, nearly 50% of patients in the ILM group maintained a weight loss of at least 5% of their initial weight.⁷

Even patients receiving insulin lost an average of 7.6% of body weight with ILM. Intervention and follow-up studies are ongoing to determine how long these benefits are sustained and whether they result in improved cardiovascular outcomes.

Diabetes Education

Diabetes education is a crucial component of care for all persons with diabetes. National standards for diabetes self-management education have been published.⁸ The National Diabetes Education Program, a partnership of the National Institutes of Health and Centers for Disease Control and Prevention, and more than 200 partner organizations, including the ADA, AACE, and the American Association of Diabetes Educators, offers resources to assist patients and their healthcare professionals with diabetes education and lifestyle adherence.⁹

Pharmacologic Therapy

Table 3

Because of the natural progression of type 2 diabetes, lifestyle changes have generally had limited long-term success in maintaining glycemic goals. Most patients with type 2 diabetes eventually require addition of medication.⁴ The ADA now recommends initiation of metformin in conjunction with lifestyle modification once type 2 diabetes is diagnosed. Currently, at least 11 classes of antihyperglycemic agents are available, each with advantages and disadvantages, as summarized in .^5,10,11

All of these glucose-lowering therapies are efficacious, but several have recognized limitations, which are discussed below.

Inadequate Control of Postprandial Hyperglycemia

In patients with relatively poor glycemic control (ie, higher A1Cs), fasting glucose is the predominant contributor to overall glycemia. As A1C decreases, the contribution of postprandial hyperglycemia increases, becoming predominant at A1Cs of less than 8.4%.¹² Most therapies are better at lowering fasting glucose levels than controlling postprandial excursions, which may explain why many patients have difficulty achieving A1C goals.

Failure to Maintain Long-Term Glycemic Control

Even when A1C goals are achieved, most therapies fail to maintain long-term control. Sulfonylureas (SUs) and glinides stimulate beta-cell secretion of insulin, while metformin and thiazolidinediones (TZDs) increase insulin sensitivity. These agents are initially effective; however, once beta-cell failure reaches a critical threshold, exogenous insulin will be required.

A Diabetes Outcome Progression Trial (ADOPT) was designed to compare the durability of glycemic control over 5 years with 3 different antihyperglycemic agents. In this double-blind trial, 4360 patients with recently diagnosed type 2 diabetes were randomly assigned to initial monotherapy with either metformin, the TZD rosiglitazone, or the SU glyburide (also called glibenclamide). The primary measure was time to monotherapy failure.¹³ During the first 6 months, all 3 agents lowered mean A1C to less than 7%, with SUs having the greatest effect. However, after 6 months, A1C rose in all 3 groups. The annual rate of increase was highest with SUs and lowest with rosiglitazone. Although durability was significantly greater with rosiglitazone than with metformin or SUs, none of the 3 monotherapies maintained mean A1C less than 7%.

Hypoglycemia

Hypoglycemia can have a significant impact on quality of life, treatment adherence, and treatment success. In a European study, questionnaires were used to examine hypoglycemic symptoms, treatment adherence, and satisfaction in 1709 patients with type 2 diabetes who added either an SU or a TZD to metformin.¹⁴ Patients who reported hypoglycemia had significantly lower satisfaction scores and were significantly more likely to report adherence barriers than those with no hypoglycemic symptoms. Furthermore, hypoglycemia severity was significantly associated with failure to achieve the A1C goal.

Oral medications differ in their risk for hypoglycemia. In ADOPT, self-reported hypoglycemia occurred in 9.8%, 11.6%, and 38.7% of patients taking rosiglitazone, metformin, and glyburide, respectively (P <.01 for the comparison between glyburide and rosiglitazone).¹³ It should be noted, however, that patients self-reported hypoglycemia at the follow-up visit and blood sugar levels were not necessarily confirmed by glucose testing. Although serious hypoglycemia (usually defined as hypoglycemia requiring third-party assistance or clinical intervention) was uncommon with these agents, it was more frequent with glyburide (occurring in 0.6% of patients) than with the other 2 agents (0.1% for both).

