Evolving Treatment for Patients With Type 2 Diabetes_ Current Guidelines and Emerging Therapeutic...

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3/13h Type 2 Diabetes: Current Guidelines and Emerging Therapeutic De

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This article is a CME certified activity. To earn credit for this activity visit:

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CME Information

CME Released: 12/14/2012; Valid for credit through 12/14/2013

Target Audience

This activity is intended for osteopathic physicians.

Goal

According to the American Association of Clinical Endocrinologists (AACE), more than 60% of patients with diabetes do not

reach HbA1c targets. Advances in the understanding of glucose homeostasis have helped to identify new targeted

treatments, such as incretin-based agents, which broaden the antidiabetic armamentarium and may address some of the

shortcomings of conventional treatments for type 2 diabetes mellitus (T2DM). Incretin-based agents are associated with a

low risk of unwanted adverse events and offer physicians additional options to deliver individualized care.

Consensus guidelines for diabetes management are updated regularly and provide an excellent starting point for clinical

decision-making. However, the rapid pace of research into new diabetic agents can cause confusion among physicians who

would benefit from education updating them on the latest findings and providing practical, evidence-based ways to use this

information.

This program is designed to bridge the gap between clinicians' current understanding of the role of guidelines, HbA1c targets

and incretin therapies in T2DM management and to support the confident application of that knowledge in clinical practice to

help more patients safely reach target goals.

Learning Objectives

This activity was designed to address the following IOM competencies: provide patient-centered care, and employ evidence-

based practice.

At the conclusion of this activity, participants should be able to demonstrate the ability to:

1. Recognize the pros and cons of using A1c to diagnose prediabetes and discuss prevention of diabetes by treating

prediabetes with lifestyle management and GLP-1 agonists

2. Summarize results from clinical trials demonstrating the long-term benefit of glycemic control in patients with T2DM,

and compare these results to those of the tight glucose control trials

3. Describe the mechanisms of action of incretin-based agents and determine their place in the current armamentarium

to facilitate early attainment and ongoing maintenance of appropriate HbA1c targets in patients with T2DM

4. Identify treatments and treatment combinations that can enhance glycemic control, facilitate weight loss, and prevent

or slow the pathophysiology of diabetes, including reduction of insulin resistance, improvement of glucose tolerance

and beta cell function, and reduction of cardiovascular (CV) risk factors5. Employ new strategies and medication treatment formulations to optimize antidiabetic treatment adherence

Credits Available

Osteopathic Physicians - maximum of 1.00 Category 1-B AOA Credit

All other healthcare professionals completing continuing education credit for this activity will be issued a certificate of

participation.

Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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Off-label Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by

the FDA.

The American Osteopathic Association and Rockpointe Corporation do not recommend the use of any agent outside of the

labeled indications.

Disclosure

The American Osteopathic Association and Rockpointe Corporation adhere to the policies and guidelines, including the

Standards for Commercial Support, set forth to providers by the Accreditation Council for Continuing Medical Education

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Authors

C. W. Spellman, DO, PhD, Chair

Professor and Associate Dean of Research, Director, Center for Diabetes and Metabolic Disorders, Department of Internal

Medicine, Division of Endocrinology, Texas Tech University Health Sciences Center at Permian Basin, Odessa, Texas

Dr. Spellman reports that he has nothing to disclose.

James LaSalle, DO, FAAFP

Director, Medical Arts Centers, Excelsior Springs, Missouri

Disclosure: Consultant: Novo Nordisk; Speakers' Bureau: Boehringer Ingelheim-Lilly, GlaxoSmithKline, Novo Nordisk

Michael D. Shapiro, DO, FACC, FSCCT

Diplomate, American Board of Clinical Lipidology; Assistant Professor of Medicine and Radiology and Director, Preventive

Cardiology and Atherosclerosis Imaging, Division of Cardiovascular Medicine, Oregon Health & Science University, Portland,Oregon

Disclosure: Consultant: LipoScience; Speaker's Bureau: Abbott, LipoScience, Merck

Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their

spouse/partner have with commercial interests:

Carole Drexel, PhD; Bradley Pine; Blair St. Amand; Jay Katz; Dana Simpler, MD; and Paula Larson report that they

have nothing to disclose.

Evolving Treatment for Patients with Type 2 Diabetes: Current


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C.W. Spellman, DO, PhD, Chair; James R. LaSalle, DO, FAAFP; Michael D. Shapiro, DO, FACC, FSCCT

How would you rate your level of knowledge regarding incretin therapies?

Not knowledgeable

Somewhat knowledgeable

Knowledgeable

Very knowledgeable

Expert

How competent do you feel in managing type 2 diabetes mellitus (T2DM) patients with incretin therapies?

Not competent

Somewhat competent

Competent

Very competent

Expert

Approximately what proportion of people with prediabetes will progress to T2DM?

50%

30%

70%

90%

Donna is a 59-year-old woman who has had a diagnosis of diabetes for 4 years. At her last office visit, her

body mass index (BMI) was 26.4 kg/m2 and her HbA1c was 7.9%. She has a strong family history of

cardiovascular disease (CVD), and she is currently being treated for hypertension and dyslipidemia.

According to American Diabetes Association (ADA) recommendations, what is Donnas HbA1c target?


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True or False: In the ACCORD, ADVANCE, and VADT trials, intensive glycemic control that exceeds an A1c

goal of < 7.0% yielded no significant reduction in CVD outcomes compared to standard glycemic control.

True

False

Incretin-based therapies significantly reduce HbA1c levels in which of the following scenarios?

Add-on to metformin

Add-on to sulfonylurea (SU)

Add-on to metformin and SU

All of the above

Which of the following antidiabetes therapies is/are associated with a reduction in body weight?

Metformin

Insulin

GLP-1 agonists

DPP-4 inhibitors

What are the most common adverse events associated with GLP-1 receptor agonists?

