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Articles  |   January 2012
Incorporating Glucagon-like Peptide-1 Receptor Agonists Into Clinical Practice
Author Affiliations & Notes
  • Craig W. Spellman, DO, PhD
    From the Center for Diabetes and Metabolic Disorders and the Division of Endocrinology in the Department of Internal Medicine at Texas Tech University Health Sciences Center in Odessa
  • Address correspondence to Craig W. Spellman, DO, PhD, Professor of Medicine and Associate Dean of Research, Department of Internal Medicine, Texas Tech University Health Sciences Center, 701 W Fifth St, Odessa, TX 79763-4206. E-mail: craig.spellman@ttuhsc.edu  
Article Information
Endocrinology / Professional Issues / Diabetes
Articles   |   January 2012
Incorporating Glucagon-like Peptide-1 Receptor Agonists Into Clinical Practice
The Journal of the American Osteopathic Association, January 2012, Vol. 112, S7-S15. doi:
The Journal of the American Osteopathic Association, January 2012, Vol. 112, S7-S15. doi:
Abstract

Two glucagon-like peptide-1 (GLP-1) receptor agonists are currently approved for use in patients with type 2 diabetes mellitus: exenatide and liraglutide. Both of these injectable agents improve glycemic control as monotherapy or as combination therapy with oral agents. Overall, GLP-1 receptor agonists provide additive effects in dual and triple therapy regimens. In a clinical trial, the use of liraglutide resulted in greater improvements in glycosylated hemoglobin and fasting plasma glucose levels compared to exenatide, although the effects of exenatide on postprandial plasma glucose levels were greater. Clinical trials have also demonstrated statistically significant weight reduction, small beneficial effects on blood pressure, and unchanged lipid profiles with GLP-1 receptor agonists. The author reviews clinical trial data on the use of GLP-1 receptor agonists for patients with type 2 diabetes mellitus, outlines potential contraindications of these agents, and discuses the role of GLP-1 receptor agonists in algorithms for the initiation and advancement of treatment.

The story of incretins is an exception to the general rule that there are 20 or more years from basic research to clinical practice. In a study published in 1906 titled, “On the Treatment of Diabetes Mellitus by Acid Extract of Duodenal Mucous Membrane,” Moore1 stated, “[T]he internal secretion of the pancreas might be stimulated and initiated … by a substance of the nature of a hormone or secretin yielded by the duodenal mucous membrane.“ In 1932, LaBarre2 investigated the effects of gut-derived factors on insulin secretion, calling these factors “incretins.” By the 1960s, most researchers accepted the idea that incretins play a role in controlling insulin secretion, although the clinical relevance of these substances remained undefined. Understanding the importance of these basic science observations awaited the seminal work of Nauck et al,3 who, in 1986, demonstrated that the effects of incretins were reduced in individuals with type 2 diabetes mellitus (T2DM).3 That report provided a rationale to investigate incretins as therapeutic agents to treat patients with T2DM. 
Although several incretins have been well characterized biochemically, the primary focus of research on incretin therapy has been glucagon-like peptide-1 (GLP-1). Two examples can serve to illustrate the clinical benefits of GLP-1 in individuals with T2DM. Rachman et al4 reported that intravenous infusions of GLP-1 into patients with T2DM restored fasting and postprandial glucose control to an extent similar to that seen in control patients without T2DM. Zander et al5 compared a continuous, 6-week, subcutaneous infusion of GLP-1 in patients with T2DM to an infusion of saline in patients with T2DM. The GLP-1 group demonstrated an average reduction in glycosylated hemoglobin (HbA1c) level of 1.3%, weight reduction of 1.9 kg, decreased free fatty acids, and improved insulin sensitivity. 
As discussed by Dr Freeman in the present supplement to JAOA—The Journal of the American Osteopathic Association (“Restoration of Normal Glucagon-like Peptide-1 Levels in Patients With Type 2 Diabetes Mellitus”6), native GLP-1 has a short biological half-life of approximately 1 to 2 minutes.7 Thus, research into the use of GLP-1 in clinical practice has mainly involved the development of long-acting GLP-1 analogs, usually referred to as GLP-1 receptor agonists. Table 1 lists GLP-1 receptor agonists currently available and in development.8 As of late 2011, the US Food and Drug Administration (FDA) had approved only 2 GLP-1 receptor agonists as treatment for patients with T2DM: exenatide and liraglutide. Exenatide is now also indicated as add-on therapy to treatment with insulin glargine.9
Table 1.
