Why and when to implement incretin therapy

Professor of Internal Medicine, Chairman, Division of Endocrinology and Metabolism, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania

Assistant Professor of Family Medicine, Loma Linda University School of Medicine, Loma Linda, California

Founder, The Unger Primary Care Medical Center, Associate Director of Metabolic Studies, Catalina Research Institute, Chino, California

Dr Freeman is on the advisory board for GlaxoSmithKline; is on the speakers bureau for Daiichi Sankyo, Inc, GlaxoSmithKline, Merck & Co., Inc., and Novo Nordisk Inc.; and has ownership interest in Novo Nordisk Inc.

Dr Unger is on the advisory board for Novo Nordisk Inc.; and is on the speakers bureaus for Eli Lilly and Company, Novo Nordisk Inc., and sanofi-aventis.

 

Incretin agents

Two agents are currently available in the United States that act upon the incretin hormone system—exenatide (Byetta), a twice-daily glucagon-like peptide-1 (GLP-1) receptor agonist, and sitagliptin (Januvia), a dipeptidyl peptidase-4 (DPP-4) inhibitor. Additional agents are currently under review by the FDA or in phase 3 clinical trials. These include the once-daily human GLP-1 analog liraglutide and the DPP-4 inhibitors alogliptin, saxagliptin, and vildagliptin. Phase 2 trials have also been competed with taspoglutide and albiglutide and various other DPP-4 inhibitors. This article describes the rationale for the use of GLP-1 receptor agonists and DPP-4 inhibitors in patients with type 2 diabetes mellitus (T2DM) in whom they might be especially useful. The incretins have often been discussed as a class of agents, while in fact there are important distinctions between the GLP-1 receptor agonists and DPP-4 inhibitors that will be reviewed in this article.

The GLP-1 receptor agonists and DPP-4 inhibitors are effective in improving glycosylated hemoglobin (A1C), fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) levels in patients with T2DM, including those previously managed only with diet and exercise. Furthermore, incretins improve β-cell function and reduce glucagon secretion, and animal and human in vitro studies have shown direct benefits on β-cell mass. Because of the lack of head-to-head trials, a direct comparison of the glucose-lowering capability and impact on β-cell function among the GLP-1 receptor agonists and DPP-4 inhibitors is not possible. Most evidence indicates that the GLP-1 receptor agonists reduce the A1C level to a greater extent than the DPP-4 inhibitors. As discussed below, exenatide generally lowers A1C levels by 0.5% to 1.0% from baseline, while liraglutide lowers A1C up to 1.6%, and the DPP-4 inhibitors generally lower A1C by 0.5% to 0.8%. (A table providing detailed information from clinical studies about the efficacy and safety of each of these agents is available at www.jfponline.com.) Patients with an especially high A1C level, eg, ≥9%, are more likely to achieve a more robust A1C reduction with a GLP-1 receptor agonist or DPP-4 inhibitor. The addition of any of these agents to existing glucose-lowering treatment with one or more oral agents or insulin results in further lowering of blood glucose. Whereas the GLP-1 receptor agonists promote weight loss, the DPP-4 inhibitors are generally weight neutral or cause slight weight gain. These agents generally exhibit a good safety profile with a low incidence of mostly mild to moderate adverse events (AEs). However, because of postmarketing reports, a precaution regarding pancreatitis has been added to the exenatide prescribing information and serious allergic and hypersensitivity reactions have been included in the sitagliptin prescribing information; in addition, safety concerns with vildagliptin have been raised during its review by the FDA.

 

Why use incretin therapy?

T2DM is recognized as a progressive metabolic disorder characterized by insulin resistance, a progressive decline in pancreatic insulin secretion, unrestrained hepatic glucose production, and other hormonal deficiencies.¹ The importance of pancreatic β-cell dysfunction in disease progression was made clear by the United Kingdom Prospective Diabetes Study (UKPDS) Group. The UKPDS found that patients with T2DM have lost approximately one-half of their pancreatic β-cell function by the time they are diagnosed.² More recent evidence suggests that the loss may be even greater, perhaps as high as 80% of β-cell function.³ The UKPDS also showed that despite aggressive use of monotherapy, the proportion of patients with T2DM who achieve glycemic control with monotherapy alone declines significantly over time. Although approximately 50% of patients are able to achieve an A1C level <7% after 3 years of maximal doses of monotherapy, only about 25% are able to do so after 9 years.⁴ Findings such as these prompted the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) to conclude in their joint consensus guidelines that most patients with T2DM will require the use of combination therapy over time to achieve and maintain glycemic control.⁵

