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Articles  |   March 2010
New Therapeutic Options: Management Strategies to Optimize Glycemic Control
Author Notes
  • From the Division of Endocrinology and Metabolism in the Department of Internal Medicine at the Philadelphia College of Osteopathic Medicine in Pennsylvania. 
  • Address correspondence to Jeffrey S. Freeman, DO, 4190 City Ave, Suite 324, Philadelphia College of Osteopathic Medicine, Philadelphia, PA 19131-1633. E-mail: jeffreyfreemando@aol.com 
Article Information
Cardiovascular Disorders / Endocrinology / Diabetes
Articles   |   March 2010
New Therapeutic Options: Management Strategies to Optimize Glycemic Control
The Journal of the American Osteopathic Association, March 2010, Vol. 110, S15-S20. doi:
The Journal of the American Osteopathic Association, March 2010, Vol. 110, S15-S20. doi:
Abstract

Management of type 2 diabetes mellitus (T2DM) can be challenging. Patients frequently present with poor glycemic control despite therapy. Other patients may be nonadherent or resistant to continuing their treatment when confronted with undesirable adverse effects, such as weight gain, that are associated with many conventional therapies. Incretin-based therapies developed to treat patients with T2DM, including oral dipeptidyl peptidase-4 inhibitor agents or glucagon-like peptide-1 agonists, offer the potential of sustained glycemic control for many patients without the adverse events associated with other classes of antihyperglycemic medications. Available safety data from clinical trials indicate that incretin-based therapies have weight-neutral or weight-reducing effects, with no apparent adverse impact on other important safety parameters, such as cardiovascular disease. The integration of these therapies into treatment algorithms, as highlighted in three case presentations, will increase treatment options for patients with T2DM.

