Selecting among ADA/EASD tier 1 and tier 2 treatment options

Associate Professor of Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Attending Physician, Department of Medicine, Barnes-Jewish Hospital, St. Louis, Missouri

Using The Checklist outlined in the previous article, along with the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) algorithm, let’s begin to answer the question, “Which medication should be added when the combination of lifestyle management and metformin therapy no longer achieves the desired glycemic control?” First, in addition to continuing metformin, unless it is contraindicated or not tolerated, lifestyle management must be continued and reinforced at each visit. ( See “Practical applications of therapy with a glucagon-like peptide-1 receptor agonist” .) Although the primary role of lifestyle management counseling can be referred to a dietitian or certified diabetes educator, ongoing reinforcement and encouragement by the physician is important for long-term patient adherence and treatment success. By simply prescribing and regularly following up on a lifestyle management plan, adherence can improve more than 5-fold.¹

Among the treatments available for patients with type 2 diabetes mellitus (T2DM) who do not achieve or maintain glycemic control with the combination of lifestyle management and metformin (ie, tier 1/step 1 therapy), 4 other classes of medications are considered preferred therapies by the ADA/EASD consensus panel.² These medications are divided into 2 groups: the tier 1/step 2 therapies, insulin and sulfonylureas, and the tier 2 therapies, the thiazolidinediones (TZDs) and the glucagon-like peptide-1 (GLP-1) receptor agonists. Among these therapies, sulfonylureas are the most cost-effective, whereas insulin is considered the most effective in achieving glycemic goals. However, even the newer formulations of sulfonylureas and insulin are associated with a substantial risk of hypoglycemia and weight gain. Tier 2 therapies are less well validated by clinical research than are tier 1 therapies. The TZDs and GLP-1 receptor agonists minimize the risk of hypoglycemia, and the TZDs cause weight gain, whereas the GLP-1 receptor agonists are associated with weight loss.

This article focuses on the tier 1/step 2 and tier 2 therapies for T2DM, as these are the preferred therapies recommended by the ADA/EASD panel and are, therefore, more likely to be widely used in the primary care management of patients with T2DM. Although the dipeptidyl peptidase-4 (DPP-4) inhibitors are considered by the ADA/EASD panel to be one of the “other” therapies and not a preferred therapy, the DPP-4 inhibitors have been included in this discussion because they also act on the incretin system.

  Tier 1/step 2 medications

When metformin and lifestyle management no longer achieve the desired glycemic goals, the ADA/EASD consensus panel recommended adding either basal insulin or a sulfonylurea. If the combination of lifestyle management, metformin, and a sulfonylurea or basal insulin does not provide the desired glycemic control, the panel advised that insulin therapy should be started or intensified.²

INSULIN

Insulin is the most effective treatment option available to lower blood glucose, and it does so in a dose-dependent manner (TABLE).^2-6 Several generations of insulin formulations have been developed over the past 2 to 3 decades, with the insulin analogs being the most recent. Compared with other insulins—including human insulin—insulin analogs more closely mimic the basal or prandial patterns of endogenous insulin secretion in healthy people than do the older insulin formulations.^7-10

The use of insulin therapy has generally been limited by concerns regarding weight gain and hypoglycemia.¹¹ However, weight gain and hypoglycemia generally appear to be less common with basal insulin analogs (eg, detemir and glargine) than with neutral protamine Hagedorn (NPH) insulin, while providing similar glycemic control.^12-17 A significant difference in weight gain of 1.2 kg and 2.8 kg (P<.001) has been reported following 24 weeks of treatment with insulin detemir and NPH insulin, respectively, and 1.0 and 1.8 kg (P=.017) following 26 weeks of treatment.^12,13 Similarly, a 24-week study of 756 overweight adults found that the addition of bedtime glargine or once-daily NPH to 1 or 2 oral antihyperglycemic agents resulted in similar glycemic control. However, symptomatic hypoglycemia was significantly less common with glargine than with NPH (13.9 vs 17.7 events/patient-year respectively; P<.02). Weight gain of approximately 3 kg was observed in both groups.¹⁷

The increasingly important role of insulin in the treatment of advanced T2DM or in patients with poor control, as recommended by the ADA/EASD panel² and previously by the American Association of Clinical Endocrinologists,⁴ makes it essential that weight gain, hypoglycemia, and other concerns regarding the use of insulin be addressed through ongoing patient education, beginning at the time of diagnosis. After β-cell failure reaches a critical threshold, some form of insulin therapy will be required. Therefore, patients should be educated about this and not “threatened” with insulin therapy if glycemic control is not achieved with other regimens.