Glucagon-like Peptide-1 (GLP-1) Receptor Agonists Approved or in Development
GLP-1 Receptor AgonistDosageApproved Exenatide 5-10 μg twice daily Liraglutide 1.2-1.8 mg daily In Development Albiglutide 30-50 mg weekly CJC-1134-PC 1.5-3 mg once or twice weekly Exenatide QW 2 mg weekly Lixisenatide 5-30 μg once or twice daily LY2189265 0.25-3 mg weekly LY2428757 0.5-17.6 mg weekly NN9535 0.1-1.6 mg weekly Taspoglutide 20-30 mg weekly
  Source: Adapted with permission from Macmillan Publishers Ltd: Nature Reviews Endocrinology, Lovshin and Drucker,8 copyright 2009.
Table 1.
Glucagon-like Peptide-1 (GLP-1) Receptor Agonists Approved or in Development
GLP-1 Receptor AgonistDosageApproved Exenatide 5-10 μg twice daily Liraglutide 1.2-1.8 mg daily In Development Albiglutide 30-50 mg weekly CJC-1134-PC 1.5-3 mg once or twice weekly Exenatide QW 2 mg weekly Lixisenatide 5-30 μg once or twice daily LY2189265 0.25-3 mg weekly LY2428757 0.5-17.6 mg weekly NN9535 0.1-1.6 mg weekly Taspoglutide 20-30 mg weekly
  Source: Adapted with permission from Macmillan Publishers Ltd: Nature Reviews Endocrinology, Lovshin and Drucker,8 copyright 2009.
×
 
The GLP-1 receptor agonists can be used as monotherapy or in various combinations with metformin, sulfonylureas, and thiazolidinediones. However, GLP-1 receptor agonists are not used in combination with dipeptidyl peptidase-4 (DPP-4) inhibitors, because both classes of medications are aimed at increasing GLP-1–related effects, though their mechanisms of action are different. 
In the present article, I examine available efficacy data on GLP-1 receptor agonists, as well as the effects of these medications on reducing levels of HbA1c and controlling levels of fasting and 2-hour postprandial plasma glucose. The nonglycemic effects of GLP-1 receptor agonists are also discussed. 
Monotherapy
Exenatide and liraglutide are effective as monotherapy in patients with T2DM to reduce levels of HbA1c, fasting plasma glucose (FPG), and 2-hour postprandial plasma glucose (PPG) (Table 2). In a 24-week randomized controlled trial of 232 drug-naive patients unable to achieve glucose control with diet and exercise, Moretto et al10 showed that exenatide reduced HbA1c levels by 0.7% and 0.9% using 5 and 10 μg twice daily, respectively, from a baseline HbA1c level of 7.9%. Levels of FPG decreased by 17 and 19 mg/dL using the 5- and 10-μg twice-daily treatment regimen. Two-hour PPG excursions decreased by 21 and 25 mg/dL using 5 and 10 μg exenatide twice daily, respectively.10 Approximately 86% of the participants completed the Moretto et al10 trial.
Table 2.
Effects of Exenatide and Liraglutide as Monotherapy on Levels of Glycosylated Hemoglobin, Fasting Plasma Glucose, and 2-Hour Postprandial Plasma Glucose
Measurement ChangeAgentHbA1c, %FPG, mg/dLPPG, mg/dLExenatide10 5 μg twice daily -0.7 -17 -21 10 μg twice daily -0.9 -19 -25 Liraglutide11 1.2 mg daily -0.8 -14 -31 1.8 mg daily -1.1 -25 -38
  Abbreviations: FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin; PPG, postprandial plasma glucose.
Table 2.
Effects of Exenatide and Liraglutide as Monotherapy on Levels of Glycosylated Hemoglobin, Fasting Plasma Glucose, and 2-Hour Postprandial Plasma Glucose
Measurement ChangeAgentHbA1c, %FPG, mg/dLPPG, mg/dLExenatide10 5 μg twice daily -0.7 -17 -21 10 μg twice daily -0.9 -19 -25 Liraglutide11 1.2 mg daily -0.8 -14 -31 1.8 mg daily -1.1 -25 -38
  Abbreviations: FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin; PPG, postprandial plasma glucose.
×
 
In the 52-week LEAD-3 study by Garber et al11 of 746 patients with T2DM, liraglutide decreased HbA1c levels by 0.8% and 1.1%, FPG levels by 14 and 25 mg/dL, and PPG levels by 31 and 38 mg/dL using 1.2- and 1.8-mg doses, respectively (Table 2). In a smaller study of approximately 100 participants, Garber et al11 showed that 1.8 mg daily of liraglutide daily reduced HbA1c levels by 0.4% in patients with T2DM of less than 3-years duration and by 1.0% in patients with T2DM of more than 3-years duration. 