Fear of hypoglycemia is also often cited as a barrier to initiating insulin therapy.¹⁵ Use of insulin analogs rather than human insulin preparations may reduce the risk of symptomatic, nocturnal, and overall hypoglycemia.^5,16

Weight Gain

Weight is a concern for most patients with type 2 diabetes, and weight gain has been associated with the use of insulin, insulin secretagogues, and TZDs.⁵ (TZD-associated weight gain, however, is probably due to a combination of fluid retention and increased adiposity.¹⁷) Use of metformin, alpha-glucosidase inhibitors, bile acid sequestrants, pramlintide, quick-release bromocriptine mesylate, and incretinrelated therapies has not been associated with an increased risk of weight gain.^5,10,11

In a substudy of the United Kingdom Prospective Diabetes Study (UKPDS), overweight patients receiving intensive metformin therapy were compared with those receiving conventional (primarily diet) therapy; these groups were also compared with overweight patients receiving intensive SU or insulin therapy.¹⁸ Of the drug therapies, metformin was associated with the least weight gain, similar to that seen with conventional therapy. SU therapy resulted in a mean weight gain of approximately 4 kg, which leveled off after several years. Mean weight gain with insulin was approximately 8 kg over 12 years and did not appear to reach a plateau.

In ADOPT, comparison of 3 oral monotherapies over 5 years demonstrated the greatest weight gain with rosiglitazone-a mean change from baseline of 4.8 kg. With glyburide, weight gain of 1.6 kg occurred during the first year but then stabilized. Metformin was associated with a mean weight loss of 2.9 kg.¹³ Figure 1 shows weight gain with different therapies as observed in UKPDS and ADOPT.

Incretin-Based Therapies

Incretin Physiology

Glucose evokes a much greater insulin response when ingested orally than when it is administered intravenously. This enhanced insulin secretion results from peptide hormones called incretins, which are secreted by the gut in response to ingestion of glucose and other nutrients.^19-21 In humans, the major incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).^19,21

Incretin activity is mediated by receptors. GLP-1 receptors are expressed in numerous tissues, including pancreatic islet cells (both alpha and beta), the stomach, and multiple regions of the central nervous system (CNS). In contrast, GIP receptors are less widely expressed,^19-21 primarily on beta cells.²¹ Incretins are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4) and have short half-lives: approximately 5 to 7 minutes for GIP, and about 2 minutes or less for GLP-1.^21,22

While GIP acts primarily on beta cells, GLP-1 lowers postprandial glucose levels via actions on multiple target tissues:

• PANCREATIC BETA CELLS. Both GIP and GLP-1 stimulate beta-cell insulin secretion in a glucose-dependent manner (ie, only when glucose levels are elevated).^19,20 As insulin levels rise and plasma glucose levels decrease, the incretin effect diminishes. Thus, incretins suppress postprandial hyperglycemia without causing hypoglycemia.²¹ GLP-1 also helps maintain insulin stores by promoting glucose-induced insulin gene transcription.^20,21 Furthermore, data in animal studies suggest that both GIP and GLP-1 promote beta-cell proliferation and inhibit apoptosis, thus helping to maintain or expand beta-cell mass.^19-22
• PANCREATIC ALPHA CELLS. GLP-1 (but not GIP) inhibits the release of glucagon from alpha cells, resulting in reduced hepatic glucose output.^19,20,22 Again, this occurs in a glucose-dependent manner; as glucose levels fall into the normoglycemic range, the inhibition subsides. Thus, the glucagon response to hypoglycemia is not impaired.^19,21
• STOMACH. GLP-1 slows gastric emptying, probably via effects on the vagus nerve. This results in slower glucose absorption, moderating the postprandial rise in glucose levels.^19-22 Delayed gastric emptying may also cause a feeling of fullness or satiety, resulting in decreased calorie intake.²¹
• CNS. GLP-1 is also believed to reduce appetite and calorie intake via direct actions in the CNS, particularly the hypothalamus.^19-22