Comparison of selected antihyperglycemic agents

SULFONYLUREAS

The glucose-lowering efficacy of the sulfonylureas (eg, glimepiride, glipizide, chlorpropamide, and glyburide) as monotherapy—a reduction in glycosylated hemoglobin (A1C) of about 1% to 2%—is similar to that of metformin (TABLE).^2,4,18-20 Insight into the efficacy and safety of glyburide was recently shown in a randomized, double-blind trial over 4 years that included 4360 patients with newly diagnosed T2DM.¹⁹ Compared with metformin and rosiglitazone, treatment with glyburide resulted in a faster onset of glucose-lowering activity, with the maximum reduction in A1C achieved in approximately 4 months for glyburide vs 12 months for metformin and rosiglitazone. However, the durability of glycemic control achieved was shortest with glyburide. Glycemic control (A1C <7.0%) was maintained for an average of 33 months with glyburide compared with 45 months for metformin and 57 months for rosiglitazone. At 5 years, maximum-dose monotherapy failed in 34% of patients treated with glyburide compared with 21% for metformin and 15% for rosiglitazone (FIGURE). A lack of improvement in insulin sensitivity over the 4 years and a more rapid decline in pancreatic β-cell function after 6 months likely contributed to the poorer durability of glycemic control with glyburide.

Weight gain is often greatest during the first year of sulfonylurea monotherapy, averaging about 2 kg, after which it stabilizes.^2,19 Hypoglycemia, including severe hypoglycemia, is more common in patients being treated with glyburide than with metformin or rosiglitazone, with about 40% of patients taking glyburide self-reporting an episode of hypoglycemia.¹⁹ This is likely a result of the non–glucose-dependent action of sulfonylureas to stimulate insulin release at lower glucose concentrations than normal,²⁰ thereby increasing the risk of hypoglycemia. Hypoglycemia is less common with glimepiride and glipizide than with chlorpropamide and glyburide.^21,22 In fact, glyburide is associated with an 83% greater risk of hypoglycemia than are other sulfonylureas.²² Consequently, glimepiride and glipizide are the preferred choices over chlorpropamide and glyburide.²

  Tier 2 medications

THIAZOLIDINEDIONES

Clinical studies of pioglitazone and rosiglitazone monotherapy have generally shown A1C reductions of 0.5% to 1.4% (TABLE).^2,4,19,20,23 As discussed above, the durability of glycemic control with rosiglitazone is longer than that with glyburide and metformin, with a 5-year monotherapy failure rate of 15%, representing a risk reduction of 63% with rosiglitazone vs glyburide and 32% vs metformin (P<.001 for both comparisons).¹⁹

Unlike most other medications used to treat T2DM, the TZDs have been shown to improve various markers of pancreatic β-cell function.^24,25 During 4 to 6 months of therapy in drugnaive, sulfonylurea-treated, sulfonylurea-withdrawn, and diet-treated patients with T2DM, treatment with rosiglitazone or pioglitazone markedly increased β-cell function, as assessed by the insulin secretion/insulin disposition index.^24,25 However, this appears to be a short-term effect. Beyond 6 months of treatment with rosiglitazone, β-cell function, as measured by the homeostasis model of assessment for β-cell function (HOMA-B), declined at an annual rate of 2.0%.¹⁹

Despite their benefits, the TZDs are not without limitations. Weight gain and edema are common with the use of these agents.¹⁹ For example, Kahn et al observed an average weight gain of 4.8 kg over 5 years in patients treated with rosiglitazone, with edema observed in 14% of patients.¹⁹

It is, however, the cardiovascular risks associated with the TZDs that have recently been the subject of several analyses. Recent studies have found a 1.2-fold to a >2-fold increased risk of heart failure with a TZD than with placebo, metformin, glyburide, or various combinations of antihyperglycemic treatments.^19,26-28 Heart failure appears more likely to occur after a median 24 weeks of therapy and is equally likely with higher or lower doses. Furthermore, the occurrence of heart failure is not limited to older adults.²⁷ Both pioglitazone and rosiglitazone carry a black box warning in the approved product labeling concerning heart failure, and rosiglitazone also carries a black box warning concerning myocardial ischemic events.