Type 2 diabetes mellitus (T2DM) can be challenging to manage. Part of this difficulty arises from limitations associated with traditional antihyperglycemic agents, such as hypoglycemia and weight gain. In addition, with convenient access to various sources of information (or misinformation), such as the Internet, online chat rooms, and support groups, patients may be inquisitive with respect to their disease and treatment. When discussing therapy, clinicians should provide patients with evidence-based treatment options that patients can understand and relate to in the context of their condition. 
Treatment guidelines from the American Association of Clinical Endocrinologists (AACE) recommend initiating lifestyle modification at the time of diagnosis, in addition to various pharmacotherapies based on the patient's glycated hemoglobin (HbA1c) level. The American Diabetes Association goals of antihyperglycemic therapy are to achieve an HbA1c of less than 7.0%, fasting plasma glucose (FPG) range of 70 mg/dL to 130 mg/dL, and a peak postprandial glucose (PPG) of less than 180 mg/dL.1 The AACE goals are an HbA1c of 6.5% or lower, an FPG of less than 110 mg/dL, and a 2-hour PPG of less than 140 mg/dL.2 
The current article presents a series of cases highlighting some commonly encountered issues in the treatment of patients with T2DM. Clinical evidence is offered to engage patients in a meaningful discussion of T2DM and treatment options. 
Case 1
The patient is a 48-year-old man who was diagnosed as having T2DM 2 years ago. He has been treated with lifestyle changes and increasing doses of metformin, which is currently at 1000 mg twice daily. Available laboratory results show his HbA1c is 7.6% (increased from 7.2% last year), his fasting plasma glucose is 170 mg/dL, and his postprandial glucose is 240 mg/dL.  
Comment
This patient has been treated with lifestyle changes and pharmacotherapy with increasing doses of metformin for his diabetes. At least one component of the disease progression in this patient is likely caused by declining β-cell function. Options for further treatment aimed at reducing the patient's HbA1c level include the use of combination therapy with metformin or a switch from metformin to another therapy. 
The natural history of T2DM typically involves progressive pancreatic islet cell dysfunction and worsening glycemic control. Traditional antihyperglycemic agents—thiazolidinediones and sulfonylureas—often fail to maintain glycemic goals long-term, in part, because they do not target the underlying pathophysiologic processes of T2DM, which include a progressive decline in β-cell function and impaired incretin response. Incretin-based therapies address these mechanisms and offer the advantage of potentially slowing disease progression by enhancing insulin secretion and suppressing glucagon release. 
Evidence from a recent clinical trial3 involving the glucagon-like peptide-1 (GLP-1) agonist exenatide showed a sustained improvement in HbA1c levels in patients with T2DM who completed at least 3 years of treatment. Patients who enrolled in a randomized, double-blind, parallel-group, 30-week study had the option to continue in their open-label extensions; completers were then given the option to enroll in a single, open-ended, open-label extension. During the blinded portion of the study, patients received combination therapy of exenatide with either metformin or a sulfonylurea, or triple therapy with exenatide, metformin, and a sulfonylurea.3 Patients who completed 156 weeks of treatment with exenatide reduced HbA1c levels by a mean (SD) of -1.0% (0.1%) (P<.0001) and reduced FPG by -23.5 (3.8) mg/dL (P<.0001). These findings demonstrated a sustained and durable control of HbA1c in patients completing 3 years of treatment with exenatide (Figure 1).3 
With other T2DM interventions, an initial improvement in glycemic control is followed by increasing levels of HbA1c over time. However, the results of this analysis suggest some stability and durability in the HbA1c response when exenatide is used as a component of the combination therapy. When discussing treatment options with patients, physicians should explain that, based on clinical trial evidence, the addition of exenatide to metformin could potentially reduce HbA1c levels by a percentage point or more. 
Sitagliptin, a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, has also shown efficacy in lowering HbA1c levels in patients with T2DM when used as monotherapy. One 24-week study4 demonstrated reductions in HbA1c of 0.79% and 0.94% for 100 mg and 200 mg sitagliptin, respectively (P<.001 for both vs placebo). In addition, 41% and 45% of patients in the respective sitagliptin groups achieved an HbA1c of less than 7.0%, compared with only 17% in the placebo group (P<.001).4 
Figure 1.
Sustained mean (SEM) reduction of glycated hemoglobin (HbA1c) in patients (N=217) with type 2 diabetes mellitus completing 3 years of exenatide therapy added to metformin, a sulfonylurea, or both in an open-ended, open-label extension study. Exenatide was prescribed at 5 mg twice a day for 4 weeks, then increased to 10 mg twice a day. Comparisons were statistically significant (P<.0001) from baseline to 30 weeks and baseline to 3 years. Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