Nausea and vomiting

Hypoglycemia

Weight gain

Pancreatitis

Which is true regarding incretin therapy?

Low risk of hypoglycemia, except when combined with SUs

Cannot be used with renal diseaseLow risk of gastrointestinal adverse events

All of the above

Which of the following may help improve patient adherence to antidiabetic therapy?

Reduced administration frequency

Lowered risk of hypoglycemia

Neutral or beneficial effects on body weight

All of the above

Save and Proceed

This CME activity is based on the slides and lectures presented by the faculty at the American Osteopathic Association

(AOA)accredited breakfast symposium, Evolving Treatment for Patients with Type 2 Diabetes: Current Guidelines and

Emerging Therapeutic Decision-Making, on October 9, 2012, at the Marriott Marquis & Marina, San Diego, California.

C. W. Spellman, DO, PhD

Diabetes is a growing epidemic with major public health implications for patients, providers, and the healthcare system. More


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than 23 million patients have been diagnosed with type 2 diabetes mellitus (T2DM) in the United States, and another 11

million have undiagnosed disease, for a total prevalence of approximately 32 million. Furthermore, an estimated 50 million

individuals have prediabetes, meaning they have blood glucose levels outside the normal range, but have not yet met the

formal criteria for a diabetes diagnosis. Overall, more than 80 million Americans have T2DM, undiagnosed diabetes, or

prediabetes.[1]

Without effective intervention, the burden of T2DM is expected to continue to increase globally. [2] One strategy for

addressing the diabetes epidemic is to target patients with prediabetes using lifestyle modifications and pharmacotherapy to

re-establish normal glucose metabolism (ie, normoglycemia), reduce the incidence of progression to T2DM, and prevent the

onset of diabetes-related complications.

What Is Prediabetes?

The formal definition of "prediabetes" has evolved to reflect advances in the understanding of diabetes progression. Until

2003, the American Diabetes Association (ADA) used the term "glucose intolerance," to describe a state of intermediate

hyperglycemia marked by impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or both. [1] In 2005, the diabetes

community adopted the term "prediabetes" to describe intermediate hyperglycemia, [3] and in 2010, the ADA expanded the

definition of prediabetes to include intermediate HbA1c values.[4]

In current clinical practice, the American Association of Clinical Endocrinologists (AACE), the ADA, and other major medica

societies around the world use different criteria to define prediabetes (Table 1).[4,5]

Table 1. Criteria for Prediabetes[4,5]

2hPG = 2-hour postload glucose; AACE = American Association of Clinical Endocrinologists; ADA = American

Diabetes Association; FPG = fasting plasma glucose; HbA1c = glycated hemoglobin; IFG = impaired fasting glucose;

IGT = impaired glucose tolerance

Significance and Diagnosis of Prediabetes

Prediabetes now affects approximately 35% of adults in the United States. [6] Up to 70% of people with prediabetes will

progress to develop T2DM and cardiovascular comorbidities.[7] Despite the magnitude of this public health crisis, basic

questions related to the diagnosis of prediabetes remain unanswered. [2] For instance, HbA1c levels reflect blood glucose

averages over the previous 812 weeks, and, as a result, may more accurately represent overall glucose control than

measures such as IFG and IGT. Therefore, is HbA1c the preferred way to diagnose prediabetes?

To address this question, Hollander and Spellman recently performed a systematic review of clinical trials, meta-analyses,

and clinical practice guidelines to evaluate the utility of various criteria for the diagnosis of prediabetes and progression to

T2DM.[1] The review incorporated studies published between 2006 and 2012 using the terms "prediabetes," "HbA1c," or

"glucose tolerance test." Findings from the analysis illustrate current variations in the definition of prediabetes, as well of the

implications of these variations on the diagnosis and management of patients who are at risk for T2DM and diabetes-related

complications.

In 1 study, investigators evaluated the strength of various diagnostic criteria for prediabetes in a cohort of 2092 Japanese

patients.[8] At the time of study enrollment, all patients met the ADA prediabetes diagnostic criteria of IFG (fasting plasma


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glucose [FPG] level of 100125 mg/dL), HbA1c level of 5.7% to 6.4%, or both. Within this group, 20% of patients met the

HbA1c criterion alone, while another 20% met both the IFG and HbA1c criteria for prediabetes. By comparison, 60% of

patients met only the IFG criterion, suggesting that the majority of patients would be missed if clinicians relied only on

HbA1c measurements to diagnose prediabetes.

Other studies have examined the role of IFG alone, IGT alone, or both values in identifying prediabetes in various patient

groups around the world. In a cohort of 1546 US adults, the overall prevalence of prediabetes was 34%, as diagnosed on the

basis of IFG alone (19%), IGT alone (5%), or both IFG and IGT (10%). [9] In a French study of 1283 overweight or obese

individuals, the overall prevalence of diabetes was 20%.[10] In this group, 15% were prediabetic on the basis of IFG alone,

while 2% met the criteria for prediabetes according to IGT alone, and 3% on the basis of both IFG and IGT. These findings

suggest that measuring IFG alone, rather than IFG and IGT, would have missed 70% of prediabetic cases.

Another French study examined the diagnostic utility of HbA1c in a high-risk population of 1157 patients who fulfilled the

ADA criteria for diabetes screening, including obesity, sedentary lifestyle, first-degree relatives with diabetes, gestational

diabetes, hypertension, and hyperlipidemia.[11] Using the current ADA threshold for HbA1c to define prediabetes (HbA1c:

5.7%6.4%), 41% of patients met the criteria for prediabetes. By comparison, only 27% of these patients met the criteria for

prediabetes on the basis of oral glucose tolerance testing (OGTT), which includes both IFG and IGT.

In a Spanish study, investigators evaluated the diagnostic value of HbA1c and OGTT in a group of 1144 patients who were

determined to have an elevated risk for diabetes according to an initial screening with the Finnish Diabetes Risk Score

questionnaire.