Combination Therapy
Both of the approved GLP-1 receptor agonists have been studied in combination with metformin, sulfonylurea, metformin plus sulfonylurea, and metformin plus thiazolidinedione.12-15 Selected data from these studies are shown in Table 3 (for exenatide) and Table 4 (for liraglutide). Several conclusions can be drawn from these data, including the following: (1) exenatide and liraglutide are roughly equally effective in reducing HbA1c levels at doses of 10 μg twice daily and 1.2 mg daily, respectively; (2) GLP-1 receptor agonists show additional benefit in dual- and triple-therapy regimens; (3) the benefit of adding a GLP-1 receptor agonist to achieve glycemic control follows the general rule for oral agents (ie, the effects are additive),16 with a further HbA1c reduction of approximately 1%; and (4) liraglutide reduces FPG level to a greater extent than does exenatide.
Table 3.
Effects of Adding Exenatide to Metformin, Sulfonylurea, and Thiazolidinedione on Levels of Glycosylated Hemoglobin and Fasting Plasma Glucose
Agent(s) Combined With ExenatideaMeasurement ChangeHbA1c, %FPG, mg/dLMetformin13 5 μg twice daily -0.5 -5 10 μg twice daily -0.9 -10 Sulfonylurea18 5 μg twice daily -0.5 -5 10 μg twice daily -0.9 -11 Metformin plus Sulfonylurea19 5 μg twice daily -0.7 -11 10 μg twice daily -0.9 -12 Metformin plus Thiazolidinedione20 5 μg twice daily Not tested Not tested 10 μg twice daily -0.7 -21
  a Dosages shown are of exenatide.
  Abbreviations: HbA1c, glycolated hemoglobin; FPG, fasting plasma glucose.
Table 3.
Effects of Adding Exenatide to Metformin, Sulfonylurea, and Thiazolidinedione on Levels of Glycosylated Hemoglobin and Fasting Plasma Glucose
Agent(s) Combined With ExenatideaMeasurement ChangeHbA1c, %FPG, mg/dLMetformin13 5 μg twice daily -0.5 -5 10 μg twice daily -0.9 -10 Sulfonylurea18 5 μg twice daily -0.5 -5 10 μg twice daily -0.9 -11 Metformin plus Sulfonylurea19 5 μg twice daily -0.7 -11 10 μg twice daily -0.9 -12 Metformin plus Thiazolidinedione20 5 μg twice daily Not tested Not tested 10 μg twice daily -0.7 -21
  a Dosages shown are of exenatide.
  Abbreviations: HbA1c, glycolated hemoglobin; FPG, fasting plasma glucose.
×
Table 4.
Effects of Adding Liraglutide to Metformin, Sulfonylurea, and Thiazolidinedione on Levels of Glycosylated Hemoglobin and Fasting Plasma Glucose
Agent(s) Combined With LiraglutideaMeasurement ChangeHbA1c, %FPG, mg/dLMetformin21 1.2 mg daily -1.1 -37 1.8 mg daily -1.1 -38 Sulfonylurea22 1.2 mg daily -1.3 -47 1.8 mg daily -1.4 -46 Metformin plus Sulfonylurea17 1.2 mg daily Not tested Not tested 1.8 mg daily -1.1 -38 Metformin plus Thiazolidinedione23 1.2 mg daily -0.9 -32 1.8 mg daily -0.9 -38
  a Dosages shown are of liraglutide.
  Abbreviations: HbA1c, glycolated hemoglobin; FPG, fasting plasma glucose.
Table 4.
Effects of Adding Liraglutide to Metformin, Sulfonylurea, and Thiazolidinedione on Levels of Glycosylated Hemoglobin and Fasting Plasma Glucose
Agent(s) Combined With LiraglutideaMeasurement ChangeHbA1c, %FPG, mg/dLMetformin21 1.2 mg daily -1.1 -37 1.8 mg daily -1.1 -38 Sulfonylurea22 1.2 mg daily -1.3 -47 1.8 mg daily -1.4 -46 Metformin plus Sulfonylurea17 1.2 mg daily Not tested Not tested 1.8 mg daily -1.1 -38 Metformin plus Thiazolidinedione23 1.2 mg daily -0.9 -32 1.8 mg daily -0.9 -38
  a Dosages shown are of liraglutide.
  Abbreviations: HbA1c, glycolated hemoglobin; FPG, fasting plasma glucose.
×
 
The effects of exenatide and liraglutide were compared in a head-to-head trial, the LEAD-6 study.17 Patients whose glucose levels were not controlled with metformin, glimepiride, or both were assigned to receive 10 μg of exenatide twice daily or 1.8 mg of liraglutide daily for 26 weeks. The average baseline HbA1c level for both groups was 8.2%. The end results showed that exenatide reduced HbA1c levels by an average of 0.8% and FPG levels by an average of 10.8 mg/dL. By comparison, liraglutide reduced HbA1c levels by an average of 1.2% and FPG levels by an average of 29.0 mg/dL.17 However, the LEAD-6 results also showed that exenatide decreased PPG levels more than liraglutide did, with estimated treatment differences of 23.9 and 18.2 mg/dL, respectively, at breakfast and dinner.17 
Nonglycemic Effects
Glucagon-like peptide-1 agonists have been evaluated for their effects on weight loss, blood pressure, and lipid levels. Substantial weight reduction was observed in monotherapy trials with both exenatide and liraglutide.10,11 Table 5 shows trial results on weight loss for the most common doses of these drugs used in clinical practice. Small effects on blood pressure were seen with exenatide and liraglutide in these trials, but lipid profiles remained essentially unchanged in trials lasting 1 year or less.