Two meta-analyses have suggested that there is an approximately 40% increase in the relative risk for myocardial infarction with the use of rosiglitazone, although in one study no increased risk of cardiovascular mortality was observed.^29,30 At the same time, pioglitazone has been shown to have a beneficial effect on cardiovascular risk.^28,31 The reason for the difference in observed cardiovascular risk between the TZDs may be that pioglitazone improves the atherogenic lipid profile, whereas the overall effect of rosiglitazone on the lipid profile is negative. Treatment with rosiglitazone results in an increase in levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides and in the ratio of total cholesterol to high-density lipoprotein cholesterol (HDL-C),³² with significantly higher levels of LDL-C than are found with metformin or glyburide (P<.001 and P=.008, respectively).¹⁹

Another newly identified concern associated with the TZDs is an increased risk of fractures, especially of the hip and wrist. The risk of fracture is >2-fold after 12 to 18 months of TZD use compared with nonuse. The risk appears to be similar for patients <70 years and those ≥70 years, with pioglitazone and rosiglitazone, and with higher or lower doses, whereas the risk for women is the same or somewhat higher than that for men.^19,33,34

As a consequence of the adverse cardiovascular events associated with rosiglitazone and the availability of other treatment options, including pioglitazone, rosiglitazone is not recommended by the ADA/EASD panel for the treatment of T2DM.²

INCRETIN-BASED THERAPIES

The gastrointestinal (GI) system plays an important role in glucose homeostasis and is briefly discussed here. A detailed review of the role of the GI system in glucose homeostasis was published as a supplement to The Journal of Family Practice in September 2008 (www.jfponline.com/supplements.asp?id=6690).

The importance of the GI system in regulating glucose homeostasis was first observed when the administration of oral nutrients stimulated a substantially greater insulinotropic response than did intravenous administration of isoglycemic glucose.³⁵ Among the gut peptides identified as being responsible for the greater insulinotropic action with oral nutrients, the most important are the incretin hormones—glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. In patients with T2DM, the secretion of GIP in response to a meal is only slightly impaired (P=.047 vs healthy controls), whereas the secretion of GLP-1 is significantly impaired (P<.001). Secretion of these peptides varies directly with the degree of insulin resistance such that the greater the insulin resistance, the lower the rise in mealtime secretion of GLP-1 and GIP.^36-39 Parenteral administration of GLP-1, but not GIP, was found to augment insulin secretion in a dose-dependent manner and to reduce glucagon secretion,³⁸ resulting in decreased concentrations of fasting plasma glucose (FPG) and postprandial glucose (PPG).^40,41 GLP-1 is rapidly degraded by the enzyme DPP-4,⁴² which has prompted the development of GLP-1 receptor agonists that mimic and extend the duration of activity of endogenous GLP-1 by resisting DPP-4. The development of DPP-4 inhibitors is another approach being used to extend the duration of activity of endogenous GLP-1.

GLP-1 receptor agonists and DPP-4 inhibitors. GLP-1 receptor agonists regulate secretion of insulin and glucagon in a glucose-dependent manner by acting directly on GLP-1 receptors located in pancreatic α- and β-cells.⁴³ Glucagon secretion is inhibited during hyperglycemia, but it is stimulated as blood glucose levels begin to fall below normal.^43-46 Administration of a GLP-1 receptor agonist results in supraphysiologic levels of GLP-1, thereby causing the physiologic actions of GLP-1 (eg, glucose lowering, decreased glucagon secretion, weight loss, early satiety, and delayed gastric emptying) to be increased.^37,38,41 DPP-4 inhibitors indirectly increase the level of endogenous GLP-1 by inhibiting the action of DPP-4.⁴⁷ Consequently, the effects of DPP-4 inhibitors are limited by the levels of endogenous GLP-1 and GIP.