Both the ADA/EASD and American Association of Clinical Endocrinologists (AACE) guidelines acknowledge the continuing challenge of treating patients with T2DM due, in part, to the progressive nature and resulting complications of the disease. In addition, the medical community is finding that conventional therapies are not sufficient because no one therapy adequately addresses the multiple pathophysiologic causes of T2DM and they do not provide a durable response for long-term glycemic control. Therefore, the ADA stresses the importance of “continuing timely augmentation of therapy with additional agents…as a means of achieving and maintaining recommended levels of glycemic control (ie, A1C <7% for most patients).”⁶

When switching from monotherapy to combination therapy, the complementary mechanisms of various antidiabetic agents should be considered, such as the combination of metformin and a thiazolidinedione (TZD) or metformin and an insulin secretagogue.⁵ This stepped-care approach is advocated by the AACE and the ADA.^1,6 However, although older antidiabetic agents lower plasma glucose by acting on one or more of the pathophysiologic defects in T2DM, none acts on the incretin hormone system (FIGURE).⁷ It is increasingly recognized that this system plays an important role in the pathogenesis of T2DM. Thus, the use of GLP-1 receptor agonists and DPP-4 inhibitors should be considered for the treatment of T2DM, as they address important pathophysiologic mechanisms that conventional therapies do not, including β-cell dysfunction and altered glucagon secretion, as well as some of the limitations associated with conventional therapies such as hypoglycemia and weight gain (TABLE 1).^8-13 In addition, preliminary evidence suggests that improvements in cardiovascular measures, such as blood pressure and lipid profile, may be observed.^14-18

Direct and indirect actions of antidiabetic agents on glucose homeostasis

 

When should an incretin be used in patients with T2DM?

Unlike the AACE guidelines, the current ADA guidelines do not specifically describe the role of incretins in the treatment of T2DM. Although incretins are newer agents and have less clinical data to support their use than older diabetes treatments, the ADA concludes that incretins may be appropriate for some patients.⁶ The results of more recent studies showing positive glucose-lowering effects and safety benefits of the GLP-1 receptor agonists and DPP-4 inhibitors compared with conventional agents suggest that the incretins are beneficial for many patients with T2DM.

The AACE guidelines are more specific, recommending the use of incretins in both treatment-naïve and previously treated patients.¹⁹ In treatment-naïve patients, the AACE recommends a DPP-4 inhibitor as monotherapy for those who have an initial A1C level of 6% to 7% or as combination therapy for those with an initial A1C >7%, whereas a GLP-1 receptor agonist can be used if the A1C goal of ≤6.5% is not achieved. A DPP-4 inhibitor can be added to metformin or a TZD for previously treated patients who are not at goal (A1C ≤6.5%).¹⁹ A GLP-1 receptor agonist can be added to sulfonylurea, metformin, or TZD monotherapy or to combination therapy with sulfonylurea/metformin or metformin/TZD for patients who are not at goal.¹⁹ These recommendations for the use of incretins are very similar to the prescribing information for exenatide and sitagliptin. Exenatide is indicated as an adjunct to various oral antidiabetic drugs (OADs) in patients who have not achieved adequate glycemic control.¹³ The prescribing information for the DPP-4 inhibitor sitagliptin recommends even earlier use, as an adjunct to diet and exercise and in combination with various OADs to improve glycemic control.⁸

The AACE guidelines make it clear that incretins can be used early and are not limited to third- or fourth-line therapy for T2DM. Perhaps the greatest insight regarding when an incretin should be used in treatment can be gained from a brief overview of the efficacy and safety of these agents and the approved labeling.