Table 5.
Effects on Body Weight of Exenatide and Liraglutide in Combination With Metformin, Sulfonylurea, and Thiazolidinedione
Agent CombinationWeight Loss, kgExenatide, 10 μg twice daily10 -3.1 + Metformin13 -2.8 + Sulfonylurea18 -1.6 + Thiazolidinedione20 -1.7 + Metformin + Sulfonylurea19 -1.6 + Metformin + Thiazolidinedione20 -1.7 Liraglutide, 1.2 mg daily11 -2.1 + Metformin21 -2.6 + Sulfonylurea22 0.3 + Metformin + Sulfonylurea17 1.0 + Metformin + Thiazolidinedione23 -1.0
  Abbreviation: +, plus.
Table 5.
Effects on Body Weight of Exenatide and Liraglutide in Combination With Metformin, Sulfonylurea, and Thiazolidinedione
Agent CombinationWeight Loss, kgExenatide, 10 μg twice daily10 -3.1 + Metformin13 -2.8 + Sulfonylurea18 -1.6 + Thiazolidinedione20 -1.7 + Metformin + Sulfonylurea19 -1.6 + Metformin + Thiazolidinedione20 -1.7 Liraglutide, 1.2 mg daily11 -2.1 + Metformin21 -2.6 + Sulfonylurea22 0.3 + Metformin + Sulfonylurea17 1.0 + Metformin + Thiazolidinedione23 -1.0
  Abbreviation: +, plus.
×
 
Specifically, monotherapy with exenatide resulted in weight reductions of 2.8 and 3.1 kg using 5 and 10 μg twice daily, respectively, over 24 weeks.10 Systolic blood pressure decreased by about 4 mm Hg with both doses of exenatide, and diastolic pressure decreased by about 0.8 and 2.3 mm Hg with the 5 and 10 μg doses, respectively. There was no measurable effect of exenatide on levels of total cholesterol, high-density lipoprotein cholesterol, or low-density lipoprotein cholesterol.10 
Monotherapy with liraglutide resulted in decreases in weight of 2.1 and 2.5 kg in patients receiving doses of 1.2 and 1.8 mg, respectively.11 Weight loss occurred during the first 4 months of the trial and was sustained for more than 1 year. Systolic blood pressure decreased by approximately 2 and 4 mm Hg using 1.2- and 1.8-mg doses, respectively.9 The effects of liraglutide on lipid levels were not investigated. 
Substantial weight loss has also been noted when GLP-1 agonists are used in combination with metformin, a sulfonylurea, or a thiazolidinedione.13,17-23 Data for the most common clinical doses of these combinations are shown in Table 5. Exenatide produced essentially no effect on blood pressure or lipids in studies lasting 1 year or less.18 However, in an open-label trial lasting 3.5 years, exenatide showed statistically significant improvements in triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol (P<.001 for all comparisons); blood pressure was also improved.24 These benefits were attributed to a slow, progressive weight loss of 5 to 12 kg, with the greatest benefit accruing to patients who lost the most weight.24 In the 26-week LEAD-6 trial,17 liraglutide consistently decreased systolic blood pressure by about 2 to 4 mm Hg and triglyceride level by about 36 mg/dL. 
Gastric adverse effects of GLP-1 agonists are discussed by Dr Gavin elsewhere in this JAOA supplement (“Initiating a Glucagon-like Peptide-1 Receptor Agonist in the Management of Type 2 Diabetes Mellitus”25). The major adverse effects are nausea, vomiting, and diarrhea.26,27 The incidence of these effects increases as the dose is increased and varies little when the drugs are used as monotherapy or as combination therapy with other, oral antidiabetic agents. Exenatide monotherapy was associated with nausea (in 8% of patients) and vomiting (in 4% of patients).26 In combination with metformin or a sulfonylurea—and subtracting the placebo control—the incidences of nausea, vomiting, and diarrhea with exenatide were 26%, 9%, and 7%, respectively.26 The incidences of adverse effects with liraglutide are similar to those observed with exenatide.27 
Hypoglycemia
A patient adhering to an antidiabetic regimen can feel defeated if hypoglycemia occurs. Many people who have experienced low blood sugar levels become reluctant to attempt tight glycemic control. However, a growing body of literature suggests that hypoglycemia is associated with adverse cardiac events. 