Figure 1.
Sustained mean (SEM) reduction of glycated hemoglobin (HbA1c) in patients (N=217) with type 2 diabetes mellitus completing 3 years of exenatide therapy added to metformin, a sulfonylurea, or both in an open-ended, open-label extension study. Exenatide was prescribed at 5 mg twice a day for 4 weeks, then increased to 10 mg twice a day. Comparisons were statistically significant (P<.0001) from baseline to 30 weeks and baseline to 3 years. Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
Similar results were seen in combination therapy with metformin: at 24 weeks, sitagliptin significantly reduced baseline HbA1c by -0.65% (P<.001).5 The percentage of patients achieving an HbA1c of less than 7.0% was 47% in the sitagliptin group and 18.3% in the placebo group (P<.001).5 As add-on therapy with ongoing pioglitazone, sitagliptin significantly reduced both HbA1c (-0.7%; P<.001) and FPG (-17.7 mg/dL; P<.001), and the percentage of patients reaching the target goal was 45.4% and 23.0% in the sitagliptin and placebo groups, respectively (P<.001).6 
In populations with a baseline HbA1c of 8.8%, sitagliptin also demonstrated moderate efficacy in combination with high-dose metformin. At week 24, the combination of sitagliptin (50 mg twice daily) with high-dose metformin (1000 mg twice daily) resulted in an HbA1c reduction of -1.9% vs baseline, and -2.07% vs placebo.7 Evidence from a 104-week study also suggested a durable and sustained reduction in HbA1c with sitagliptin as add-on therapy to metformin (Figure 2).8 Results with both exenatide and sitagliptin demonstrated durable and apparently sustainable reductions in HbA1c, and could theoretically cause islet or β-cell function regeneration or an improvement in viability of β cells. However, further study will be needed to determine whether such increases in β-cell mass or function are occurring. 
Results with saxagliptin, another DPP-4 inhibitor, in combination with metformin have also demonstrated significant reductions in HbA1c and have shown evidence of durability during a 2-year study (Figure 3). In this case, however, the HbA1c pattern did not appear to show a plateau effect, but instead indicated an initial response was followed by a gradual increase between 30 and 102 weeks.9 Further follow-up may be needed to determine whether the efficacy of saxagliptin is sustainable over the long-term. 
Summary
Based on available evidence, combination treatment, which includes incretin-based therapy (ie, GLP-1 agonist or DPP-4 inhibitor), may be beneficial in patients with disease progression despite treatment and an increase in metformin dosage. Long-term studies showed that incretin-based therapies can be used in combination with metformin, with an expected HbA1c reduction of about 1.2% and with durability of response of at least 1 year.3,4,7,9 
Figure 2.
Effectiveness and durability of combination sitagliptin (100 mg/d) and metformin (1500 mg/d) therapy on glycemic control for 2 years in patients with type 2 diabetes mellitus. Source: Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569-583.8
Figure 2.
Effectiveness and durability of combination sitagliptin (100 mg/d) and metformin (1500 mg/d) therapy on glycemic control for 2 years in patients with type 2 diabetes mellitus. Source: Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569-583.8
Case 2
The patient is a 50-year-old woman recently diagnosed as having T2DM. She takes 500 mg metformin twice daily. Her height is 5 ft 5 in and her weight is 180 lbs. Her body mass index is 30, which is consistent with obesity. The patient has had difficulty losing weight, despite attempts at lifestyle modification. Her family history is notable for T2DM and insulin resistance in her older sister.  
Figure 3.
Effect of saxagliptin (2.5 mg, 5.0 mg, or 10 mg) or placebo in combination with metformin therapy on glycated hemoglobin (HbA1c) levels over 102 weeks in patients with inadequate glycemic control on metformin alone. Mean baseline HbA1c was 8.1%. Source: DeFronzo R et al. Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9, 2009; New Orleans, LA. Abstract 547-P. 9
Figure 3.
Effect of saxagliptin (2.5 mg, 5.0 mg, or 10 mg) or placebo in combination with metformin therapy on glycated hemoglobin (HbA1c) levels over 102 weeks in patients with inadequate glycemic control on metformin alone. Mean baseline HbA1c was 8.1%. Source: DeFronzo R et al. Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9, 2009; New Orleans, LA. Abstract 547-P. 9
Comment
When considering treatment for this patient, weight loss should be a desired goal. Traditional antihyperglycemic agents, including thiazolidinediones and sulfonylureas, are associated with weight gain. In contrast, recent evidence3,4 associates incretin-based therapy and GLP-1 agonists combination therapy with weight loss and DPP-4 inhibitors with weight-neutrality. 
In a 3-year follow-up study of patients who completed treatment with exenatide (n=217), the overall weight loss was -5.3 kg (P<.0001 vs baseline), or approximately 10 lbs (Figure 4).3 Although this decrease may not be substantial as a weight-loss intervention for some patients, the key point in this long-term follow-up study is that the patients did not gain weight during the 3 years. At present, because the study lasted only 3 years, it may be too soon to ascertain whether this weight loss will continue or reach a plateau over the longer-term. The relevant results to consider are an effective HbA1c reduction with some degree of durable weight loss over time. 