[12,13]

In this high-risk group, 45% of patients met the criteria for prediabetes. Of these, 34% were diagnosedon the basis of HbA1c values, while 66% were diagnosed using FPG level, 2 hour postload glucose (2hPG) level, or both.

These findings do not support the use of HbA1c testing alone to identify prediabetes in a high-risk population, and instead

substantiate a strategy that combines HbA1c testing with traditional OGTT in the diagnosis of prediabetes.

The DEAL (Diet Exercise Activity Lifestyle) study also evaluated the role of HbA1c testing in 242 patients with a provisional

diagnosis of IFG based on a standard FPG test. [14] Using the formal OGTT, 56% of patients were classified with prediabetes

on the basis of IFG alone, and 37% of patients met the criteria for prediabetes based on both IFG and IGT values. However,

only 63% of patients diagnosed with prediabetes on the basis of IFG alone had HbA1c values that fell within the range of

5.7%6.4%, while 70% of patients diagnosed on the basis of both IFG and IGT also met the HbA1c diagnostic criteria. This

suggests that HbA1c testing would miss approximately one-third of individuals who were diagnosed with prediabetes on the

basis of IFG and IGT.

Prevention of T2DM and Return to Normoglycemia

Intensive lifestyle modifications and pharmacotherapy are effective tools for preventing progression to T2DM in patients who

meet the criteria for prediabetes. Although many studies support the rationale for intervening in prediabetes, most clinical

trial data gathered to date is limited by short follow-up periods (Table 2). Although patients with prediabetes can progress to

T2DM relatively quicklyin the range of 3 to 5 yearsstudies that fall short of this timeline may not measure the full benefits

of lifestyle changes or pharmacotherapy.[15]

Table 2. Lifestyle Interventions and Pharmacotherapy in the Prevention or Delay of T2DM [15]


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IFG = impaired fasting glucose; IGT = impaired glucose tolerance

For patients with prediabetes, interventions such as intensive lifestyle modifications, metformin, and incretin-based therapy

slow the progression to T2DM and promote the return to normal blood glucose levels. In 1 study, 77% of patients treated with

exenatide in addition to lifestyle changes regressed to euglycemia, compared with 56% of patients managed with lifestyle

modifications alone.[18] In another trial, treatment with liraglutide resulted in an 84% to 96% decrease in the prevalence of

diabetes, depending on liraglutide dose.[15]

In 2012, Perreault and colleagues reported long-term findings from an extension of DPPOS (Diabetes Prevention Program

Outcomes Study), which randomly assigned 1990 patients who were at risk for diabetes to treatment with intensive lifestyle

therapy, metformin, or placebo.[19] Patients who became normoglycemic at least once were 56% less likely to develop

diabetes during 5.7 years of follow-up observation than patients who were persistently classified as having prediabetes,


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regardless of the method of achieving normal blood glucose (ie, lifestyle changes or metformin). These findings underscore

the importance of timely intervention with effective therapies that allow patients with prediabetes to achieve glucose control.

Summary

Nearly one-third of adults in the US have prediabetes, and 70% of patients with prediabetes will develop T2DM. Although

early identification of prediabetes is necessary to initiate effective intervention, only 7% of patients with prediabetes are

aware of their diagnosis. Better tools for screening and diagnosis are urgently needed to enhance the care of patients at risk

for diabetes.

No single test is 100% effective in the diagnosis of prediabetes, and using all options for screening (ie, FPG, IFG, and

HbA1c) may not be feasible in routine clinical practice. HbA1c testing is emerging as a key tool for identifying patients with

prediabetes, but current testing methods present challenges for health care providers. The sensitivity and specificity of

HbA1c as a diagnostic test for prediabetes depend on the characteristics of the patient population, and may vary by body

mass index (BMI), age, sex, and race. The ADA, AACE, and other societies in the diabetes community recommend HbA1c

testing to identify patients with prediabetes, but not all societies use the same HbA1c cut-points to define prediabetes.

Recent data suggest that HbA1c may have greater utility as a diagnostic test for prediabetes in overweight and obese

patients, as well as those with multiple other cardiovascular risk factors.

Although there is a continuum from prediabetes to diabetes, it is important to remember that patients can move in 2

directions: progression toward T2DM and diabetes-related complications, or regression to normoglycemia. Preliminaryclinical trial evidence suggests that incretin-targeted therapies such as exenatide and liraglutide enable more patients with

prediabetes to regress to normoglycemia than other medications or intensive lifestyle interventions. Future clinical trial data

will clarify the best methods for diagnosing prediabetes, as well as the optimal interventions for preventing the progression to

T2DM.

James LaSalle, DO, FAAFP

The incretin hormones regulate glucose homeostasis and play key roles in the pathophysiology and treatment of

T2DM.[20,21] The "incretin effect" was first observed in studies showing that the pancreas secreted more insulin when

glucose was administered orally through the gastrointestinal tract than when glucose bypassed the gut and was delivered by

intravenous (IV) infusion. Nutrient intake stimulates the release of incretins such as glucagon-like peptide-1 (GLP-1), which

act on the pancreas to potentiate insulin secretion from the beta cells and lower glucagon secretion from the islet cells in a

glucose-dependent manner.[20,21]

The glucose-dependent effects of incretins are well characterized. One trial examined changes in glucose, insulin, and

glucagon levels in response to a pharmacologic infusion of GLP-1 in patients with poorly controlled T2DM (mean HbA1c of

11.6%).[22] In the study, blood was drawn every 30 minutes during a 4-hour IV infusion of GLP-1 (and during a placebo

infusion the following day) to evaluate glucose, insulin, and glucagon levels. The GLP-1 infusion reduced plasma glucose to

normal basal levels in all patients, with significant mean reductions at each time point from 60 minutes onward compared

with placebo (P< .05). Patients had a mean baseline plasma glucose level of 228.6 mg/dL. At the start of the GLP-1

infusion, plasma insulin initially increased and glucagon decreased in response to GLP-1. However, as plasma glucose

approached normal basal levels, insulin returned to near-baseline levels. Furthermore, glucagonwhich was suppressed

when glucose levels were highalso started rebounding toward normal levels, even in the presence of the continuous GLP-1infusion. These patterns in glucose, insulin, and glucagon levels illustrate the glucose-dependent nature of GLP-1, and

demonstrate the potential therapeutic benefits of exogenous GLP-1 for normalizing fasting plasma glucose concentrations in

patients with poorly-controlled T2DM.[22]