The GLP-1 receptor agonist exenatide and the DPP-4 inhibitor sitagliptin are the only agents in their respective classes currently available in the United States. Saxagliptin was recently approved by the US Food and Drug Administration (FDA). New drug applications for the GLP-1 receptor agonist liraglutide and a long-acting form of exenatide, as well as the DPP-4 inhibitor alogliptin, are currently being reviewed by the FDA. Liraglutide was recently approved in the European Union.

Efficacy as monotherapy. Although exenatide is not approved as monotherapy in the United States, the GLP-1 receptor agonists and DPP-4 inhibitors have been studied as monotherapy in patients naive to drug treatment and in those who have not achieved acceptable glycemic control with their current antihyperglycemic treatment.^48-55 A summary of the glycemic effects observed in these clinical trials (APPENDIX) may be found on page S34. (Additional detailed information, including the use of GLP-1 receptor agonists in combination with other antihyperglycemic agents, appears in the article, “Practical applications of therapy with a glucagon-like peptide-1 receptor agonist” .)

Based on clinical trials comparing monotherapy with GLP-1 receptor agonists or DPP-4 inhibitors with other glucose-lowering agents, A1C levels are generally reduced by 0.5% to 1.5% with the GLP-1 receptor agonists and by 0.5% to 0.8% with the DPP-4 inhibitors (TABLE). GLP-1 receptor agonists and DPP-4 inhibitors reduce both FPG and PPG levels.^48-52,54,56 The glucose-lowering effect of both GLP-1 receptor agonists and DPP-4 inhibitors is greater when the baseline A1C is higher, generally ≥9%. For example, after 24 weeks of monotherapy with sitagliptin, 100 mg once daily, the placebo-subtracted reductions in A1C were 0.6%, 0.8%, and 1.5% for a baseline A1C level of <8.0%, 8.0% to <9.0%, and ≥9.0%, respectively.⁵¹ Similar results have been observed in trials with alogliptin.⁵⁷

Previous antihyperglycemic treatment has also been shown to affect glycemic response to incretin therapy. In a study by Garber et al,⁴⁹ patients with recently diagnosed T2DM (N=746) were randomized to once-daily treatment with liraglutide, 1.2 or 1.8 mg, or glimepiride, 8 mg, for 52 weeks. In the patients treated with liraglutide, 1.2 mg once daily, A1C was reduced by 1.2% in those previously treated with diet and exercise alone compared with 0.5% for those previously treated with oral antihyperglycemic monotherapy. The respective A1C reductions in those treated with liraglutide, 1.8 mg once daily, were 1.6% and 0.7%.

Safety and tolerability. Because of the potential consequences and frequent occurrence of hypoglycemia with sulfonylureas, glinides, and insulin, the incidence at which the GLP-1 receptor agonists and DPP-4 inhibitors cause hypoglycemia is an important factor when considering their use. In monotherapy studies of GLP-1 receptor agonists, severe hypoglycemia has not been reported.^48,49 Mild to moderate hypoglycemia has been reported to occur in 5% to 9% of patients treated with exenatide monotherapy⁴⁸ and in 8% to 12% of patients treated with liraglutide monotherapy, the latter in comparison to a 24% incidence of mild to moderate hypoglycemia with glimepiride monotherapy.⁴⁹

Among the DPP-4 inhibitors, hypoglycemia is also generally mild to moderate and appears to be less common, occurring in 0% to 4% of patients treated with sitagliptin compared with 0% to 2% for placebo and 21% for glipizide.^50-52 Hypoglycemia appears to be similarly infrequent with alogliptin^53,54 and saxagliptin.⁵⁵