By comparison, available data with DPP-4 inhibitors indicate a weight-neutral impact. A number of trials have examined the use of sitagliptin alone and in combination with other therapies. Findings were as follows: 
  • sitagliptin 100 mg monotherapy vs placebo for 24 weeks: -0.2 and -0.1 kg vs -1.1 kg, respectively (P<.01)4
  • sitagliptin 100 mg monotherapy vs placebo for 18 weeks: -0.6 vs -0.7 kg, respectively10
  • add-on sitagliptin therapy with metformin for 24 weeks: between-group difference change in body weight (P=.835)5
  • sitagliptin with ongoing pioglitazone for 24 weeks: no statistically significant difference6
  • sitagliptin initial combination therapy with high-dose metformin for 24 weeks: small reductions (-0.6 to -1.3 kg)7
  • sitagliptin alone for 24 weeks: no change
These findings are also highlighted in Figure 5.4-7,10 
These trials either reduced the weight by approximately 1 kg or had no effect on weight, regardless of the combination used. Therefore, patients treated with sitagliptin combination therapy may achieve better glycemic control than those treated with metformin or a sulfonylurea monotherapy while maintaining weight-neutrality. 
Summary
Based on the available clinical results, treatment options for patients with T2DM who desire to lose weight or to maintain weight are either GLP-1 agonists such as exenatide or DPP-4 inhibitors such as sitagliptin. 
Figure 4.
Reduction in weight in patients with type 2 diabetes mellitus (N=217) completing 3 years of exenatide therapy in an open-ended, open-label extension study. Baseline weight was 99 kg. No diet and exercise regimen was provided. Data provided as mean (SEM). Comparisons were statistically significant (P<.0001) from baseline to 3 years and from 30 weeks and 3 years. Mean (SEM) HbA1c level was 8.2% (1.0%), and the mean (SEM) change in HbA1c: -1.0% (0.1%). Source: Klonoff DC et al. Curr Med Res Opin. 2008; 24(1):275-286.3
Figure 4.
Reduction in weight in patients with type 2 diabetes mellitus (N=217) completing 3 years of exenatide therapy in an open-ended, open-label extension study. Baseline weight was 99 kg. No diet and exercise regimen was provided. Data provided as mean (SEM). Comparisons were statistically significant (P<.0001) from baseline to 3 years and from 30 weeks and 3 years. Mean (SEM) HbA1c level was 8.2% (1.0%), and the mean (SEM) change in HbA1c: -1.0% (0.1%). Source: Klonoff DC et al. Curr Med Res Opin. 2008; 24(1):275-286.3
Case 3
The patient is a 68-year-old man who was recently diagnosed as having T2DM and was initially treated with metformin 500 mg twice daily. His HbA1c increased despite attempts at lifestyle modification.  
The patient's medical history is notable for a coronary artery bypass graft 6 years ago as well as hypertension, hyperlipidemia, and obesity. His family history is notable for coronary artery disease in his father and T2DM in his mother.  
On physical examination, blood pressure is 138/90 mm Hg; heart rate, 82 beats per minute, and respiratory rate, 18 breaths per minute. Cardiac examination is notable for an audible S4, but it is otherwise unremarkable. His respiratory, gastrointestinal, and neurologic examinations are normal, and electrolytes are within normal limits. Fundoscopic examination reveals hypertensive changes suggesting microvascular involvement. Available laboratory values show a random plasma glucose level of 232 mg/dL and an HbA1c of 8.2%.  
The patient is a retired pharmaceutical industry representative and is aware of the diverse treatment options for T2DM, including incretin-based therapies. However, he is concerned about their cardiovascular disease safety profiles. He asks if there have been any studies that have evaluated cardiovascular disease safety and lipid-lowering benefits.  
Comment
In the case of cardiovascular disease risk with incretin-based therapies, there is currently evidence for up to 3.5 years of treatment without a statistically significant signal for concern. The effect of exenatide treatment on cardiovascular risk factors was shown in a subgroup of 151 patients in a 3-year extension analysis (Table).3 Study data demonstrated an HbA1c reduction of approximately 0.8%; an improvement in lipid profile, with reductions in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol; and an improvement in blood pressure. All changes were statistically significant. Clearly, such improvements would have a positive impact on long-term outcomes.3 A key question, however, that is not addressed by these data is whether these lipid effects are mediated directly by exenatide or by the secondary effect of weight loss in these patients. Based on these data, cardiovascular risk factors, including lipid parameters and blood pressure, may improve while on exenatide, but they may also be contingent upon weight reduction while on the therapy. 
Table
Change in Cardiovascular Risk Factors in Patients Completing 3.5 Years of Exenatide Therapy* (N=151)