Desouza et al28 reported on simultaneous monitoring of blood glucose, cardiac rhythms, self-reported episodes of hypoglycemia, and chest pain in patients with diabetes mellitus. The results were interpreted to suggest that hypoglycemia is a conditioning event that precipitates cardiac ischemia.28 Since the publishing of those results in 2003, many reports have described the relationship between hypoglycemia and adverse events, including cardiac ischemia, rhythm disturbances, myocardial infarction, induction of proinflammatory cytokines, altered platelet function and fibrinolysis, and death.29 
The data shown in Table 6 (exenatide combination therapy) and Table 7 (liraglutide combination therapy) indicate that mild hypoglycemia can occur with any regimen using GLP-1 receptor agonists.10,11,13,18-21,23,30,31 However, the salient message from these investigations is that essentially no severe adverse reactions have been attributed to the GLP-1 receptor agonists.
Table 6.
Percentages of Mild and Severe Hypoglycemia Observed With Exenatide in Monotherapy and in Combination With Metformin, Sulfonylurea, and Thiazolidinedione, Compared With Placebo
Patients With Hypoglycemia, %Type of HypoglycemiaPlaceboExenatide, 5 μg twice dailyExenatide, 10 μg twice dailyMonotherapy10 Mild 1.3 5.2 3.8 Severe 0 0 0 Metformin13 Mild 5.3 4.5 5.3 Severe 0 0 0 Sulfonylurea18 Mild 3.3 14.4 35.7 Severe 0 0 0 Metformin Plus Sulfonylurea19 Mild 12.6 19.2 27.8 Severe 0 0.4 0 Thiazolidinedione20 Mild 7.1 Not reported 10.7 Severe 0 Not reported 0
Table 6.
Percentages of Mild and Severe Hypoglycemia Observed With Exenatide in Monotherapy and in Combination With Metformin, Sulfonylurea, and Thiazolidinedione, Compared With Placebo
Patients With Hypoglycemia, %Type of HypoglycemiaPlaceboExenatide, 5 μg twice dailyExenatide, 10 μg twice dailyMonotherapy10 Mild 1.3 5.2 3.8 Severe 0 0 0 Metformin13 Mild 5.3 4.5 5.3 Severe 0 0 0 Sulfonylurea18 Mild 3.3 14.4 35.7 Severe 0 0 0 Metformin Plus Sulfonylurea19 Mild 12.6 19.2 27.8 Severe 0 0.4 0 Thiazolidinedione20 Mild 7.1 Not reported 10.7 Severe 0 Not reported 0
×
Table 7.
Percentages of Mild and Severe Hypoglycemia Observed With Liraglutide in Monotherapy and in Combination With Metformin, Sulfonylurea, and Thiazolidinedione, Compared With Placebo
Patients With Hypoglycemia, %Type of HypoglycemiaPlaceboLiraglutide 1.2 or 1.8 mg dailyMonotherapy11 Mild Not reported 9.7 Severe Not reported 0 Metformin21 Mild 2.5 3.6 Severe 00.1 Sulfonylurea30 Mild 2.6 7.5 Severe 00.1 Metformin Plus Thiazolidinedione23 Mild 4.6 7.9 Severe 00 Metformin Plus Sulfonylurea31 Mild 16.7 27.4 Severe 0 2.2
Table 7.
Percentages of Mild and Severe Hypoglycemia Observed With Liraglutide in Monotherapy and in Combination With Metformin, Sulfonylurea, and Thiazolidinedione, Compared With Placebo
Patients With Hypoglycemia, %Type of HypoglycemiaPlaceboLiraglutide 1.2 or 1.8 mg dailyMonotherapy11 Mild Not reported 9.7 Severe Not reported 0 Metformin21 Mild 2.5 3.6 Severe 00.1 Sulfonylurea30 Mild 2.6 7.5 Severe 00.1 Metformin Plus Thiazolidinedione23 Mild 4.6 7.9 Severe 00 Metformin Plus Sulfonylurea31 Mild 16.7 27.4 Severe 0 2.2
×
 
Data derived from studies with sulfonylureas appear to be quite divergent, but the differences can be explained by the use of various sulfonylureas in exenatide studies, whereas only glimepiride was used in liraglutide trials.11 As reported by Phung et al,32 the incidence of hypoglycemia associated with sulfonylureas can range from 6% to 38%, depending on the particular drug and research protocol. 