In type 2 diabetes, the incretin effect is impaired. Betacell response to GIP is greatly reduced, despite normal or even elevated GIP secretion.^21,22 In contrast, the beta-cell response to GLP-1 is better preserved.²² Some reports have suggested that GLP-1 is undersecreted,^21,22 while others have found normal GLP-1 secretion in patients with type 2 diabetes.²¹ Because GLP-1 response is preserved to some extent, the concept of GLP-1-related agents for type 2 diabetes treatment has been of interest. Furthermore, GLP-1-related therapies should be associated with (1) a low risk for hypoglycemia; (2) reduction in appetite and calorie intake which may lead to weight loss; (3) reduced postprandial hyperglycemia; and (4) if effects seen in animal studies occur in humans, GLP-1-related therapies may even slow or prevent disease progression (this has also been observed with TZDs²³). For example, GLP-1 receptor agonists improve beta-cell function by restoring the first-phase insulin response.²⁴

Figure 2

The glucose-dependent effect of GLP-1 was demonstrated in a study involving 10 patients with poor glycemic control on diet and oral therapy. Each patient received (on different days, in random order) an intravenous (IV) infusion of GLP-1 or placebo, while in a fasting state.²⁵ After GLP-1 infusion, insulin increased and glucagon decreased significantly compared with basal levels; plasma glucose levels decreased to normal fasting range. These effects did not occur after placebo infusion ().²⁵

The white boxes in the figure highlight the glucose-dependent nature of GLP-1 effects. As glucose levels decrease into the normal range, the incretin effects on insulin and glucagon begin to decline.

Because of its rapid degradation by DPP-4, in order to use GLP-1 therapeutically, it would have to be given as an IV or subcutaneous infusion, which is impractical for long-term therapy. Strategies for overcoming this problem include the use of either DPP-4 inhibitors or GLP-1 receptor agonists resistant to DPP-4.^21,22,26 These include exendin-based therapies (eg, exenatide) and GLP-1 analogs (eg, liraglutide).

DPP-4 Inhibitors

Two oral DPP-4 inhibitors, sitagliptin and saxagliptin, are currently available in the United States. A third DPP-4 inhibitor, vildagliptin, has been approved in Europe.²⁷

SITAGLIPTIN. The first DPP-4 inhibitor to be approved by the US Food and Drug Administration (FDA), sitagliptin is indicated as an adjunct to diet and exercise in adults with type 2 diabetes.²⁸ It can be used either as monotherapy or in combination with other oral agents. It has not been approved for use in combination with insulin. The usual recommended dose is 100 mg/day, taken with or without food; however, dosage reductions are recommended for patients with moderate renal insufficiency (50 mg/day) and those with severe renal insufficiency or end-stage renal disease (ESRD ) requiring hemodialysis or peritoneal dialysis (25 mg/day).²⁸

The efficacy of sitagliptin as monotherapy, and as add-on therapy with other oral agents (metformin, SU, or TZD), was demonstrated in a series of randomized, double-blind, placebo-controlled, 24-week trials. Sitagliptin (100 mg/day) significantly improved glycemic control (P <.001), with placebo-subtracted A1C reductions ranging from 0.65% to 0.79%.^29-32 Fasting plasma glucose (FPG) and 2-hour postprandial glucose (PPG) values were also significantly reduced. The homeostasis model assessment of beta-cell function (HOMA-β) was improved,^30-32 but results were not significantly different in the TZD add-on study.²⁹

Weight changes with sitagliptin were comparable to placebo,^29,31,32 except in the SU add-on study. Addition of sitagliptin to an SU resulted in a 1.1-kg mean weight gain compared with SU + placebo.³⁰ Hypoglycemia incidence also was similar to that with placebo^29,31,32 again, except in the SU add-on study, where hypoglycemia increased when sitagliptin was added to an SU (especially SU plus metformin).³⁰ When sitagliptin is combined with an SU, a lower SU dose may be needed to reduce the risk of hypoglycemia.²⁸ Another 24-week, randomized, double-blind, placebo-controlled trial examined initial therapy with either sitagliptin (100 mg/day), metformin (500 or 1000 mg twice daily), or both. Metformin monotherapy reduced A1C more than sitagliptin monotherapy, but the difference was not statistically significant. Combination therapy (especially at the higher metformin dose) was significantly more effective than either agent alone.³³

