Grant Applications/CME content

 

New and Emerging Therapies to Manage Type 2 Diabetes Mellitus

 

Learning Objectives

 

Upon completion of this program participants will be able to:

1. Describe the unmet needs associated with traditional treatments of type 2 diabetes mellitus (T2DM)

2. Describe the physiological effects of incretins on glycemic control

3. List the incretin based treatments of T2DM and describe their mechanisms of action efficacy and adverse effects

4. Integrate incretin based treatments of T2DM into their practice

 

 

Needs Assessment

 

Challenges in the Treatment of Type 2 Diabetes Mellitus

Type 2 diabetes mellitus has a high and increasing prevalence in the US. Based on the 2005 National Health and Nutrition Examination Surveys (NHANES), an estimated 20 million people in the United States had diabetes. Of these 90-95% had Type 2 diabetes mellitus and approximately 30% had undiagnosed cases ^1,2. The number of diagnosed cases is expected to triple by 2050³. In 2002 diabetes was the 6^th leading cause of death^1,4 and associated with $92 billion in direct and $40 billion in indirect costs¹.

The development of complications in diabetes is strongly associated with the glycemic level. Effective glycemic control can reduce a patient's risk for microvascular complications including retinopathy, nephropathy, and neuropathy. However, patients with higher glycosylated hemoglobin (Hb A_1c) levels at diagnosis as well as those experiencing and upward drift of Hb A_1c levels over time were at an increased risk of complications as evidenced by higher healthcare costs.⁵

The goal in diabetes treatment is to maintain Hb A_1c levels below 7%.⁶ However, this goal is not routinely achieved in medical practice,^7,8 and several barriers to normalizing glycemia exist. First, established diabetes treatments poorly control postprandial hyperglycemia, limiting the effort to restore Hb A_1c levels to the non-diabetic 4-6% range.⁹ Second, treatment with insulin or oral secretagogue may lead to hyperglycemia, thereby putting patients at risk for accidental injuries and limiting the willingness of both physicians and patients to intensify treatment.^10,11 Third, treatment with insulin, secretagogues, and thiazolidinediones may cause weight gain of up to 8 Kg with intensive insulin treatment of T2DM.^10,12 Finally, oral agents are subject to loss of efficacy over time.¹⁰

 

Pathophysiological Mechanisms and Novel Drug Targets

Traditionally diabetes has been described in terms of insulin secretion and hepatic sensitivity to insulin.¹⁰ While this description is most accurate in the fasted state, avoiding postprandial hyperglycemia requires a rapid and sustained release of insulin.¹³ This enhanced release of insulin is mediated by gut-related factors termed incretins, in particular amylin and the glucagon-like peptide 1 (GLP-1).^10,14,15

Amylin is a 37–amino acid peptide that is co-secreted together with insulin from islet β-cells. Its plasma levels increase in response to food intake.¹⁰Exogenous amylin inhibits both gastric emptying and glucagon secretion, which in turn leads to reduced food intake and weight loss.¹⁶ GLP-1 is a 30 –amino acid gut peptide produced in enteroendocrine L cells located in the distal ileum and colon. GLP-1 is rapidly secreted from the distal gut within minutes of food ingestion. The effects of GLP-1 secretion include stimulation of insulin secretion, inhibition of both gastric emptying and glucagon secretion as as well as activation of CNS regions involved in the control of satiety^..^14,17 In preclinical models of experimental diabetes, GLP-1 also induces an expansion of β-cell mass via stimulation of cell proliferation and inhibition of apoptosis.^18,19

In keeping with these physiological properties, administration of native GLP-1(7–36) amide or GLP-1(7–37) inhibits gastric emptying and glucagon secretion and potentiates of glucose-dependent insulin secretion and thereby limits postprandial hyperglycemia.^14,15Exogenous GLP-1 also reduces food intake and enhances satiety in normal and diabetic subjects²⁰ and induces weight loss in healthy obese subjects.²¹Native GLP-1 is substrate to cleavage by dipeptidyl peptidase 4(DPP-4) which together with renal clearance limits its half life to several minutes.²²Because of this short half life, pharmacological strategies for enhancing GLP-1 action involve either the development of GLP-1R agonists that are not subject to enzymatic cleavage or increasing the levels of circulation native GLP-1 by inhibition of DPP-4.¹⁰

 

Efficacy, Safety and Clinical Application of Incretin Based Treatments for Type 2 Diabetes Mellitus