Risk Factor

Change From Baseline, mean (SD)

P Value
Body Weight, kg-5.3 (0.5)<.0001
HbA1c, % -0.8 (0.1) <.0001
Total Cholesterol, mg/dL-10.8 (3.1).0007
Triglycerides, mg/dL -44.4 (12.1) .0003
LDL-C, mg/dL-11.8 (2.9)<.0001
HDL-C, mg/dL +8.5 (0.6) <.0001
SBP, mm Hg-3.5 (1.2).0063
DBP, mm Hg -3.3 (0.8) <.0001
 Abbreviations: DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure.Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
 *Exenatide therapy was administered at 10 μg twice daily for 3.5 years. The study design was an open-ended, open-label extension study.
Table
Change in Cardiovascular Risk Factors in Patients Completing 3.5 Years of Exenatide Therapy* (N=151)

Risk Factor

Change From Baseline, mean (SD)

P Value
Body Weight, kg-5.3 (0.5)<.0001
HbA1c, % -0.8 (0.1) <.0001
Total Cholesterol, mg/dL-10.8 (3.1).0007
Triglycerides, mg/dL -44.4 (12.1) .0003
LDL-C, mg/dL-11.8 (2.9)<.0001
HDL-C, mg/dL +8.5 (0.6) <.0001
SBP, mm Hg-3.5 (1.2).0063
DBP, mm Hg -3.3 (0.8) <.0001
 Abbreviations: DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure.Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
 *Exenatide therapy was administered at 10 μg twice daily for 3.5 years. The study design was an open-ended, open-label extension study.
×
Figure 5.
Impact of sitagliptin on weight change when used as monotherapy or as a component of combination therapy in patients with type 2 diabetes mellitus. Sources: Aschner P et al. Diabetes Care. 2006;29(12):2632-26374; Raz I et al. Diabetologia. 2006;49:2564-257110; Charbonnel B et al. Diabetes Care. 2006;29(12):2638-26435; Rosenstock J et al. Clin Ther. 2006;28(10):1556-15686; Goldstein BJ et al. Diabetes Care. 2007;30(8):1979-1987.7
Figure 5.
Impact of sitagliptin on weight change when used as monotherapy or as a component of combination therapy in patients with type 2 diabetes mellitus. Sources: Aschner P et al. Diabetes Care. 2006;29(12):2632-26374; Raz I et al. Diabetologia. 2006;49:2564-257110; Charbonnel B et al. Diabetes Care. 2006;29(12):2638-26435; Rosenstock J et al. Clin Ther. 2006;28(10):1556-15686; Goldstein BJ et al. Diabetes Care. 2007;30(8):1979-1987.7
An unpublished meta-analysis11 examined cardiovascular end points in patients enrolled in 12 completed, long-term (between 3 and 12 months), randomized, placebo- and insulin-comparator–controlled trials using exenatide twice daily. The intent-to-treat population consisted of 3945 subjects: 2316 were exposed to exenatide and 1629 were not exposed to exenatide (comparator group).11 Subject years totaled 1072 in the exenatide group and 780 in the comparator group, with an average exposure time of 24 weeks.11 In Kaplan-Meier analysis, there was a lower incidence of cardiovascular end points with exenatide relative to the comparator in major adverse cardiac events end points (ie, nonfatal myocardial infarction, stroke, and cardiovascular death). These results indicate that exenatide may be safer to use with regard to cardiovascular end points compared to other therapies. In addition, no evidence exists for an adverse cardiovascular risk with exenatide therapy compared with other agents. 
The US Food and Drug Administration requires an evaluation of diabetes therapies that can potentially affect cardiovascular disease using clinical trials that specifically address these safety outcomes under a particular set of circumstances and qualifiers. The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is currently recruiting patients taking sitagliptin with the composite cardiovascular outcome end point that includes cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina.12 Randomization in the trial will be 1:1 with double-blinded sitagliptin 100 mg or matching placebo added as a component of the patient's existing diabetes care regimen. Initial follow-up will consist of 4-monthly visits in year 1 followed by twice-yearly visits for a minimum of 4 years until the statistical end point (1300 primary end point events) is achieved.12 Patient accrual into the trial began in December 2008 and is expected to take 2 years. Results from this well-designed, placebo-controlled study should yield further data pertaining to the cardiovascular safety of incretin-based therapies. 
Summary
The available cardiovascular safety data indicate that incretin-based therapies are safe, or perhaps even safer than, other T2DM therapies with respect to cardiovascular outcomes. Incretin-based therapies may even improve certain cardiovascular risk factors. Exenatide use may promote weight loss, which can also reduce a patient's overall cardiovascular risk. In the case of the DPP-4 inhibitors, studies such as TECOS will evaluate cardiovascular outcomes for patients on sitagliptin. 
Other Considerations in Choosing Therapy
Have the results of comparative studies between GLP-1 agonists and DPP-4 inhibitors been published? The two classes of incretin-based therapy have been compared in a recent double-blind, randomized, double-dummy, crossover, multicenter study.13 Patients received the GLP-1 agonist exenatide or the DPP-4 inhibitor sitagliptin during an initial treatment period, followed by a crossover to the other therapy during a second treatment period. 