GI disturbances are the most common adverse events observed with these agents, particularly with the GLP-1 receptor agonists. Nausea, generally mild to moderate in intensity, is the most common GI disturbance, although vomiting and diarrhea may also occur. In early clinical trials without using a dose-escalation strategy, which is now the standard approach, nausea was observed in 57% of patients treated with exenatide, 10 mcg twice daily, vs 4% in those receiving placebo, and vomiting occurred in 22% and 4% of patients, respectively.⁴⁸ Using a dose-escalation strategy, nausea was observed in 28% to 29% of patients treated with liraglutide, 1.2 or 1.8 mg once daily, compared with 9% of those treated with glimepiride (P<.0001 for both comparisons). By week 4 of therapy, <10% of patients treated with liraglutide, 1.8 mg, experienced nausea. The dropout rate due to an adverse GI event (eg, nausea, vomiting, diarrhea) was 2% to 4% in patients treated with liraglutide.⁴⁹ In patients treated with the DPP-4 inhibitor sitagliptin, an adverse GI event occurred in 9% to 16% of patients, compared with 6% to 14% for placebo.^50-52

Of potentially greater concern is the issue of acute pancreatitis with exenatide.⁵ Through August 2008, 36 postmarketing cases of acute pancreatitis involving exenatide have been reported.⁵⁸ The relationship of exenatide with pancreatitis is unclear because of the occurrence of pancreatitis in patients with T2DM. A recent epidemiologic study found that patients with T2DM were at 2.8 times greater risk of pancreatitis compared with nondiabetic subjects.⁵⁹ Two cases of acute pancreatitis have also been observed in clinical trials with liraglutide.⁴⁹ One case occurred after 197 days of treatment with liraglutide, 1.2 mg, and the other after 333 days of treatment with liraglutide, 1.8 mg. Both patients recovered, and the patient taking liraglutide, 1.2 mg, continued in the study.

Among patients treated with sitagliptin, there have been postmarketing reports of serious hypersensitivity reactions (eg, anaphylaxis, angioedema, and exfoliative dermatitis) occurring within 3 months of initiating sitagliptin therapy. These reactions sometimes occur after the first dose. While other potential causes are investigated, sitagliptin should be discontinued.⁶

In clinical trials with alogliptin, headache, dizziness, and constipation have been the most commonly reported adverse events, occurring in slightly more patients treated with alogliptin than in those receiving placebo.^53,54 Skin-related adverse events, mostly pruritus, have also been reported to occur slightly more frequently with alogliptin than with placebo.⁵³

Headache is the most common adverse event observed with saxagliptin, occurring in up to 16% of patients. Other adverse events occurring in 5% to 12% or more of patients include respiratory tract infection, urinary tract infection, nasopharyngitis, arthralgia, nausea, and cough.⁵⁵

Extraglycemic effects. Weight. Because overweight and obesity are important risk factors for T2DM and the potential for weight gain influences patient adherence to treatment, the effect of a treatment for T2DM on weight is an important consideration. Patient engagement in self-management is the most important factor, and using antihyperglycemic agents that are consistent with the overall goal of weight loss offer valuable new advantages. Treatment with insulin, sulfonylureas, and TZDs has been shown to promote weight gain, whereas GLP-1 receptor agonists promote weight loss, generally in the range of 1 to 4 kg.^48,49 This weight loss appears to result from a mechanism other than nausea, as the mean change in body weight from baseline was found to be similar in patients who experienced liraglutide-associated nausea for >7 days, ≤7 days, or not at all.⁴⁹ The DPP-4 inhibitors are generally considered to be weight neutral, with slight increases to slight decreases in body weight observed in clinical trials.^50-55 The difference in the effect on weight between the GLP-1 receptor agonists and the DPP-4 inhibitors may be due to the ability of the GLP-1 receptor agonists to promote early satiety and reduce caloric intake⁴⁰; this is a consequence of the higher pharmacologic levels of GLP-1 achieved with the GLP-1 receptor agonists^37,38,41 compared with those achieved with DPP-4 inhibitors.⁴⁷