Incretin-based Therapies for T2DM

Healthcare providers currently have several options for incretin-based therapies for the management of T2DM, and other

investigational options may soon join the treatment armamentarium (Figure 1).[23,24]


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Figure 1. Incretin-Based Therapies for T2DM[23,24]

DPP-4 Inhibitors

One approach to incretin-based therapy involves blocking the degradation of endogenous incretins through the inhibition of

dipeptidyl peptidase-4 (DPP-4). The DPP-4 inhibitors include sitagliptin, saxagliptin, and linagliptin, which are currently

approved for the treatment of T2DM (Table 3), as well as the investigational agents vildagliptin and alogliptin. DPP-4 inhibitors

can be taken orally without regard to meals.

Table 3. DDP-4 Inhibitors in T2DM[23]


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The efficacy and safety of DPP-4 inhibitors have been well studied in patients with T2DM. Saxagliptin added to metformin

reduces HbA1c (P< .0001), fasting plasma glucose (P< .0001), and postprandial glucose (P< .0001) after 24 weeks

compared with metformin alone.[25] Linagliptin significantly reduces HbA1c by -0.5% to -0.7% when given as single-agent

therapy or when added to metformin; thiazolidinedione (TZD); sulfonylurea; and metformin and sulfonylurea.[26-30] In a head-

to-head trial, sitagliptin added to metformin showed similar glucose-lowering effects after 52 weeks of treatment compared

with glipizide added to metformin, but with a more favorable effect on body weight (1.5 kg weight loss vs 1.1 kg weight gain;

P< .001) and a reduced risk of hypoglycemia (4.9% vs 32.0%). [31]

GLP-1 Receptor Agonists (RAs)

GLP-1 RAs are indicated for the treatment of T2DM as an adjunct to lifestyle modifications including diet and exercise.

Currently available agents include twice-daily exenatide, once-weekly exenatide, and once-daily liraglutide (Table 4). GLP-1

analogs improve glycemic control in patients with T2DM by enhancing glucose-dependent insulin secretion and reducing

postprandial glucagon secretion. The GLP-1 RAs also slow gastric emptying, resulting in increased satiety, reduced food

intake, and weight loss. However, decreased gastric emptying may also lead to nausea, vomiting, and diarrhea for some

patients.

Table 4. Properties of GLP-1 Agonists[32]


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* Not head-to-head trials

Liraglutide is a long-acting subcutaneous GLP-1 analog that is administered once daily. The LEAD-6 (Liraglutide Effect and

Act ion in Diabetes) trial compared liraglutide 1.8 mg once daily and exenatide 10 g twice daily in patients with poorly

controlled T2DM despite treatment with metformin and/or a sulfonylurea.[33]

Add-on treatment with l iraglutide provided agreater reduction in HbA1c compared with add-on exenatide (1.1% vs -0.8%; P< .05) and a greater reduction in fasting

plasma glucose (-29.0 mg/dL vs -10.8 mg/dL; P< .05). Moreover, more patients in the liraglutide group than in the exenatide

group reached the treatment goal of HbA1c < 7.0% (54.0% vs 43.0%; P< .05). Both agents were well-tolerated, and

liraglutide and exenatide promoted similar levels of weight loss (-3.24 kg vs -2.87 kg). [33]

Newer formulations with reduced administration frequency may help improve patient adherence to antidiabetes therapy. The

DURATION-1 (Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention

with Exenatide Once Weekly) trial evaluated long-term treatment with different formulations of exenatide in patients with

T2DM.[34] Patients were randomly assigned to treatment with exenatide 2 mg once weekly or exenatide 10 g twice daily fo

30 weeks, followed by 1.5 years of exenatide 2 mg once weekly for all patients. Compared with twice-daily exenatide,

treatment with once-weekly exenatide provided a greater reduction in mean HbA1c (-1.5% vs -1.9%). The DURATION-5 trial

compared exenatide twice daily with exenatide once weekly over 24 weeks in 252 patients with T2DM. [35] The once-weekly

formulation provided superior glycemic control compared with standard twice-daily dosing. The mean reduction in HbA1c was

-1.6% in the exenatide once-weekly group and -0.9% in the exenatide twice-daily group (P< .0001).

The DURATION-6 trial compared once-weekly exenatide and daily liraglutide in 911 patients with T2DM.[36] After 26 weeks,

the mean reduction in HbA1c was 1.26% in the exenatide group and 1.48% in the liraglutide group (P< .05). Once-weekly

exenatide was associated with fewer adverse gastrointestinal events than daily liraglutide, including less nausea (9.3% vs

20.4%), vomiting (3.7% vs 10.7%), and diarrhea (6.1% vs 13.1%). More than twice as many patients in the liraglutide group

(5.3%) than in the exenatide group (2.6%) discontinued treatment due to adverse events. Patients in both groups had a

modest reduction in body weight, with no significant differences between treatments. [36]


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Treatment Considerations

Nausea: Nausea and vomiting related to delayed gastric emptying are the most common adverse events associated with

GLP-1 RAs. Nausea is mostly mild-to-moderate, and is most common at initiation of therapy; it tends to decrease with

continuing treatment. In 1 prospective study, the frequency of nausea was similar during weeks 26 to 52 of treatment for

patients treated with liraglutide 1.8 mg/d, liraglutide 1.2 mg/d, or sitagliptin 100 mg/d. [37] In the LEAD-6 trial, the risk of

nausea was significantly higher for patients treated with exenatide 10 g twice daily compared with those treated with

liraglutide 1.8 mg/d (P< .0001).[33] In DURATION-6, nausea was less frequent among patients who received once-weekly

exenatide (9.3%) than among those who received liraglutide (20.4%).[36]