Pharmacological strategies that enhance the action of incretins have to avoid the biological limitations of the native molecules. In the case of amylin a synthetic analogue had to be developed to avoid the potential of fibril formation found in human amylin. The synthetic analogue, pramlitide has three amino acid substitutions that prevent fibril formation but do not impair the the biological potency of the molecule.¹⁰Pramlitide lowers glucose excursions after meals and also reduces appetite; it is approved for the treatment of type 1 and insulin-requiring type 2 diabetes.^10,23

Two different drug classes have been developed to potentiate the effects of GLP-1, namely degradation resistant GLP-1R agonists and DDP-4 in inhibitors which suppress the enzymatic inactivation of GLP-1. GLP-1R agonists are delivered via subcutaneous injection whereas DDP-4 inhibitors can be taken orally.²⁴

Exenatide is the first The first GLP-1R agonist to be approved for human clinical use.²⁴ It mimics the full spectrum of GLP-1R dependent actions including slowing of gastric emptying, suppression of glucagon secretion, promotion of satiety and nutrient-stimulated insulin secretion, but is resistant to cleavage by DDP-4. The most prominent side effects are nausea and vomiting, especially at the beginning of treatment. ^10,24In a head to head comparison with insulin, exanatide achieved comparable glycemic control, but whereas patients on insulin showed a mean weight gain of 1.8 Kg, a mean weight loss of 2.3 Kg was observed in patients on exenatide.²⁵To date, the evidence form clinical trials suggests that exenatide represents a reasonable alternative to insulin therapy in patients whose diabetic symptoms are suboptimally controlled with oral hypoglycemic agents, particularly for those who are concerned about weight gain. However, the available data do not yet support the hypothesis that therapy with GLP-1R agonists produces durable improvements in β-cell function.²⁴

Liraglutide was developed to have phamacokinetic properties that allow once daily injection by binding noncovalently to albumin.^10,24 The efficacy of liraglutide versus that of exenatide, or insulin was investigated in several phase III clinical trials. The results suggest that liraglutide was at least as efficacious in lowering HbA1c as comparator treatments and was usually associated with weight loss of several kilograms. As with exenatide, nausea is the most common adverse effect associated with liraglutide administration.²⁴

In addition to nausea and vomiting, the formation of antibodies and pancreatitis are known side effects of GLP-1R agonists.²⁴While the presence of antibodies does not appear to be a major determinant of effectiveness, pancreatitis is of more concern. Pancreatitis has been reported form post-marketing surveillance of exenatide and during the liraglutide clinical test program. As of 2009, at least 6 deaths have occurred in GLP-1R agonist treated patients due to pancreatitis.^24,26

DPP-4 inhibitors suppress enzymatic cleavage of GLP-1 and so exert their glucose-regulatory actions through prolongation of the actions of native GLP-1. The DPP-4 inhibitor sitagliptin was approved in the US in 2006 for use as monotherapy or in combination with metformin, or a sulfonylurea, or a thiazolidinedione.27-31In clinical trials, a significant proportion of patients treated with sitagliptin achieved their target Hb A1c levels. Sitagliptin can be taken orally once daily, and it does not influence body weight.²⁴

The increased number of choices for treating type 2 diabetes mellitus has caused heightened uncertainty to physicians and patients regarding the most appropriate way to treat the disease.^32,33

The Consensus Algorithm for the Initiation and Adjustment of Therapy by the American Diabetes Association and the European Association for the Study of Diabetes³³ divides the available therapies for diabetes into a well validated tier 1, a less well validated tier 2 therapies and other therapies. GLP-1R agonists are ranked as tier 2 therapies because of their unknown long tern safety profile. They are however included in the treatment algorithm for T2DM, as an adjunctive therapy to be used when diabetes is not well managed by lifestyle and metformin. The choice of a GLP-1R agonist is appropriate when hypoglycemia is particularly undesirable e.g. in patients with hazardous jobs.

Unlike GLP-1R agonists, DPP-4 inhibitors are not listed in the 2 tiers of preferred treatments, because of their lower or equivalent overall glucose-lowering effectiveness compared with the first- and second-tier agents, limited clinical data and relative expense.³³ Nevertheless, DPP-4 inhibitors may be appropriate for selected patients.