Head-to-Head Trials
The LEAD-6 trial17 was a 26-week study involving 464 patients with inadequately controlled T2DM receiving maximally tolerated doses of metformin, sulfonylurea, or both. The goal was to compare addition of 1.8-mg daily liraglutide or 10-μg twice-daily exenatide to participants already receiving metformin, glimepiride, or both.17 The patients' average baseline HbA1c level was 8.2%. The average reductions in HbA1c level were 1.1% with liraglutide and 0.8% with exenatide.17 
Changes in FPG levels, weight, and incidences of hypoglycemia and nausea were also evaluated in LEAD-6.17 The FPG levels decreased by 29 mg/dL with liraglutide and 11 mg/dL with exenatide. Weight loss was similar with both GLP-1 receptor agonists (-3.2 kg with liraglutide, -2.9 kg with exenatide). Minor hypoglycemia occurred, with 1.9 and 2.6 events per patient-year with liraglutide and exenatide, respectively. Major hypoglycemic events were reported in 2 patients, both of whom had received exenatide plus sulfonylurea. Nausea occurred in 25% of liraglutide-treated patients and in 28% of exenatide-treated patients.17 
In a 14-week extension of the LEAD-6 trial,17 a group of participants was switched from twice-daily exenatide to once-daily liraglutide.33 The HbA1c levels in those patients was further reduced by an average of 0.3%, FPG levels by 16 mg/dL, and weight by 0.9 kg. These additional reductions were similar to those observed in the group of participants who continued receiving liraglutide during the 14-week extension period. 
Data on Emerging Agents
Administration of the GLP-1 receptor agonists requires subcutaneous injection. Therefore, a research goal has been to develop long-acting agonists to simplify patient adherence to the treatment regimen. Exenatide requires twice-daily injections. The FDA's approval of once-weekly exenatide (ie, exenatide QW) has been delayed because of uncertainty regarding whether the drug prolongs the QT interval.34 
The DURATION-1 study34 was a 30-week randomized controlled trial comparing exenatide QW 2 mg weekly with exenatide 10 μg twice daily. Trial participants were either drug-naive or allowed to continue their current oral regimen of 1 or more antidiabetic agents. The trial results showed that exenatide QW reduced HbA1c levels by 1.9% vs 1.5% for standard exenatide.34 Weight reduction was similar for both preparations, and there was no difference in the incidence of minor hypoglycemia. Regarding possible cardiac effects of exenatide QW, the DURATION-1 data showed a small increase in heart rate (ie, approximately 3 beats/min) and a statistically insignificant increase in the Fridericia corrected QT interval (representing the duration of ventricular depolarization and subsequent repolarization).35 
The GLP-1 receptor agonist most likely to be approved next is lixisenatide, a once-daily formulation. Data presented at the 71st Scientific Sessions of the American Diabetes Association (ADA) in June 2011 described the results of a 24-week, phase III clinical trial of patients whose T2DM was not controlled with insulin or insulin and a sulfonylurea.34 Addition of 20-mg lixisenatide to the regimen resulted in a 0.9% reduction in HbA1c level, as well as improvement in 2-hour PPG control. Data suggest that weight loss, adverse effects, and tolerability with lixisenatide are similar to those seen with other GLP-1 receptor agonists.36 
Recommendations for Starting and Advancing T2DM Treatment
Among the algorithms outlining strategies to initiate and advance treatment for patients with T2DM, 1 of the best known was developed jointly by the ADA and the European Association for the Study of Diabetes (EASD) (Figure 1),37 and another was developed by the American Association of Clinical Endocrinologists (AACE) (Figure 2).38
Figure 1.
Consensus algorithm of the American Diabetes Association and European Association for the Study of Diabetes for treating patients with type 2 diabetes mellitus. Reprinted from Nathan et al37 with permission of the American Diabetes Association. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety. Abbreviations: CHF, congestive heart failure; GLP-1, glucagon-like peptide-1.
Figure 1.
Consensus algorithm of the American Diabetes Association and European Association for the Study of Diabetes for treating patients with type 2 diabetes mellitus. Reprinted from Nathan et al37 with permission of the American Diabetes Association. aSulfonylureas other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety. Abbreviations: CHF, congestive heart failure; GLP-1, glucagon-like peptide-1.
Figure 2.
Consensus algorithm of the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) for treating patients with type 2 diabetes mellitus. Reprinted from Rodbard et al38 with permission from the American Association of Clinical Endocrinologists. aMay not be appropriate for all patients. bFor patients with diabetes and HbA1c <6.5%, pharmacologic prescription may be considered. cIf HbA1c goal is not achieved safely. Abbreviations: HbA1c, glycosylated hemoglobin; AGI, α-glucosidase inhibitor; DPP4, dipeptidyl peptidase-4 inhibitor; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1 receptor agonist; MET, metformin; NAFLD, nonalcoholic fatty liver disease; PPG, postprandial plasma glucose; SU, sulfonylurea; TZD, thiazolidinedione.
Figure 2.