Weight loss: In a meta-analysis of GLP-1 RAs, the magnitude of weight loss was similar for exenatide once weekly (mean:

-2.8 kg; 95% CI: -5.2 to -0.3 kg), exenatide twice daily (mean: -2.8 kg; 95% CI: -2.9 to -2.7 kg), and liraglutide (mean: -2.8

kg; 95% CI: -3.5 to -0.9 kg).[38] Several studies have demonstrated that the weight loss associated with GLP-1 RA treatment

is sustained for at least 2 years.[39-41]

Use in patients on insulin therapy: Twice-daily exenatide has also been evaluated as add-on therapy in patients treated

with glargine insulin.[42] In the prospective trial, 259 patients who were taking glargine insulin were randomly assigned to add

on therapy with placebo or twice-daily exenatide. Compared with placebo, exenatide was associated with a greater reduction

in HbA1c (-1.0% vs -1.7%), more favorable effects on body weight (+1.0 kg vs -1.8 kg), and a smaller increase in glargine

dose (20 units vs 13 units). Patients had a similar risk of hypoglycemia regardless of treatment group. However, more

patients in the exenatide group than in the placebo group dropped out of the study (13 vs 1).

Use in patients with comorbid renal impairment: Renal impairment appears to impact the clearance of exenatide in

patients with T2DM, but does not affect the metabolism of liraglutide. [43,44] This is because exenatide is eliminated

predominantly via glomerular filtration, whereas no specific organ serves as the major route of elimination for liraglutide.[23]

Table 5 summarizes the recommended dosing for exenatide and liraglutide for patients with T2DM and comorbid renal

impairment.[23]

Table 5. GLP-1 Receptor Agonist Dosing in Patients with Renal Impairment[23]

*Hypovolemia due to nausea/vomiting may worsen renal function

CrCl = creatinine clearance; ESRD = end-stage renal disease

Safety Considerations

Pancreatitis: In 2008, the Food and Drug Administration (FDA) issued an alert to healthcare professionals regarding the risk

of pancreatitis with incretin-related drugs.[45] The FDA report described several issues with incretin agents including:


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Reports of pancreatitis in liraglutide clinical trials[46-48]

Postmarketing reports of pancreatitis in patients taking exenatide, including cases of hemorrhagic/necrotizing

pancreatitis that resulted in patient deaths[45]

Later, an analysis from the FDA Adverse Event Reporting System (AERS) reported[45]:

A 6-fold increase of pancreatitis with sitagliptin or exenatide compared with other antidiabetes medications, including

rosiglitazone, nateglinide, repaglinide, and glipizide[49]

An increase in the reporting rate of pancreatic cancer in patients treated with sitagliptin or exenatide[49]

Despite the value of these safety warnings, the AERS has limitations for understanding true pancreatitis risk, including

potential reporting bias.[50] In addition, the AERS reporting system did not collect information on BMI, a known risk factor for

pancreatitis.

Healthcare professionals should consider the following precautions related to pancreatitis when treating patients with

incretin-based therapies[45,51-52]:

Adhere to label warnings

Observe patients for symptoms of acute pancreatitis (persistent severe abdominal pain that may be accompanied by

vomiting)

Discontinue drug if pancreatitis is suspected

Do not restart drug if pancreatitis is confirmed

Consider other antihyperglycemic therapies in patients with a history of pancreatitis

Thyroid cancer: Liraglutide and once-weekly exenatide carry boxed warnings for thyroid C-cell tumors based on data from

rodent models of T2DM.[53,54] Clinical trials and postmarketing data show conflicting results regarding the effects of GLP-1

analogs on calcitonin levels, with small increases in calcitonin levels in some studies and reduced levels in others. [33,53] To

date, no definitive cases of medullary thyroid carcinoma related to liraglutide have been detected. [53,54] No cases of thyroid

cancer have been reported in the exenatide clinical trials.

Renal impairment: Postmarketing reports have also tracked renal outcomes in patients treated with GLP-1 RAs. To date,

no evidence indicates that GLP-1 RAs are directly toxic to kidney cells. [23,55,56] However, renal impairment may occur in

patients who have experienced nausea, vomiting, diarrhea, and dehydration.[23,56-60] In some cases, renal impairment has

been observed in patients who are taking concurrent medication known to affect renal function or hydration status (eg,

angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs], or diuretics). [23,56-60] In

addition, cases of patients requiring hemodialysis or transplantation have also been reported. [23] Impaired renal function has

also been observed in patients without known underlying renal disease.[23]

In many cases, treatment-emergent renal impairment is reversible with supportive treatment and discontinuation of potentiall

causative agents.[23] Current labeling includes a warning against GLP-1 RA use in patients with severe renal impairment or

end-stage renal disease (ESRD).[23] Furthermore, GLP-1 RAs should be used with caution in patients with a history of renal

transplantation (exenatide and exenatide once weekly), and when initiating or escalating exenatide doses in patients with

T2DM and comorbid renal impairment (exenatide, exenatide once weekly, and liraglutide). [23]

Patient Case: Uncontrolled T2DM in a Patient with Poor Treatment Adherence

Robert is a 58-year-old man with a history of hypertension, T2DM, and dyslipidemia. His physical examination shows that he

is overweight (BMI of 38.8 kg/m2) with a blood pressure of 130/78 mm Hg, a heart rate of 76 bpm, and 2-mm pitting edema.

His laboratory results include the following: HbA1c: 7.8%; LDL: 105 mg/dL; HDL: 32 mg/dL; triglycerides: 225 mg/dL; blood

urea nitrogen (BUN): 19 mg/dL; and serum creatinine: 1.5 mg/dL.