In the study,13 61 patients with T2DM who had been treated with a stable regimen of metformin were randomized to either an exenatide-to-sitagliptin or a sitagliptin-to-exenatide treatment sequence. The primary study end point was the effect of sitagliptin and exenatide on 2-hour PPG.13 Results showed that, for patients in the exenatide-to-sitagliptin sequence, 2-hour PPG decreased to a mean (SD) value of 133 (10) mg/dL from a baseline value of 245 mg/dL while on exenatide. The subsequent sitagliptin treatment in period 2 increased the 2-hour PPG to 205 (12) mg/dL. By comparison, for patients in the sitagliptin-to-exenatide sequence, 2-hour PPG decreased to 208 (6) mg/dL while on sitagliptin. Subsequent exenatide treatment further reduced the 2-hour PPG to 133 (9) mg/dL.13 
A reduction in PPG was thus observed with either agent when used as an initial therapy, albeit with a greater reduction observed with exenatide.11 However, when the exenatide group crossed over to therapy with sitagliptin, there was an apparent deterioration in PPG control, whereas sitagliptin-treated patients who crossed over to exenatide continued to maintain control over 2-hour PPG. The two drugs were similar in their effects on FPG, with no significant difference observed (FPG with exenatide: -15 mg/dL vs sitagliptin; -19 mg/dL; P=.3234).13 Overall, these results suggest that patients receiving incretin-based therapy with GLP-1 agonists such as exenatide may experience a more robust decrease in 2-hour PPG compared with an oral DPP-4 inhibitor such as sitagliptin. 
Are there benefits of incretin-based therapy on congestive heart failure? There is evidence that incretin-based therapies may have beneficial effects on cardiac function in patients with congestive heart failure. In one study of patients with New York Heart Association class III or IV heart failure, a 5-week continuous infusion of GLP-1 was shown to significantly improve multiple functional status parameters, including left ventricular ejection fraction (LVEF), maximum myocardial ventilation oxygen consumption, Minnesota Quality of Life score, and 6-minute walk test compared to control patients receiving standard therapy alone.14 Moreover, the observed changes in LVEF could not be accounted for by changes in blood pressure and were observed in patients both with and without diabetes.14 Although at present this represents an off-label use and requires confirmation in double-blind, randomized controlled trials, the results nonetheless suggest a hemodynamic and metabolic benefit of GLP-1 therapy in patients with severe congestive heart failure.14 
Have studies assessed the efficacy and safety of incretin-based therapies in patients aged 65 years or older? 
A common concern in patients aged 65 years or older is safety. In the case of the DPP-4 inhibitor sitagliptin, evidence exists for both its efficacy and safety. In a placebo-controlled study,15 mean age was 71 years in both placebo (n=62) and sitagliptin (n=59) treatment groups, with subjects matched for body mass index and baseline HbA1c levels.15 After 24 weeks, HbA1c levels, FPG levels, and 2-hour PPG decreased (-0.7%, -27 mg/dL, and -61 mg/dL, respectively) in the sitagliptin arm compared to the placebo arm (P<.001). Importantly, the incidence of hypoglycemia and gastrointestinal distress was not different in the sitagliptin group compared to placebo. Results of this study suggest that sitagliptin is safe and effective to use in individuals aged 65 years or older. 
What are the risks of hypoglycemia associated with incretin-based therapies? 
Hypoglycemia is a concern with many conventional T2DM therapies. Available evidence with DPP-4 inhibitors and GLP-1 agonists has shown the overall incidence of hypoglycemia is fairly low.16 In a study of patients with T2DM inadequately controlled with diet and exercise, patients treated with the DPP-4 inhibitor saxagliptin as monotherapy had a similar incidence of mild-to-moderate hypoglycemic events (5.2%) compared with those treated with placebo (6.3%).17 Rates of hypoglycemia were also similar between treatment and placebo groups when sitagliptin was used as monotherapy among patients with inadequately controlled T2DM.4 
Conclusion
When choosing optimal therapies for patients with T2DM, considerations include the patient's stage and progression of disease, the viability of their β cells, comorbid conditions, predisposition for weight gain, renal function, possible aversions to injectable treatments, and cost of therapy. Ultimately, many patients will require insulin therapy as their T2DM progresses.2 In choosing the best therapies for a patient, insulin secretion, insulin resistance, and glucagon suppression should be considered. Incretin-based therapies can effectively target these key pathogenic processes of T2DM2 and offer the potential for durable and sustainable improvement in glycemic control, along with long-term safety and tolerability. 
 This article was developed in part from a CME-certified symposium held on November 4, 2009, during the American Osteopathic Association's 114th Annual Osteopathic Medical Conference and Exposition in New Orleans, Louisiana.
 