Consensus algorithm of the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) for treating patients with type 2 diabetes mellitus. Reprinted from Rodbard et al38 with permission from the American Association of Clinical Endocrinologists. aMay not be appropriate for all patients. bFor patients with diabetes and HbA1c <6.5%, pharmacologic prescription may be considered. cIf HbA1c goal is not achieved safely. Abbreviations: HbA1c, glycosylated hemoglobin; AGI, α-glucosidase inhibitor; DPP4, dipeptidyl peptidase-4 inhibitor; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1 receptor agonist; MET, metformin; NAFLD, nonalcoholic fatty liver disease; PPG, postprandial plasma glucose; SU, sulfonylurea; TZD, thiazolidinedione.
 
The ADA/EASD algorithm recommends lifestyle modification (ie, 5%-10% weight loss and an exercise program of 3-5 hours per week) and metformin as initial “step-1” therapy.37 Lifestyle modification remains the cornerstone of all subsequent strategies of glycemic control, and its importance cannot be overemphasized. Individuals with diabetes mellitus can defeat any regimen if they do not participate fully in the management of their disease. Typically, 3 months of initial therapy is allowed before the patient's progress toward glycemic control is evaluated. 
If glycemic goals are not met, the ADA/EASD recommends advancing therapy using a 2-tier system.37 Tier 1, or “well-validated core therapies,” focuses on adding a sulfonylurea or insulin as step 2. If goals are still not reached, the patient advances to metformin and an intensified insulin regimen. Alternatively, tier 2, or “less well-validated therapies,” presents the option of adding pioglitazone or a GLP-1 receptor agonist to the base regimen of lifestyle modification plus metformin. If glycemic control is not achieved by means of either tier, step 3 involves triple oral therapy or metformin augmented with basal insulin. The final pathway for both tier 1 and tier 2 is metformin and intensive insulin therapy complemented with lifestyle modifications37 
The AACE algorithm38 ultimately brings the patient to similar therapeutic regimens as the ADA/EASD algorithm,37 but the approach is different. The decision to begin monotherapy, dual therapy, or insulin is based on the initial HbA1c measurement. Monotherapy is recommended if the HbA1c level is between 6.5% and 7.5%, and dual therapy is started if the HbA1c level is between 7.6% and 9.0%.38 All classes of oral agents are acceptable as treatment. 
The AACE regimen is advanced approximately every 2 to 3 months, and the rules for adding drugs are straight-forward.38 Lifestyle modification and metformin are the building blocks of treatment if the initial HbA1c level is 9% or less, and advancing therapy involves merely selecting any other antidiabetic agent as long as it is from a different class. For patients whose HbA1c level is greater than 9%, the decision to initiate insulin or GLP-1 receptor agonists plus oral agents is based on clinical judgment. The end pathway for patients in whom all previous interventions fail is intensive insulin therapy.38 
It should be noted that both consensus algorithms include GLP-1 receptor agonists as recommended interventions early in therapy and as prime agents when therapy is advanced.37,38 The ADA/EASD treatment options recommend exenatide or liraglutide as tier 2 therapy for obese patients who do not respond adequately to monotherapy with metformin, who cannot risk an episode of hypoglycemia, or who have comorbid cardiac conditions.39 The AACE guidelines are more aggressive, offering the GLP-1 receptor agonists as an option for initial monotherapy.39 Furthermore, when moving from single to dual to triple therapy, the AACE guidelines suggest GLP-1 receptor agonists at every decision point.38 
With increasing concerns about the risks of cardiac events and bladder cancer from using thiazolidinediones, and with safety risks of hypoglycemia with the use of sulfonylureas and insulin,40 the GLP-1 receptor agonists and metformin are assuming major roles in the treatment of patients with diabetes mellitus. 
Glycemic Control and Comorbidities of Diabetes Mellitus
According to the Centers for Disease Control and Prevention (CDC), there are approximately 26 million people with T2DM in the United States, including some 19 million diagnosed cases and 7 million undiagnosed cases.39 These estimates are based on FPG and HbA1c diagnostic criteria. In 2010 alone, 2 million people were newly diagnosed as having T2DM.39 
The clinical significance of these numbers increases when we consider that most cases of T2DM progressed from prediabetes. Glycosylated hemoglobin values indicate that 35% of individuals aged 20 years or older and 50% of individuals aged 65 years or older have prediabetes, translating into almost 80 million people with prediabetes in the United States.39 With a conversion rate from prediabetes to T2DM of approximately 5% per year, the consequences are obvious.31 
The complications of diabetes mellitus are well known. The CDC reports that 68% of people aged 65 years or older who died of coronary heart disease in 2004 had diabetes mellitus.39 The risk of stroke is 2 to 4 times higher in those with diabetes mellitus than in those without diabetes mellitus.39 Furthermore, hypertension occurs in about 70% of all individuals with diabetes mellitus, and retinopathy develops in approximately 30% of people with diabetes who are aged 40 years or older.39 Diabetes mellitus remains the leading cause of new cases of legal blindness, the leading cause of renal failure, and a major cause of distal sensory neuropathy. 