Robert has been trying to lose weight for years but cannot stick with any regimen. He also admits that he does not always

remember to take his medications. His current medications include metformin 2000 mg/d, glimepiride 4 mg/d, pioglitazone

30 mg/d, metoprolol 100 mg twice daily, simvastatin 20 mg/d, and aspirin 75 mg/d.


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In addition to lifestyle changes and referral to a dietitian, what changes would you make to get the patients

HbA1c to the ADAs recommended goals?

Increase the dose of metformin

Discontinue metformin, glimepiride, and pioglitazone, and initiate basal insulin therapy

Discontinue metformin and pioglitazone, continue glimepiride, and add incretin-based therapy

Discontinue pioglitazone, continue metformin and glimepiride, and initiate GLP-1 therapy

Save and Proceed

Summary

The incretin hormone system is a powerful driver of postprandial blood glucose control. In patients with T2DM, this system is

defective, leading to a range of adverse effects on glycemic control. Incretin-based therapies provide an intriguing

constellation of effects for patients with T2DM. The GLP-1 RAs provide effective postprandial glucose control and stimulate

weight loss with the convenience of once-weekly dosing. The DPP-4 inhibitors also control postprandial glucose with weight-

neutral effects, and can be used in combination with other oral agents in a single tablet. The incretin-based therapies are

associated with a low risk of hypoglycemia, except when used in combination with sulfonylurea. In addition, these agents

are safe in patients with renal disease, although they may require dose adjustments depending on the severity of renal

impairment. The gastrointestinal side effects associated with GLP-1 RAs are typically transient, with longer-acting

formulations associated with less severe nausea.

Achieving effective glycemic control in T2DM is a challenge for both patients and healthcare providers. Incretin-based

therapies represent an important new treatment option for patients who remain poorly controlled despite lifestyle

modifications and standard first-line pharmacotherapy. During treatment with incretin-based therapies, patients and clinicians

should be aware of the signs and symptoms of pancreatitis and other possible side effects of therapy. These agents should

be used with caution in patients with a history of thyroid cancer, and renal status should be monitored for the duration of

treatment. When necessary, treatment regimens should be modified to improve tolerability and/or convenience to increase

the likelihood of patient adherence and improved glycemic control.

Michael D. Shapiro, DO, FACC, FSCCT

Cardiovascular disease (CVD) is a major burden for patients with diabetes. Indeed, CVD is the major cause of morbidity and

mortality in patients with T2DM, and the largest contributor to direct and indirect costs related to diabetes care.[62] T2DM is

regarded as a coronary artery disease (CAD)-equivalent, because it elevates patients with T2DM to the same risk category

as nondiabetic patients with a history of myocardial infarction (MI). In a long-term study of MI risk in diabetic and nondiabetic

patients, those with T2DM and no history of MI were just as likely to suffer a future MI as were nondiabetic patients who had

already sustained an MI (20% vs 19%, respectively). [63]

Atherosclerosis, the progressive accumulation of cholesterol in the arterial wall and resultant narrowing of the arterial lumen,

is the central pathologic mechanism of CAD and other macrovascular complications such as peripheral artery disease (PAD

and stroke in patients with diabetes.[64] The Emerging Risk Factors Collaboration (ERFC) group conducted a meta-analysis

of 102 prospective studies enrolling 698,782 patients to measure the association between T2DM and the development of

vascular disease.[65] Compared with normal fasting blood glucose, a diagnosis of T2DM approximately doubled the risk for

vascular disease and adverse vascular outcomes, including coronary heart disease (CHD) (HR: 2.0); ischemic stroke (HR:

2.27); and vascular deaths (HR: 1.73).

T2DM represents a ticking clock of cardiovascular risk, as the deleterious effects of endothelial dysfunction begin to

accumulate long before a clinical diagnosis of T2DM is made. The Nurses' Health Study evaluated long-term cardiovascular

risk in 117,629 women without CVD at baseline. [66] Of these, 5894 women developed T2DM during the 20-year follow-up.

Compared with women who never developed diabetes, those who eventually developed T2DM were 3 times more likely to

have an MI in the time period before their diabetes diagnosis (RR: 3.17; 95% CI: 2.613.85), and nearly 4 times as likely to


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have an MI after they were diagnosed with T2DM (RR: 3.97; 95% CI: 3.35-4.71). [66] These findings underscore the

importance of early and aggressive detection and treatment of cardiovascular risk factors for patients with T2DM.

There is unequivocal evidence that aggressive management of traditional cardiovascular risk factors in patients with T2DM

results in improved clinical outcomes. Numerous trials have demonstrated the benefits of blood pressure control on both

micro- and macrovascular events.67-77] In addition, aggressive LDL cholesterol control, specifically with statins, has resulted

in improvements in macrovascular outcomes.[67,75,76,78] With that in mind, there have been several large trials to test the

hypotheses that intensive glucose lowering would improve both micro- and macrovascular event rates. Indeed, the clinical

trials have demonstrated consistent reductions in microvascular disease outcomes with aggressive glucose control in both

patients with T1DM and T2DM.[67,74-76,78]

Intensive glycemic control confers a range of benefits for patients with T2DM, and has become the standard of care for

reducing the microvascular complications of diabetes. The first major trial to demonstrate the benefits of intensive therapy in

patients with T2DM was the landmark UKPDS (United Kingdom Prospective Diabetes Study), which compared conventional

dietary therapy with intensive glucose-lowering therapy with sulfonylurea, metformin, or insulin in patients with newly-

diagnosed T2DM.[78] A long-term follow-up analysis of data from UKPDS revealed a "legacy effect" of intensive glucose

control in T2DM, showing that the magnitude of the benefits of intensive therapy grew over time.[67] Compared with patients

who received standard treatment during the UKPDS trial, those in the sulfonylurea-insulin group had a 24% reduction in

microvascular disease (P= .001), a 15% reduction in MI (P= .014), a 13% reduction in all-cause mortality (P= .007), and a

9% reduction in any diabetes-related endpoint (P= .040) that persisted during 10 years of posttrial follow-up.[67]

Glycemic Control: How Much Is Too Much?