 

GLP-1 receptor agonists

Because of their ability to stimulate insulin secretion only under hyperglycemic conditions, reduce glucagon secretion, slow gastric emptying, enhance early satiety, and decrease appetite, the GLP-1 receptor agonists lower both FPG and PPG levels. As a consequence of these actions, they also lower A1C levels by approximatley 1.5% (TABLE 2).²⁰ Unlike many of the drugs that are used to lower blood glucose, an advantage of the GLP-1 receptor agonists is that they promote weight loss. The use of exenatide leads to a weight loss of 1 to 3 kg over 30 weeks.¹³ After 52 weeks of liraglutide monotherapy, weight loss of up to 2.5 kg has been observed.²¹ When liraglutide is used in combination with other agents, weight loss of up to 4.4 kg has been observed in patients with a body mass index (BMI) of 35 kg/m² or greater.^22,23

Although patients may initially experience gastrointestinal discomfort, the GLP-1 receptor agonists are generally well-tolerated. Data from multiple studies using a range of doses in different populations show that mild to moderate nausea is the most frequent AE, occurring in 44% of patients treated with exenatide vs 18% of those taking placebo.¹³ Mild to moderate nausea occurred in 6% to 29% of patients treated with liraglutide compared with 1% to 4% of patients treated with placebo.^21,22,24,25 The frequency and severity of nausea generally decreases with continued use of these agents. Because GLP-1 agonists stimulate insulin secretion and reduce glucagon secretion in a glucose-dependent manner while not interfering with counter-regulatory mechanisms, the risk of symptomatic hypoglycemia is low. When exenatide is combined with metformin, the incidence of symptomatic hypoglycemia is the same as that with metformin alone (5% vs 5%).¹³ Compared with an incidence of 7% with placebo, symptomatic hypoglycemia occurs in 11% of patients treated with exenatide plus a TZD with or without metformin.¹³ Monotherapy with liraglutide 1.2 or 1.8 mg once daily has been reported to cause minor hypoglycemia in 12% and 8% of patients, respectively, compared with 24% for glimepiride, 8 mg once daily.²¹ When liraglutide is combined with metformin 1000 mg twice daily for 26 weeks, minor hypoglycemia was observed in 3.7% of patients compared with 2.5% for metformin plus placebo.²²

Characteristics of antidiabetic interventions as monotherapy

 

DPP-4 inhibitors

The DPP-4 inhibitors are thought to work primarily—if not completely—through their competitive inhibition of DPP-4, thereby increasing the levels of endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP).²⁶ As a consequence, the DPP-4 inhibitors can only prevent the inactivation of endogenous GLP-1, while GLP-1 receptor agonists can achieve supraphysiologic levels of GLP-1, thereby magnifying their effects, including both weight loss and gastric emptying.^27-29 Similarly, use of a DPP-4 inhibitor potentiates the physiologic action of GIP, which augments glucose-induced insulin secretion after meals.^26,30

Sitagliptin reduces A1C levels by 0.5% to 0.6%, with mean reductions in FPG and 2-hour PPG levels of 12 to 13 mg/dL and 49 mg/dL, respectively, compared with placebo.⁸ Vildagliptin reduces A1C levels by 0.5% (P=.011 vs placebo) to 1.1% (P<.001 vs baseline), with mean reductions in FPG levels ranging from 11 mg/dL (P=.001 vs placebo) to 23 mg/dL (P<.001 vs baseline).^18,31 Both sitagliptin and vildagliptin are weight neutral, whereas the GLP-1 receptor agonists promote weight loss of 1 to 4 kg, possibly because pharmacologic levels of GLP-1 are needed to promote satiety and suppress gastric emptying.^8,18,31

Although the DPP-4 enzyme is found in the cell membranes of numerous tissues throughout the body—which has raised some concerns about the long-term safety of the DPP-4 inhibitors—current clinical experience indicates that the DPP-4 inhibitors are generally well tolerated.³² In controlled trials of sitagliptin, the overall incidence of adverse events, including those that led to discontinuation of therapy and hypoglycemia, was similar to placebo.⁸ The same observation has generally been true for monotherapy with vildagliptin, except that concerns regarding adverse skin reactions and increased liver enzymes have been raised during FDA review.³³ A meta-analysis found no significant difference in mild to moderate hypoglycemia between a DPP-4 inhibitor and the comparative glucose-lowering agent (1.6% vs 1.4%, respectively).³² The same analysis found no difference in the risk of nausea, vomiting, diarrhea, and abdominal pain compared with placebo. There was, however, an increased risk of nasopharyngitis, urinary tract infection, and headache with the DPP-4 inhibitor vs the comparative glucose-lowering agent.