 SciMed staff have planned and implemented this educational activity in accordance with the ACCME's Essential Areas and Elements.
 
 Dr Freeman discloses that he is on the speakers bureau for GlaxoSmithKline, Merck & Co, Inc, and Novo Nordisk Inc.
 
 This supplement is supported by an independent educational grant from Novo Nordisk Inc.
 
American Diabetes Association. Standards of medical care in diabetes—2008. Diabetes Care. 2008;31(suppl 1):S12-S54. http://care.diabetesjournals.org/content/31/Supplement_1/S12.long. Accessed February 16, 2010.
Rodbard HW, Blonde L, Braithwaite SS, Brett EM, Cobin RH, Handelsman Y, et al; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus [published correction appears in Endocr Pract. 2008;14(6):802-803]. Endocr Pract. 2007;13(suppl 1):1-68.
Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24(1):275-286.
Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE; Sitagliptin Study 021 Group. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632-2637. http://care.diabetesjournals.org/content/29/12/2632.long. Accessed February 16, 2010.
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29(12):2638-2643. http://care.diabetesjournals.org/content/29/12/2638.long. Accessed February 16, 2010.
Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006;28(10):1556-1568.
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes [published online ahead of print May 7, 2007] [published correction appears in Diabetes Care. 2007;31(8):1713]. Diabetes Care. 2007;30(8):1979-1987. http://care.diabetesjournals.org/content/30/8/1979.long. Accessed February 16, 2010.
Williams-Herman D, Johnson J, Teng R, Luo E, Davies MJ, Kaufman KD, et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin. 2009;25(3):569-583.
DeFronzo R, Hissa MN, Garber AJ, Gross JL, Duan RY, Ravichandran S, et al. Once-daily saxagliptin added to metformin provides sustained glycemic control and is well tolerated over 102 weeks in patients with T2D. Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9 , 2009; New Orleans, LA. Abstract 547-P.
Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H; for the Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49:2564-2571.
Chen L, Han J, Yushmanova I, Bruce S, Porter L.Cardiovascular safety of exenatide BID: an integrated analysis from long-term controlled clinical trials in subjects with type 2 diabetes . Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9 , 2009; New Orleans, LA. Abstract 366-OR.
Bethel MA, Green J, Califf RM, Holman RR. Rationale and design of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9 , 2009; New Orleans, LA. Abstract 2152-PO.
DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study [published online ahead of print September 10, 2008]. Curr Med Res Opin. 2008;24(2):2943-2952.
Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12(9):694-699.
Barzilai N, Mahoney EM, Guo H, Lu K, Golm GT, Williams-Herman D, et al. Sitagliptin is well tolerated and leads to rapid improvement in blood glucose in the first days of monotherapy in patients aged 65 years and older with T2DM. Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9 ,2009; New Orleans, LA. Abstract 587-P.
Kendall DM, Cuddihy RM, Bergenstal RM. Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use [review]. Am J Med. 2009;122(suppl 6):S37-S50.
Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R; CV181-011 Study Investigators. Effect of saxagliptin monotherapy in treatmentnaïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25(10):2401-2411.
Figure 1.
Sustained mean (SEM) reduction of glycated hemoglobin (HbA1c) in patients (N=217) with type 2 diabetes mellitus completing 3 years of exenatide therapy added to metformin, a sulfonylurea, or both in an open-ended, open-label extension study. Exenatide was prescribed at 5 mg twice a day for 4 weeks, then increased to 10 mg twice a day. Comparisons were statistically significant (P<.0001) from baseline to 30 weeks and baseline to 3 years. Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
Figure 1.
Sustained mean (SEM) reduction of glycated hemoglobin (HbA1c) in patients (N=217) with type 2 diabetes mellitus completing 3 years of exenatide therapy added to metformin, a sulfonylurea, or both in an open-ended, open-label extension study. Exenatide was prescribed at 5 mg twice a day for 4 weeks, then increased to 10 mg twice a day. Comparisons were statistically significant (P<.0001) from baseline to 30 weeks and baseline to 3 years. Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
Figure 2.
Effectiveness and durability of combination sitagliptin (100 mg/d) and metformin (1500 mg/d) therapy on glycemic control for 2 years in patients with type 2 diabetes mellitus. Source: Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569-583.8
Figure 2.
Effectiveness and durability of combination sitagliptin (100 mg/d) and metformin (1500 mg/d) therapy on glycemic control for 2 years in patients with type 2 diabetes mellitus. Source: Williams-Herman D et al. Curr Med Res Opin. 2009;25(3):569-583.8
Figure 3.
Effect of saxagliptin (2.5 mg, 5.0 mg, or 10 mg) or placebo in combination with metformin therapy on glycated hemoglobin (HbA1c) levels over 102 weeks in patients with inadequate glycemic control on metformin alone. Mean baseline HbA1c was 8.1%. Source: DeFronzo R et al. Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9, 2009; New Orleans, LA. Abstract 547-P. 9
Figure 3.
Effect of saxagliptin (2.5 mg, 5.0 mg, or 10 mg) or placebo in combination with metformin therapy on glycated hemoglobin (HbA1c) levels over 102 weeks in patients with inadequate glycemic control on metformin alone. Mean baseline HbA1c was 8.1%. Source: DeFronzo R et al. Presented at: 69th Scientific Sessions of the American Diabetes Association; June 5-9, 2009; New Orleans, LA. Abstract 547-P. 9
Figure 4.
Reduction in weight in patients with type 2 diabetes mellitus (N=217) completing 3 years of exenatide therapy in an open-ended, open-label extension study. Baseline weight was 99 kg. No diet and exercise regimen was provided. Data provided as mean (SEM). Comparisons were statistically significant (P<.0001) from baseline to 3 years and from 30 weeks and 3 years. Mean (SEM) HbA1c level was 8.2% (1.0%), and the mean (SEM) change in HbA1c: -1.0% (0.1%). Source: Klonoff DC et al. Curr Med Res Opin. 2008; 24(1):275-286.3
Figure 4.
Reduction in weight in patients with type 2 diabetes mellitus (N=217) completing 3 years of exenatide therapy in an open-ended, open-label extension study. Baseline weight was 99 kg. No diet and exercise regimen was provided. Data provided as mean (SEM). Comparisons were statistically significant (P<.0001) from baseline to 3 years and from 30 weeks and 3 years. Mean (SEM) HbA1c level was 8.2% (1.0%), and the mean (SEM) change in HbA1c: -1.0% (0.1%). Source: Klonoff DC et al. Curr Med Res Opin. 2008; 24(1):275-286.3
Figure 5.
Impact of sitagliptin on weight change when used as monotherapy or as a component of combination therapy in patients with type 2 diabetes mellitus. Sources: Aschner P et al. Diabetes Care. 2006;29(12):2632-26374; Raz I et al. Diabetologia. 2006;49:2564-257110; Charbonnel B et al. Diabetes Care. 2006;29(12):2638-26435; Rosenstock J et al. Clin Ther. 2006;28(10):1556-15686; Goldstein BJ et al. Diabetes Care. 2007;30(8):1979-1987.7
Figure 5.
Impact of sitagliptin on weight change when used as monotherapy or as a component of combination therapy in patients with type 2 diabetes mellitus. Sources: Aschner P et al. Diabetes Care. 2006;29(12):2632-26374; Raz I et al. Diabetologia. 2006;49:2564-257110; Charbonnel B et al. Diabetes Care. 2006;29(12):2638-26435; Rosenstock J et al. Clin Ther. 2006;28(10):1556-15686; Goldstein BJ et al. Diabetes Care. 2007;30(8):1979-1987.7
Table
Change in Cardiovascular Risk Factors in Patients Completing 3.5 Years of Exenatide Therapy* (N=151)

