Pharmacologic Management of Type 2 Diabetes Mellitus: Available ...

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Choices for the treatment of type 2 diabetes mellitus (T2DM) have multiplied as our understanding of the underlying pathophysiologic defects has evolved.
Accepted Manuscript Pharmacologic Management of Type 2 Diabetes Mellitus: Available Therapies James Thrasher PII:

S0002-9149(17)30799-3

DOI:

10.1016/j.amjcard.2017.05.009

Reference:

AJC 22622

To appear in:

The American Journal of Cardiology

Please cite this article as: Thrasher J, Pharmacologic Management of Type 2 Diabetes Mellitus: Available Therapies, The American Journal of Cardiology (2017), doi: 10.1016/j.amjcard.2017.05.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT AJC AJM CVD T2DM Suppl T2DM Available Therapies

April 12_ Resubmission

Article title Pharmacologic Management of Type 2 Diabetes Mellitus: Available Therapies

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James Thrasher Medical Investigations, Inc.

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James Thrasher, MD

500 S University Ave #615 Little Rock, AR 72205 Phone: (501) 666-3666

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email: [email protected]

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Medical Investigations, Inc.

Article for supplement for American Journal of Cardiology (AJC) and American Journal of Medicine (AJM):

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“Cardiovascular disease and sodium glucose cotransporter 2 inhibitors: a new era for T2DM”

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ACCEPTED MANUSCRIPT AJC AJM CVD T2DM Suppl T2DM Available Therapies

April 12_ Resubmission

Abstract (250/250) Choices for the treatment of type 2 diabetes (T2DM) have multiplied as our understanding of the underlying pathophysiologic defects has evolved. Treatment should target multiple defects in T2DM,

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and follow a patient-centered approach that considers factors beyond glycemic control, including

cardiovascular risk reduction. The American Association of Clinical Endocrinologists/American College of Endocrinology and the American Diabetes Association (ADA) recommend an initial approach consisting

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of lifestyle changes and monotherapy, preferably with metformin. Therapy choices are guided by

glycemic efficacy, safety profiles, particularly effects on weight and hypoglycemia risk, tolerability,

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patient comorbidities, route of administration, patient preference, and cost. Balancing management of hyperglycemia with the risk of hypoglycemia, as well as consideration of the effects of pharmacotherapy on weight, figure prominently in US-based T2DM recommendations, whereas less emphasis has been placed on the ability of specific medications to affect cardiovascular outcomes. This is likely because,

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until very recently, specific glucose-lowering agents had not been shown to affect cardiorenal outcomes. Recently, the EMPA-REG OUTCOME®, LEADER, and SUSTAIN-6 trials have shown a reduction in overall cardiovascular risk with empagliflozin, liraglutide, and semaglutide treatment, respectively. Moreover,

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empagliflozin has become the first glucose-lowering agent indicated to reduce the risk of cardiovascular death in adults with T2DM and established cardiovascular disease. Results from cardiovascular

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outcomes trials have prompted an update to the 2017 ADA standards of care, which now recommend consideration of empagliflozin or liraglutide for patients with suboptimally controlled long-standing T2DM and established atherosclerotic cardiovascular disease because these agents have been shown to reduce cardiovascular and all-cause mortality when added to standard care.

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ACCEPTED MANUSCRIPT AJC AJM CVD T2DM Suppl T2DM Available Therapies

April 12_ Resubmission

Keywords: Type 2 diabetes, Treatment, Guidelines, Sodium glucose cotransporter 2 inhibitors,

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Glucagon-like peptide-1 receptor agonist, Dipeptidyl peptidase-4 inhibitors

Introduction

Eight core defects, collectively known as “the ominous octet,” contribute to the pathophysiology of

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type 2 diabetes mellitus (T2DM).1,2 These include decreased insulin secretion, decreased incretin effect, increased lipolysis, increased glucose reabsorption, decreased glucose uptake, neurotransmitter

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dysfunction, increased hepatic glucose production, and increased glucagon secretion (Figure 1).1-3 Therapy choices should target these established pathophysiologic defects in T2DM,1,2 as well as follow a patient-centered approach that considers factors beyond glycemic control, including reduction of overall cardiovascular risk.4-6 This review discusses current consensus recommendations for the management of hyperglycemia in patients with T2DM, focusing on major drug classes, their mechanisms of action,

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efficacy, and key safety points for appropriate use.

The American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology

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(ACE)4 and the American Diabetes Association (ADA)6 support a stepwise, progressive approach to pharmacotherapy. This includes individualization of glycated hemoglobin (HbA1c) goals based on

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patient-specific variables (eg, comorbidities) and the adverse effects of therapy, especially hypoglycemia. The AACE/ACE recommends an initial HbA1c goal ≤6.5% for most patients based on the trial results comparing intensive versus standard glucose-lowering strategies.4 They stress the importance of individualizing therapy; thus a goal of >6.5%, even 7%-8%, may be appropriate for some patients, such as those with limited life expectancy, history of severe hypoglycemia, or advanced comorbid disease.4 Similarly, the ADA recommends an HbA1c goal