In summary, the efficacy and safety of the GLP-1 receptor agonists and DPP-4 inhibitors indicate that these agents can be used early in the treatment of T2DM. Their unique mechanisms of action and safety profiles suggest they may be especially well suited in patients with T2DM in whom they may ameliorate progressive β-cell destruction and reduce glucagon secretion. Examples of such patients are outlined in the following case studies that illustrate the possible role of GLP-1 receptor agonists and DPP-4 inhibitors in managing the spectrum of T2DM.

CASE 1: Combination Therapy

JL is a 58-year-old male who was diagnosed with T2DM 6 years ago. He was initially treated with lifestyle management and glimepiride, which lowered his A1C level from 8.9% to 7.8% within 15 months. As his A1C level increased to 8.4% over the next year, metformin was added to his treatment regimen. His A1C level decreased to 7.4% within a few months but climbed to 8.1% within 3 years. JL has refused insulin because of a fear of needles and concern that he will gain additional weight. His BMI is 31 kg/m².

Comment: Among the available treatment options, a GLP-1 receptor agonist or a DPP-4 inhibitor may be the best choices for JL because both further lower blood glucose when used in combination with other agents. Although the A1C reduction with the GLP-1 receptor agonists is greater than with the DPP-4 inhibitors, a DPP-4 inhibitor would be the initial choice if JL’s needle phobia persists despite appropriate education. Compared with many glucose-lowering agents, the DPP-4 inhibitor has the advantage of being weight neutral; the GLP-1 receptor agonists promote weight loss. In addition, since symptomatic hypoglycemia is infrequent with a DPP-4 inhibitor (unless used in combination with a sulfonylurea), self-monitoring of blood glucose can be performed less frequently than the multiple times per day that would be required with insulin. If the addition of a DPP-4 inhibitor does not achieve the glycemic goals, a GLP-1 receptor agonist might be a better choice because of its A1C and weight-loss effects. Education about today’s fine-gauge needles and pen delivery options usually helps patients overcome resistance to injections.

CASE 2: Postprandial Hyperglycemia and Cardiovascular Risk

ML is a 72-year-old female with long-standing T2DM. Her BMI is 28 kg/m². She was initially treated with glyburide, with subsequent addition of metformin and then rosiglitazone. Her A1C level has ranged from 6.8% to 7.2% over the past 16 months on the triple-drug regimen. Her FPG and PPG values from 3 weeks ago were 128 mg/dL and 196 mg/dL, respectively. A decision is made to discontinue rosiglitazone because of cardiovascular concerns. ML has been on statin therapy for the past 4 years. Her lipids are: total cholesterol, 224 mg/dL; low-density lipoprotein cholesterol (LDL-C), 129 mg/dL; high-density lipoprotein cholesterol (HDL-C), 56 mg/dL; triglycerides, 185 mg/dL. Her blood pressure (BP) is 128/92 mm Hg.

Comment: The options to replace rosiglitazone include an α-glucosidase inhibitor, glinide, amylin analog, GLP-1 receptor agonist, DPP-4 inhibitor, and insulin. The advantages and disadvantages of each option should be discussed with ML to arrive at the best choice for her. Although pramlintide, amylin analogs, GLP-1 receptor agonists, and insulin require injections, today’s devices make injections almost painless. Regarding dosing, α-glucosidase inhibitors, glinides, or amylin analogs require 3 doses per day, whereas exenatide requires 2 doses per day, liraglutide or DPP-4 inhibitors require 1 dose per day, while insulin requires 1 to 4 doses per day depending on the formulation. Glinides and insulin promote weight gain, α-glucosidase inhibitors and DPP-4 inhibitors are weight neutral, and amylin analogs and GLP-1 receptor agonists promote weight loss. The GLP-1 receptor agonists and DPP-4 inhibitors work through mechanisms different from ML’s current glucose-lowering medications (glyburide and metformin). They may also lower her blood pressure and lipids, which would be helpful, given ML’s cardiovascular comorbidities.