SAXAGLIPTIN. Saxagliptin was approved by the FDA in July 2009 as an adjunct to diet and exercise in adults with type 2 diabetes. It can be used either as monotherapy, or in combination with other oral agents.³⁴ The recommended dose is 2.5 or 5 mg/day, taken regardless of meals. In patients with moderate or severe renal insufficiency or ESRD, the dose should be limited to 2.5 mg/day.³⁴

The efficacy of saxagliptin was established in a series of 24-week, placebo-controlled, double-blind studies, including 2 monotherapy trials and 3 add-on trials (1 with metformin, 1 with TZD, and 1 with SUs).³⁴ In all of these trials, saxagliptin (2.5 or 5 mg/day) significantly improved A1C, FPG, and PPG compared with placebo. Two of the trials also evaluated doses of 10 mg/day; however, 10 mg was no more effective than 5 mg.³⁴

In another randomized, double-blind, placebo-controlled trial, drug-naïve patients were randomized to either saxagliptin (10 mg/day), metformin, or metformin + saxagliptin (5 or 10 mg/day). The initial metformin dose was 500 mg/day, and was titrated to a maximum of 2000 mg/day.^34,35 Initial combination therapy significantly improved A1C, FPG, and PPG compared with either drug alone.

SAFETY AND TOLERABILITY OF DPP-4 INHIBITORS. A number of concerns have been raised about the potential for adverse events with DPP-4 inhibitors:

• There were 88 postmarketing cases of acute pancreatitis reported in patients taking sitagliptin between October 2006 and February 2009.³⁶ As with all adverse-event postmarketing reports, however, it is not possible to determine causality. Furthermore, patients with type 2 diabetes are at increased risk of developing pancreatitis. Data through June 2008 from a retrospective review of a large claims-based surveillance system showed no increase in the incidence of pancreatitis with sitagliptin compared with metformin or SU.³⁷
• DPP-4 is expressed on T-cells. Its role in T-cell function is unclear; there has been concern that inhibition of the enzyme could alter immune function, resulting in an increased risk for infections.³⁸
• There have been postmarketing reports of serious hypersensitivity reactions with sitagliptin, including anaphylaxis, angioedema, and Stevens-Johnson syndrome.⁸ With saxagliptin, hypersensitivity reactions such as urticaria and facial edema were reported in 1.5% of patients in the clinical trials; none of these events were life-threatening or required hospitalization.³⁴

No long-term DPP-4 inhibitor safety data are available yet; however, a safety analysis of sitagliptin involving 6139 patients (3415 exposed to sitagliptin vs 2724 receiving placebo or an active comparator) has been performed using pooled data from 12 double-blind phase 2B and phase 3 studies lasting up to 2 years.³⁸ The analysis found that overall drug-related adverse events, and discontinuations due to drug-related adverse events, were more frequent in those not receiving sitagliptin-primarily due to higher hypoglycemia rates in SU-treated patients. Among adverse events reported in more than 5% of either group, only nasopharyngitis occurred more frequently with sitagliptin, and that difference was not statistically significant. Overall incidence rates of gastrointestinal disorders, immune system disorders, and infections did not differ significantly between the 2 groups. Angioedema incidence among patients taking angiotensin-converting enzyme inhibitors was the same in both groups; angioedema in the absence of angiotensinconverting enzyme inhibitors was slightly lower in the sitagliptin group.

GLP-1 Receptor Agonists

The GLP-1 receptor agonist, exenatide, has been available in the United States since 2005. A second agent, the human GLP-1 analog liraglutide, was approved in Europe in 2009 and in January 2009 received FDA approval in the United States. Several other GLP-1 receptor agonists, including taspoglutide, albiglutide, and lixisenatide (AVE0010), are in phase 3 trials.