 

Program Outline

 

Talks

  1. Current Challenges in the Management of Type 2 Diabetes Mellitus

• Give an overview of epidemiological data and socioeconomic cost

• State treatment goals for T2DM and show where traditional treatments fall short

  • control of postprandial hyperglycemia

  • avoiding hypoglycemia

  • loss of effectiveness

  • weight gain

2. The Pathophysiology of Type 2 Diabetes Mellitus Reexamined

• Briefly describe T2DM pathophysiology in the fasted state

• Describe the physiological functions of incretins

• Describe the effects of administration and blockade of native incretins

3. An Introduction to Incretin Based Treatments of Type 2 Diabetes Mellitus

• Introduce the various classes of incretin based drugs on the market and in late stage development

• discuss mechanisms of action

• Show efficacy and safety data from clinical trials

• Explain how incretin based drugs fit into the treatment algorithm for T2DM and the considerations for their use

 

Enduring Activity

 

New and Emerging Therapies to Manage Type 2 Diabetes Mellitus

• Record a moderated round table discussion with the presenters of the talks proposed above. The discussion will touch on

  • The shortcomings of traditional T2DM treatments

  • The physiological functions of incretins

  • Incretin based treatments of T2DM

  • Treatment algorithms for T2DM that include incretin based options

 

 

 

 

Writing for Peer Review

The Clinical Efficacy and Safety of Bortezomib in the Treatment of Relapsed Multiple Myeloma

Multiple myeloma is a hematologic malignancy of B-cell origin and is generally considered incurable.¹ There is currently no standard treatment for relapsed multiple myeloma, but the use of high dose dexamethasone is common.²

The proteasome inhibitor bortezomib (VELCADE; Ortho Biotech, a division of Janssen-Cilag, Beerse, Belgium; and Millennium Pharmaceuticals, Cambridge, Massachusetts, USA) is indicated as a monotherapy for the treatment of progressive multiple myeloma in patients who have received at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.¹

Two phase II trials demonstrated the efficacy of bortezomib as a treatment for relapsed multiple myeloma and established the dose regimen as 1.3 mg/m² on days 1, 4, 8, and 11 in 3-week cycles.¹ Approval of bortezomib was based on the multinational, randomized phase III Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial.^1,3 The APEX trial compared a regimen of 1.3 mg/m² bortezomib given as an intravenous bolus to high dose dexamethasone (40 mg orally).² The trial showed that patients treated with bortezomib had longer time to progression as well as significantly higher response and one year survival rates than patients treated with dexamethasone. For detailed results see Table 1.

The safety population of the APEX trial comprised 663 patients, 331 on bortezomib and 332 on dexamethasone. The duration of treatment did not differ significantly between the bortezomib and dexamethasone groups. Early discontinuation for adverse events occurred in 121 patients (37%) in the bortezomib group.² Adverse events leading to discontinuation included peripheral neuropathy (8%) and thrombocytopenia, various gastrointestinal disorders, fatigue, hypercalcemia, and spinal cord compression (2 % each). In the dexamethasone group, discontinuation for adverse events occurred in 96 patients (29%), and adverse events leading to discontinuation included psychotic disorder, hyperglycemia, or thrombocytopenia (2 % each).

An extended analysis of the APEX trial data with a mean follow up of 22 months showed an overall survival of 29.8 months (95% CI: 23.2–not evaluable) in the bortezomib arm versus 23.7 months (95% CI: 18.7-29.1) in the dexamethasone arm (hazard ratio .77, P .027).⁴ In the extended analysis, overall and complete response rates were 43% and 9%, respectively. Among responders, 56% showed an improvement of response quality with longer therapy. The extended analysis did not identify any new safety concerns, nor did it yield any evidence of new cumulative toxicity.

An exploratory cohort analysis of the bortezomib arm of the APEX study revealed that patients achieving complete response had a significantly longer median treatment free interval and longer time to alternative therapy than patients achieving very good partial response, see Figure 1.

Bortezomib is the only single agent to have shown a survival benefit in patients with relapsed multiple myeloma.³ The sum of data form phase II and phase III trials as well as an extension study indicate indicate that prolonged therapy is associated with a manageable safety profile.⁴

 

Table 1: Results of the APEX trial.² Abbreviations: TTP, time to progression; CR, complete response; PR, partial response

 

 

 

 

Figure 1: The effect of response quality on clinical outcomes. Abbreviations: CR, complete response; VGPR, very good partial response; PR, partial response; TFI, treatment free interval; TTAT, time to alternative treatment