While intensive glucose lowering has translated into a consistent reduction in microvascular complications, demonstrating a

beneficial effect of intensive glucose lowering on macrovascular complications has been elusive. However, recent trials have

shown a potential for harm associated with intensive glucose control, including an increased risk of severe hypoglycemia and

death. These findings have led the diabetes community to re-evaluate the appropriateness of aggressive treatment goals for

certain subgroups of patients with T2DM.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial included 10,251 patients with a mean age of 62 years,

a median duration of T2DM of 10 years, and known heart disease or at least 2 risk factors for CHD at the time of

enrollment.[72] Patients in the intensive glucose-lowering arm were treated to an HbA1c goal of < 6.0%, while those in the

standard therapy group were treated to an HbA1c goal of 7.0% to 7.9%. The primary endpoint was the composite outcome o

nonfatal MI, nonfatal stroke, or death from CVD. The ACCORD trial was discontinued early due to excess deaths in the

intensive therapy group and no reduction in total cardiovascular events compared with standard therapy (HR: 0.90; P= .16).

In particular, more cardiovascular deaths occurred with intensive therapy than with standard therapy (14 vs 11 deaths per

1000 patients per year).

The excess deaths in the intensive therapy group in ACCORD contributed to the growing concern that there may be a

threshold for target HbA1c levels, below which the risk of adverse events increases. Moreover, these findings highlight the

importance of selecting patients for whom the risk/benefit ratio favors aggressive therapy. For instance, subgroup analyses

from ACCORD showed a significant reduction in the primary endpoint for patients with no history of prior cardiovascular

events (P= .04 vs a history of prior cardiovascular events) and in those with baseline HbA1c levels 8.0% ( P= .03 vs

HbA1c > 8.0%).[72]

Other major studies in T2DM provide conflicting results about the role of intensive glucose-lowering therapy in controlling

diabetes-related complications. The VADT (VA Diabetes Trial) included 10,251 patients with a mean age of 60 years, a

median duration of T2DM of 11.5 years, and a mean HbA1c of 9.4% at the time of enrollment. [73] Patients were randomly

assigned to treatment with standard (HbA1c < 9.0%) or intensive (HbA1c < 6.0%) treatment goals. In VADT, intensive

glucose-lowering therapy in this population of patients with advanced, long-standing T2DM increased the risks of

hypoglycemia and weight gain without providing additional vascular benefits beyond those achieved with s tandard therapy. In

contrast with VADT, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled

Evaluation) study found that intensive glucose-lowering therapy may provide some benefit to high-risk patients with T2DM.

ADVANCE enrolled 11,140 patients with a mean age of 66 years, a median duration of T2DM of 8 years, a mean HbA1c of


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7.48%, and a history of a major cardiovascular event or at least one risk factor at baseline.[74] These patients were randomly

assigned to standard care or to an intensive regimen targeting an HbA1c level 6.5%. In this high-risk population, intensive

glucose-lowering therapy lowered the risk of renal complications by 21%.

In general, the major trials of intensive glucose-lowering therapy in T2DM suggest a benefit related to microvascular

complications such as nephropathy, retinopathy, and neuropathy (Table 6). Long-term follow-up of patients enrolled in the

UKPDS study demonstrated statistically significant reductions in nonfatal MI (RR: 15%; P= .014) and all-cause mortality

(RR: 13%; P= .007) as a result of intensive therapy.[67,78] By comparison, there was no evidence of improvement in

cardiovascular endpoints in the ACCORD, ADVANCE, or VADT trials.[72-74,77]

Table 6. Impact of Intensive Glycemic Therapy on T2DM Outcomes[67,72-78]

Intensive therapy confers some cardiovascular benefits, but does not protect patients from all adverse outcomes. A meta-

analysis of the UKPDS, ACCORD, ADVANCE, and VADT trials included 27,802 patients with T2DM who were treated with

intensive glucose-lowering therapy or standard care.[79] In the pooled analysis, intensive therapy was associated with a 16%reduction in nonfatal MI (RR: 0.84; 95% CI: 0.750.94), with an absolute overall risk reduction of 9 events per 1000 patients

over 5 years of treatment. However, intensive glucose-lowering therapy had no significant effect on either cardiovascular

mortality (RR: 0.97; 95% CI: 0.761.24) or all-cause mortality (RR: 0.98; 95% CI: 0.841.15). [79]

New Options for Cardiovascular Risk Reduction in T2DM

Patients with T2DM may benefit from interventions that reduce the risk of CVD over and above what can be expected from

glucose lowering itself. New therapeutic targets with important implications for cardiovascular risk reduction include the

incretin-based therapies, including the GLP-1 RAs and the DPP-4 antagonists.

GLP-1 is associated with diverse physiologic effects across several organ systems that may translate into cardiovascular

benefits. Such favorable effects include deceleration of gastric emptying; reduction in appetite; earlier induction of satiety;

weight reduction; increased beta-cell mass; enhanced insulin sensitivity in the liver, muscle, and adipose tissue; and

improvements in traditional cardiovascular risk factors and function. The GLP-1 receptor (GLP-1R) is expressed in several

key structures that affect cardiac function, including myocytes, the pericardium, vascular epithelium, and vascular smooth

muscle. In preclinical studies, GLP-1R agonism induces dose-dependent vasodilation.[80] Furthermore, GLP-1R agonism is

associated with increased myocardial glucose uptake; attenuation of ischemic injury; limitation of infarct size; improvement

in hemodynamic measures such as stroke volume, cardiac output, and ejection fraction; and systemic resistance.[81-85]

Conversely, the protective effects on cardiac function are diminished by GLP-1R antagonism. [81]