EXENATIDE. Exenatide is a synthetic version of a GLP-1 receptor agonist, exedin-4.³⁹ It is indicated as monotherapy along with diet and exercise to improve glycemic control in adults with type 2 diabetes⁴⁰ and as adjunctive therapy in patients with type 2 diabetes who have not achieved glycemic goals on oral therapy (metformin, SUs, TZD, metformin + SU, or metformin + TZD).³⁹ Exenatide is administered by twice-daily subcutaneous injection, within an hour before the 2 main meals of the day (but not less than 6 hours apart). The recommended starting dose is 5 mcg twice daily; depending on response, after 1 month this can be increased to 10 mcg twice daily.³⁹ Exenatide is eliminated by glomerular filtration and should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) or ESRD.³⁹ In patients with moderate renal impairment (creatinine clearance 30-50 mL/min), caution should be applied when initiating or escalating doses of exenatide. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

Exenatide (5 or 10 mcg twice daily) as an add-on to metformin and/or SU was studied in 3 randomized, placebo-controlled, 30-week trials. Exenatide at both dose levels was associated with significant reductions in A1C^41-43 and PPG values.^41,43 In all 3 trials, exenatide 10 mcg significantly reduced FPG values, as did the 5-mcg dose in 2 of the 3 trials.^41-43 Both FPG decreases and sustained PPG reductions contributed to the A1C improvement.⁴¹

Exenatide (10 mcg twice daily) as an add-on to TZD + metformin was studied in a randomized, placebo-controlled, 16-week trial. Compared with placebo, exenatide significantly improved A1C, FPG, self-monitored PPG, and HOMA-β.⁴⁴

In the trials of exenatide with metformin and/or TZD, hypoglycemia incidence was similar across treatment arms.^41,44 In the trials with an SU, exenatide was associated with a doserelated increase in hypoglycemia incidence. Most of these events were mild to moderate.^42,43 When adding exenatide to an SU, an initial SU dose reduction, with subsequent titration as needed, may lower hypoglycemia risk.^39,43

In all 4 trials, the 10-mcg exenatide dose resulted in significant, progressive weight loss compared with placebo^41-44; the 5-mcg dose also resulted in significant, progressive weight loss in the trials with metformin or metformin + SU.^42,43 In the trial with an SU alone, the weight loss was not statistically significant.⁴²

In the placebo-controlled trials, the most common adverse event was nausea. Incidences ranged from approximately 40% to 51% with the 10-mcg dose, and 36% to 39% with the 5-mcg dose, compared with 7% to 23% in the placebo groups.^41-44 Nausea was generally mild or moderate, and was most frequent during the initial 8 weeks of treatment. Discontinuation rates due to nausea or vomiting were generally low-approximately 2% in the 5-mcg groups and 4% in the 10-mcg groups, compared with less than 1% with placebo^42,43; however, in 1 trial, 14% of patients receiving the exenatide 10-mcg dose discontinued because of nausea or vomiting.⁴⁴ Gradual dose escalation may reduce the incidence of dose-limiting nausea.⁴⁵

As of October 2008, the FDA received 36 postmarketing reports of acute pancreatitis-including 6 cases of hemorrhagic or necrotizing pancreatitis (2 fatal)-in patients taking exenatide.⁴⁶ Type 2 diabetes itself may be a risk factor for pancreatitis,⁴⁷ and most of these patients had at least 1 other risk factor. However, in some cases there was a temporal association with exenatide use.⁴⁶ Data through June 2008 from a retrospective review of a large claims-based surveillance system showed no increase in the incidence of pancreatitis with exenatide compared with metformin or SU.³⁷ The exenatide product label includes acute pancreatitis in the Warning and Precautions section.³⁹ If pancreatitis is suspected, exenatide should be discontinued and the pancreatitis should be managed appropriately. If pancreatitis is confirmed, exenatide therapy should not be resumed. In patients with a history of pancreatitis, diabetic therapies other than exenatide should be considered.

LIRAGLUTIDE. Liraglutide is a human GLP-1 analog with 97% sequence identity to human GLP-1.⁴⁸ Its slow absorption from subcutaneous tissue and resistance to DPP-4 degradation result in a half-life of approximately 12 hours,²⁴ suitable for once-daily administration independent of meals. Compared with twice-daily exenatide, once-daily liraglutide has a more favorable pharmacokinetic profile, with lower peak-to-trough fluctuations at steady state.⁴⁹

Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.⁴⁸ Liraglutide is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials, the incidence of pancreatitis was higher with liraglutide than with comparators. Liraglutide has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using liraglutide. Therefore, liraglutide should be used with caution in patients with a history of pancreatitis.