Risk Factor

Change From Baseline, mean (SD)

P Value
Body Weight, kg-5.3 (0.5)<.0001
HbA1c, % -0.8 (0.1) <.0001
Total Cholesterol, mg/dL-10.8 (3.1).0007
Triglycerides, mg/dL -44.4 (12.1) .0003
LDL-C, mg/dL-11.8 (2.9)<.0001
HDL-C, mg/dL +8.5 (0.6) <.0001
SBP, mm Hg-3.5 (1.2).0063
DBP, mm Hg -3.3 (0.8) <.0001
 Abbreviations: DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure.Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
 *Exenatide therapy was administered at 10 μg twice daily for 3.5 years. The study design was an open-ended, open-label extension study.
Table
Change in Cardiovascular Risk Factors in Patients Completing 3.5 Years of Exenatide Therapy* (N=151)

Risk Factor

Change From Baseline, mean (SD)

P Value
Body Weight, kg-5.3 (0.5)<.0001
HbA1c, % -0.8 (0.1) <.0001
Total Cholesterol, mg/dL-10.8 (3.1).0007
Triglycerides, mg/dL -44.4 (12.1) .0003
LDL-C, mg/dL-11.8 (2.9)<.0001
HDL-C, mg/dL +8.5 (0.6) <.0001
SBP, mm Hg-3.5 (1.2).0063
DBP, mm Hg -3.3 (0.8) <.0001
 Abbreviations: DBP, diastolic blood pressure; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure.Source: Klonoff DC et al. Curr Med Res Opin. 2008;24(1):275-286.3
 *Exenatide therapy was administered at 10 μg twice daily for 3.5 years. The study design was an open-ended, open-label extension study.
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