Blood pressure and lipids. The association of T2DM with increased cardiovascular disease emphasizes the importance of modifying risk factors such as blood pressure and blood lipids.⁶⁰ Although most evidence demonstrating improvements in blood pressure and the lipid profile has been found when a GLP-1 receptor agonist or DPP-4 inhibitor has been used in combination with other antihyperglycemic agents,^50,61-64 similar improvements have been observed in monotherapy trials. For example, liraglutide has been shown to reduce systolic blood pressure by 2.1 and 3.6 mm Hg in once-daily doses of 1.2 and 1.8 mg, respectively, compared with 0.7 mm Hg with glimepiride, 8 mg once daily. Diastolic blood pressure was not significantly changed.⁴⁹

Sitagliptin in daily doses of 50 to 100 mg is associated with a slight increase in triglyceride and total cholesterol levels from baseline, although the increase in triglyceride levels seen with sitagliptin was significantly smaller than that observed with placebo (P<.05).⁵⁰ Treatment with alogliptin, 12.5 to 25 mg once daily, reduced total cholesterol levels by 1 to 4 mg/dL after 26 weeks compared with an increase of 10 mg/dL with placebo (P<.001); no significant changes in LDL-C or HDL-C levels were observed. Triglyceride levels were significantly reduced with the alogliptin 25 mg dose (-18 mg/dL; P=.015) but not with the 12.5 mg dose (-6 mg/dL; P=.074) vs placebo.⁵³

These improvements in systolic blood pressure and lipid profile are beneficial in patients with T2DM who are at high risk for cardiovascular disease; however, these relatively modest effects preclude the use of antihyperglycemic agents as primary therapy for these comorbidities.

Pancreatic β-cell function. The central role of the pancreatic β-cell in the pathogenesis of T2DM makes it a logical focus of treatment. Evolving data suggest that GLP-1 receptor agonists and DPP-4 inhibitors may have a beneficial effect on β-cell function. In monotherapy studies, treatment with sitagliptin, 50 mg twice daily for 12 weeks, has been shown to increase β-cell function by 17% over baseline, compared with a 25% increase for a daily dose of glipizide, 5 mg.⁵⁰ An 11% to 13% increase has been observed with sitagliptin, 100 mg once daily for 18 to 24 weeks, as assessed by HOMA-B.^51,52 Improvements in β-cell cell function have also been observed with saxagliptin⁵⁵ but not with alogliptin.⁵³ However, while encouraging, these data should be viewed as preliminary until long-term data are available.

Ease of use and cost. The factors contributing to clinical inertia remind us that issues concerning ease of use and cost must also be considered. GLP-1 receptor agonists require subcutaneous administration, whereas DPP-4 inhibitors are taken orally. As is the case with many insulin preparations, the use of self-injecting pens and fine-gauge needles makes the injection of GLP-1 receptor agonists relatively painless and fairly simple. As with most antihyperglycemic medications, GLP-1 receptor agonists and DPP-4 inhibitors use a fixed-dose regimen. The usefulness of self-monitoring of blood glucose for the GLP-1 receptor agonists and DPP-4 inhibitors and other non-insulin therapies is unclear.⁶⁵ The cost of GLP-1 receptor agonists and DPP-4 inhibitors is greater than that for insulin, metformin, or pioglitazone, ranging from about $9 a day for exenatide to $6.50 a day for sitagliptin (www.drugstore.com as of July 27, 2009). The actual cost to individual patients will, of course, depend on their insurance coverage and copayments.

  Summary

Each of the 4 groups of medications considered preferred therapies for treatment of T2DM by the ADA/EASD panel—insulin, sulfonylureas, TZDs, and incretin-based therapies (GLP-1 receptor agonists)—possesses significant advantages and disadvantages to be considered when individualizing treatment. Insulin and the sulfonylureas are the most researched therapies available, as well as the most cost-effective and the most effective in achieving glycemic goals. The TZDs have been shown to improve various markers of pancreatic β-cell function; however, there is a risk of edema and heart failure with the TZDs; rosiglitazone has been associated with an increase in cardiovascular events. GLP-1 receptor agonists and DPP-4 inhibitors address different pathophysiologic causes than do other diabetes medications and offer the benefit of a low incidence of hypoglycemia. Moreover, GLP-1 receptor agonists promote weight loss, whereas DPP-4 inhibitors are generally weight neutral.

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Selected incretin monotherapy trials

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