Concurrent use of liraglutide and insulin has not been studied.⁴⁸ Liraglutide can be administered once daily at any time of day, independent of meals, and can injected subcutaneously into the abdomen, thigh, or upper arm. The injection site and timing can be changed without dose adjustment. For all patients, liraglutide should be initiated at a dose of 0.6 mg/day for 1 week. The 0.6-mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. After 1 week at 0.6 mg/day, the dose should be increased to 1.2 mg. If the 1.2-mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. When initiating liraglutide, physicians should consider reducing the dose of concomitantly administered insulin secretagogues (such as SUs) to reduce the risk of hypoglycemia.

The Liraglutide Effect and Action in Diabetes (LEAD) program was a series of 6 randomized, double-blind, phase 3 trials evaluating liraglutide as monotherapy⁵⁰ or as add-on therapy to 1 or 2 oral agents.^51-55 Active comparators included SUs,^50,52 TZD,⁵¹ insulin glargine,⁵⁴ and exenatide.⁵⁵ All trials were 26 weeks,^51-55 except the monotherapy trial (liraglutide vs SUs), which had a 52-week double-blind phase,⁵⁰ followed by a 1-year open-label extension.⁵⁶

In the monotherapy trial (LEAD 3), liraglutide (1.2 or 1.8 mg/day) significantly reduced A1C, FPG, and PPG compared with SUs; these improvements were sustained during the open-label extension.^50,56

Added to oral agents, liraglutide (1.2 or 1.8 mg/day) was generally superior to addition of other oral agents or placebo, resulting in significantly lower A1C, FPG, and PPG.^51,53 However, in one trial (LEAD 2), glycemic control was comparable when either liraglutide or the SU, glimepiride, was added to metformin; however, more hypoglycemia and weight gain occurred with the SU.⁵²

Based on the LEAD 6 trial, addition of liraglutide significantly lowered A1C (-1.1% vs -0.8%, respectively) and FPG (-1.6 mmol/L and -0.6 mmol/L, respectively) more than exenatide. However, exenatide resulted in significantly more PPG reduction after breakfast and dinner.⁵⁵ Additionally, in LEAD 5, liraglutide lowered A1C significantly more than insulin glargine (-1.3% vs -1.1%, respectively).⁵⁴

In both the 52-week randomized LEAD 3 trial and its 52-week open-label extension, patients taking liraglutide had sustained weight loss, while those taking SUs gained weight.^50,56 In most of the add-on trials, liraglutide resulted in weight loss, which was significantly different from weight gain with either placebo,⁵³ SUs,⁵² or insulin glargine added onto background therapy.⁵⁴ In LEAD 1, liraglutide added to SU therapy resulted in minimal weight change, which was similar to placebo but significantly different from weight gain with a TZD.⁵¹ Add-on therapy with liraglutide versus exenatide produced similar weight loss in both groups.⁵⁵

In the LEAD trials, hypoglycemia risk was low with liraglutide as monotherapy⁵⁰ or combined with metformin.⁵² Combined with SU, liraglutide increased hypoglycemia risk compared with SUs alone.⁵¹ Buse et al recently reported a head-to-head trial of once-daily liraglutide versus twice-daily exenatide.⁵⁵ Compared with exenatide, liraglutide resulted in greater A1C reduction despite somewhat less hypoglycemia. As might be expected from liraglutide pharmacokinetics, which provides 24-hour GLP-1 receptor activation, FPG reductions were greater with liraglutide while postprandial glycemic excursions after breakfast and dinner were less with exenatide. Weight loss was similar with the 2 agents.