Treatment with GLP-1 agonists also shows beneficial effects on cardiometabolic markers in patients with diabetes. In a

prospective study of 217 patients with T2DM, treatment with add-on exenatide was associated with sustained improvements


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in systolic blood pressure (BP) (P< .01) and diastolic BP (P< .0001) over 3 years of treatment compared with baseline.[39]

Long-term treatment with adjuvant exenatide also significantly improves endothelial function, as measured by flow-mediated

vasodilation, in patients with T2DM (P< .05 vs baseline).[86]

GLP-1 agonists also promote weight reduction in overweight and obese patients with T2DM. The phase 3 AMIGO (AC2993

Diabetes Management for Improving Glucose Outcomes) trials compared twice-daily subcutaneous exenatide with placebo in

patients with T2DM who were also taking metformin (AMIGO 1), a sulfonylurea (AMIGO 2), or both metformin and a

sulfonylurea (AMIGO 3).[87-89] In each of these patient groups, add-on therapy with exenatide significantly reduced HbA1c

compared with placebo.[87-89] The mean absolute reduction in HbA1c varied from -0.4% to -0.6% with exenatide 5 g twice

daily and from -0.8% to -0.9% with exenatide 10 g twice daily in patients on background oral therapy. [87-89] In the AMIGO

clinical trials program, add-on treatment with exenatide also resulted in significant weight loss compared with placebo. Mean

reductions in body weight with high-dose exenatide ranged from -1.6 kg to -2.8 kg after 30 weeks (P< .05 vs placebo) of

treatment.[87-89]

Exenatide also compares favorably to insulin in patients with poorly controlled T2DM. In 3 head-to-head studies of exenatide

compared with insulin glargine or insulin aspart, the glycemic effects of treatment were comparable. [90-92] The mean HbA1c

reduction ranged from -0.9% to -1.4% in the insulin groups and from -1.0% to -1.4% in the exenatide groups. However,

patients in the insulin groups gained weight during the study (mean increase: 1.8 kg to 2.9 kg), while those in the exenatide

groups lost weight (mean decrease: -2.2 kg to -2.5 kg). [90-92]

Liraglutide, another GLP-1 analog, is also associated with a dose-dependent reduction in body weight.[93]

In a phase 2 studyof patients with T2DM, those in the liraglutide 1.9 mg group had a mean loss of -3.0 kg after 14 weeks of treatment (P= .04

vs placebo).[93] In addition to promoting weight loss, both exenatide and liraglutide improve other markers of cardiovascular

risk (Table 7).

Table 7. GLP-1 Agonists and Cardiovascular Risk Factors[39,94,95]


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LAR = long-acting release; NR = not reported

*P< .05 vs baseline; P< .05 vs placebo

Beyond improving biomarkers of cardiovascular risk, preliminary data suggest that treatment with GLP-1 agonists confers

direct benefits on cardiac function in the setting of established CVD. For example, in a preclinical model of T2DM, GLP-1

administration following coronary artery occlusion reduced infarct s ize and activated other prosurvival signaling pathways

associated with improved outcomes and prolonged survival. [96] In a small trial of patients with severe heart failure, infusion of

GLP-1 over 5 weeks significantly improved left ventricular function, functional status, and quality of life. [97]

Recent safety data provide additional insight on the potential role of incretin-based therapy in the management of patients

with T2DM. A meta-analysis of 8 randomized, double-blind, phase 2 and 3 trials evaluated the cardiovascular safety of the

DPP-4 inhibitor saxagliptin in 4607 patients with T2DM. [98] There was no evidence of increased cardiovascular risk with

saxagliptin used either as monotherapy or in combination with other oral antidiabetes agents. Indeed, treatment with

saxagliptin was associated with a 66% reduction in the risk of major adverse cardiovascular events (HR: 0.44), and a 41%

reduction in the risk of acute clinically significant events (HR: 0.59) compared with control. Saxagliptin was also associated

with a lower risk of all-cause mortality compared with control (0.3% vs 1.0%), as well as a lower risk of cardiovascular death

(0.2% vs 0.8%).


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Ongoing and planned clinical trials will provide further evidence to guide the safe and effective use of incretin-based therapies

in patients with T2DM. Together these trials will enroll more than 60,000 patients and collect 304,170 patient-years of follow-

up data on hard cardiovascular endpoints (Table 8).

Table 8. Ongoing and Planned Cardiovascular Outcome Trials[24]

Source: National Institutes of Health

Patient Case: Mary

Mary is a 50-year-old woman who was diagnosed with T2DM 5 years ago. Her creatinine level is 1.4 mg/dL. She stopped

metformin and started treatment with glimepiride. She has had 2 episodes of hypoglycemia with glucose levels of 5055

mg/dL. She is a nonsmoker with a history of longstanding hypertension, hyperlipidemia, stage 3 chronic kidney disease,

sleep apnea, and osteoarthritis. On her last exam, her ejection fraction (EF) was 45% by echocardiography. Her mother died

of heart failure at age 70, and her father died following an MI at age 50. Her current medications include aspirin 81 mg/d,

glimepiride 4 mg/d, lisinopril 20 mg/d, simvastatin 40 mg/d, and fish oil 1 g/d.

On her physical exam, she is obese (BMI: 46.7 kg/m2) and has 2+ pitting edema. Her BP is 126/70 mm Hg. Her laboratory

findings include the following: LDL: 90 mg/dL; HDL: 35 mg/dL; triglycerides: 170 mg/dL; HbA1c: 7.5%; creatinine: 1.4 mg/dL

Stress echocardiography demonstrated no evidence of ischemia.

What is your next step regarding Marys glucose-lowering therapy?

No change in therapy; schedule follow-up in 3 months

Discontinue glimepiride and restart metformin

Add an incretin agent to background glimepiride

Decrease glimepiride and initiate an incretin agent

Discontinue glimepiride and initiate a TZD


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Discontinue glimepiride and initiate basal insulin

Save and Proceed



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