The following are other grim statistics about the effects of diabetes mellitus as reported by the CDC39: more than 60% of nontraumatic lower-limb amputations occur in people with diabetes mellitus; periodontal disease is increased about 3-fold in people with diabetes; infections often take a more serious course in people with diabetes; and diabetes is associated with a 60% increased risk of depression. 
Considering that pharmacotherapy is highly effective, why do only approximately 50% of people with diabetes mellitus achieve goals for glycemic control?41 The major reason is nonadherence. Data indicate that patient adherence to a treatment regimen is poor, ranging from 36% to 87% with oral agents and 54% to 81% with insulin.41 Reasons for failing to adhere to an antidiabetic regimen include adverse effects from medication, with the most commonly reported problems being weight gain and hypoglycemia.42-44 As previously noted, however, weight loss occurs in patients treated with GLP-1 receptor agonists, and no major episodes of hypoglycemia have been associated with this class of antidiabetic agents. Thus, GLP-1 receptor agonists can control blood glucose levels while circumventing weight gain and hypoglycemia as barriers to achieving glycemic goals. 
Contraindications to GLP-1 Receptor Agonists
In selecting a GLP-1 receptor agonist to treat a patient with diabetes mellitus, several contraindications must be considered. These agents should not be used in patients who have type 1 diabetes mellitus or ketoacidosis. Such patients produce essentially no insulin, and GLP-1 cannot serve as a substitute for insulin. Thus, patients with type 1 diabetes mellitus should be given insulin. 
Glucagon-like peptide-1 receptor agonists should not be used in persons with a history of pancreatitis.26,27 The incidence of pancreatitis associated with treatment with exenatide equaled 36 reported cases as of August 2008,45 and the incidence of pancreatitis reported with liraglutide in 2010 was 0.8 cases per 1000 patient-years.46 In 2011, Elashoff et al47 reported that a meta-analysis of data from 2004 through 2009 suggested that the risk of pancreatic cancer may be increased 2.9-fold in patients receiving exenatide. However, this matter remains unresolved because the published analyses did not adjust for pancreatic cancer risk factors, including obesity, smoking, family history, and chronic pancreatitis. Dr Gavin discusses this topic further in his previously mentioned article25 in this JAOA supplement. 
The FDA has issued a black box warning that GLP-1 receptor agonists are contraindicated in individuals with a history of medullary C-cell cancer and in individuals with multiple endocrine neoplasia type 2.26,27 Although GLP-1 receptor agonists have been shown to cause thyroid C-cell tumors in rodents, the FDA noted that the relevance of this finding to humans could not be determined from clinical studies.48 
Therapy With GLP-1 Receptor Agonists and Insulin
On the basis of studies of GLP-1 receptor agonists used in combination with insulin, the FDA recently approved exenatide as add-on therapy to insulin glargine.9 Buse et al49 reported the results of a 30-week multicenter study that compared the use of exenatide 10 μg twice daily vs placebo in patients with T2DM who were using insulin glargine, glargine plus metformin or pioglitazone, or glargine plus both oral agents. The glargine was titrated to reach fasting glucose goals. Those patients receiving exenatide demonstrated an additional HbA1c reduction of approximately 0.7% compared to those given placebo, their weight decreased almost 2 kg (while weight increased in patients given placebo), and they required less insulin than those taking placebo.49 
At the 71st Scientific Sessions of the ADA in June 2011, several abstracts were presented that described the use of exenatide, lixisenatide, and liraglutide in combination with insulin. The results reported in these abstracts were similar to those reported by Buse et al49—including further reductions in HbA1c levels, decreases in weight, and reduced need for insulin.36,50,51 
Conclusion
The GLP-1 receptor agonists can be used as monotherapy or in combination with other agents in the intensification of treatment for patients with T2DM. Clinical trials have established the safety and beneficial effects of GLP-1 receptor agonists in terms of glycemic control and nonglycemic parameters, including body weight, blood pressure, and lipid levels. Currently available GLP-1 receptor agonists are increasingly being used in novel ways, including in combination with insulin therapy, and there are several additional GLP-1 receptor agonists in various stages of development. 
   This article was developed with assistance from DIME, the Discovery Institute of Medical Education. The author approved the article and all of its contents.
 
   Financial Disclosures: Dr Spellman discloses that he is a consultant for sanofi-aventis and a speaker for Eli Lilly and Company and Boehringer Ingelheim Pharmaceuticals, Inc.
 
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