As with other GLP-1 receptor agonists, nausea is a common side effect of liraglutide, but is usually transient, occurring most frequently in the first 4 weeks of treatment.^50-53

Persistent nausea does not appear to be a significant factor in liraglutide-induced weight loss.⁵⁰ In the LEAD 6 trial, nausea was initially as frequent with liraglutide compared with exenatide, but was less persistent.⁵⁵

EXENATIDE ONCE WEEKLY. Exenatide once weekly is an investigational exenatide formulation that is administered subcutaneously once weekly. In a randomized, open-label, 30-week comparison versus the twice-daily formulation, exenatide once weekly resulted in significantly greater A1C reduction, with a significantly higher percentage of patients achieving A1C less than 7%.⁵⁷ Furthermore, significantly fewer patients reported nausea with the once-weekly formulation. Weight loss was similar in both groups. In an open-label extension study, patients who completed 2 years of exenatide once weekly had sustained A1C reduction and weight loss throughout the treatment period.⁵⁸

Individualizing and Optimizing Pharmacologic Therapy

Type 2 diabetes is a complex disease affecting patients with widely varying demographic and genetic characteristics as well as various comorbidities. The goals, type, and intensity of therapy should be tailored to the individual patient.

Medication Choice

Table 4

There are now at least 11 classes of antihyperglycemic agents. While some data support that insulin, SUs, and metformin have the greatest A1C-lowering potential,⁵ most comparisons do not come from head-to-head trials and the baseline level of glycemia has often differed in clinical trials with various agents. A meta-regression analysis of 61 studies involving 5 classes of oral agents (SUs, glinides, metformin, TZDs, and alpha-glucosidase inhibitors) found that treatment-induced A1C and FPG reductions are strongly influenced by baseline glycemic status: the higher the baseline A1C, the greater the observed reductions, as shown in .⁵⁹

Mean baseline A1C in placebo-controlled clinical trials has decreased during the past decade.⁵⁹ Therefore, the relative effectiveness of the newer agents cannot easily be judged by comparing data from placebo-controlled trials in different patient populations at different times.

Beyond possible differences in glycemic reduction, differences in adverse-effect profiles should be considered when selecting drugs or drug combinations to match patients' individual characteristics and goals. Table 3 lists some important adverse effects of the 11 drug classes. In choosing drug combinations, agents with different mechanisms of action should be combined to achieve synergistic effects.

Figure 3

In a 2009 consensus statement, the ADA and the European Association for the Study of Diabetes (EASD) proposed an algorithm for therapy selection that takes into account the characteristics and synergies of various agents, as well as their costs and the strength of evidence supporting their use.⁵ The algorithm includes 2 tiers of regimens, each with 3 steps ().

Tier 1 consists of what the authors call "well-validated core therapies." They refer to tier 2 therapies as "less well-validated," but indicate that they may be preferred in certain cases-eg, if avoidance of hypoglycemia is a major concern, pioglitazone or a GLP-1 agonist may be selected. GLP-1 agonists are a good option if weight loss is an important consideration.⁵

The ADA/EASD writing group's algorithm specifically includes only metformin, insulin, SUs, pioglitazone, and GLP-1 agonists.⁵ The amylin agonists, alpha-glucosidase inhibitors, glinides, and DPP-4 inhibitors were not included as preferred agents because the authors determined that they had lower or equivalent overall glucose-lowering effectiveness and/or limited clinical data or relative expense compared with those agents cited in tiers 1 and 2. However, the authors indicated that these other drug classes may be appropriate in selected cases.

AACE/ACE published 2 discrete algorithms, one that featured road maps addressing treatment and prevention of type 2 diabetes.^60,61 The most recent algorithm (available at: http://www.aace.com/pub/pdf/GlycemicControlAlgorithmPPT.pdf) also stratifies recommendations by the baseline A1C and includes all of the antihyperglycemic therapies approved by the FD A. Choices of medications are prioritized according to efficacy, safety, simplicity, anticipated degree of patient adherence, and cost. Minimizing risk and severity of hypoglycemia and risk and magnitude of weight gain were also priorities.⁶¹ Both of the AACE/ACE algorithms recommend the option of initial oral combination therapy (when monotherapy would unlikely achieve glycemic targets) with classes of medications that have complementary mechanisms of action.^60,61

Conclusion

There are many treatment options available for antihyperglycemic management of type 2 diabetes, including lifestyle modification and pharmacologic agents. There are benefits and challenges associated with all of these modalities. Newer therapies, such as incretin-based agents, may address some common challenges by reducing the risk for hypoglycemia and improving glycemia with weight neutrality or weight loss. As with all new therapies, however, the optimal roles for these agents will be established with additional experience.

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