CASE 3: Obesity and Delayed Satiety

AT is an obese (BMI , 41 kg/m²) 37-year-old male who was diagnosed with T2DM 2 years ago. Initial treatment with intensive lifestyle modification, consisting of exercise and nutrition management under the guidance of an exercise instructor and dietitian, lowered his BMI to 39 kg/m² and his A1C level from 9.1% to 8.7%. In addition, his lipid profile improved somewhat, but his LDL-C and triglyceride levels were still elevated. Metformin was added to his treatment regimen and titrated over several months; pharmacologic treatment for hyperlipidemia was refused. After 7 months of treatment with metformin, AT’s levels were: A1C, 8.3%; FPG, 158-183 mg/dL; and PPG, 196-229 mg/dL. During a session with the dietitian, AT admitted that he was having difficulty with his nutrition program, as he found it difficult to stop overeating at mealtime although he knew he was eating too much. He stated that he regularly eats for ≥30 to 40 minutes before he begins to feel full.

Comment: The patient’s weight and delayed satiety are important factors contributing to his T2DM. Although further intensification of his nutrition program is needed, his pharmacologic treatment also needs to be intensified. A sulfonylurea, glitinide, or TZD could be initiated, but all cause weight gain. Alternatively, a GLP-1 receptor agonist is a reasonable choice for this patient, as it promotes weight loss and may further encourage him with the progress he has already made. A GLP-1 receptor agonist has the added advantages of promoting early satiety, delaying gastric emptying, lowering triglycerides, and raising HDL-C. Furthermore, significant further lowering of blood glucose would be expected since he should have β-cell reserve.

CASE 4: Prediabetes

RB is an overweight (BMI, 28 kg/m²) 46-year-old female. Laboratory testing showed a normal lipid profile, but revealed the presence of impaired fasting glucose (IFG); her FPG level was 118 mg/dL. Physical examination showed a current BP of 124/78 mm Hg; it was 118/72 mm Hg at her last visit 3 years ago. There were no findings on eye examination. RB has a family history of diabetes and cardiovascular disease: her 72-year-old mother was diagnosed with T2DM 14 years ago and has suffered a minor stroke. Initial treatment for RB was dietary intervention, which reduced her BMI to 25 kg/m² over 16 months. Follow-up laboratory tests showed her FPG to be 109 mg/dL. A subsequent 2-hour oral glucose tolerance test measured 153 mg/dL. RB was diagnosed with prediabetes. Over the next 7 months, RB underwent more intensive dietary management and began exercising 3 times per week. Her FPG is now 107 mg/dL, and her A1C is 6.9%. What are the next steps for RB?

Comment: RB’s diet and exercise program have produced positive results; however, further intensification is unlikely to return her to euglycemia. Her efforts should be commended and encouraged to continue. She is clearly in the prediabetes stage and at significant risk of developing T2DM and hypertension. Although not FDA approved, treatment has been shown to be effective in preventing diabetes in individuals who have impaired glucose tolerance but not in those with IFG alone.⁶ The American College of Endocrinology (ACE ) recommends intensive lifestyle management since it has been shown to be effective in reducing the risk of prediabetes.^34-36 For those at especially high risk of T2DM, such as those with cardiovascular disease, the ACE recommends considering the addition of either metformin or acarbose because of their demonstrated efficacy and safety.^34,35,37 Pioglitazone and rosiglitazone have also been shown to reduce the risk of prediabetes.^38,39 Therapy aimed at preserving β-cell mass and function may also be beneficial.

 

Summary

The GLP-1 receptor agonists and DPP-4 inhibitors are useful in the management of T2DM because they provide effective reductions in FPG and PPG levels, partly through their actions on pathogenic causes of T2DM that are not addressed by other glucose-lowering agents. In addition, the GLP-1 receptor agonists promote weight loss, whereas the DPP-4 inhibitors are weight neutral, and there is a low risk of symptomatic hypoglycemia. The GLP-1 receptor agonists and DPP-4 inhibitors are effective as monotherapy in drug-naïve patients as well as in those who have been treated pharmacologically. When combined with other glucose-lowering agents, the GLP-1 receptor agonists and DPP-4 inhibitors further lower FPG and PPG levels. Consequently, these agents can be used for all stages of T2DM.

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