AACE/ACE Consensus Statement
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AACE/ACE Consensus Statement
CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF
CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF
ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES
MANAGEMENT ALGORITHM – 2018 EXECUTIVE SUMMARY
Alan J. Garber, MD, PhD, FACE1; Martin J. Abrahamson, MD2; Joshua I. Barzilay, MD, FACE3;
Lawrence Blonde, MD, FACP, MACE4; Zachary T. Bloomgarden, MD, MACE5; Michael A. Bush, MD6;
Samuel Dagogo-Jack, MD, FACE7; Ralph A. DeFronzo, MD8; Daniel Einhorn, MD, FACP, FACE9;
Vivian A. Fonseca, MD, FACE10; Jeffrey R. Garber, MD, FACP, FACE11;
W. Timothy Garvey, MD, FACE12; George Grunberger, MD, FACP, FACE13;
Yehuda Handelsman, MD, FACP, FNLA, FACE14; Irl B. Hirsch, MD15; Paul S. Jellinger, MD, MACE16;
Janet B. McGill, MD, FACE17; Jeffrey I. Mechanick, MD, FACN, FACP, FACE, ECNU18;
Paul D. Rosenblit, MD, PhD, FACE, FNLA19; Guillermo E. Umpierrez, MD, FACP, FACE20
This document represents the official position of the American Association of Clinical Endocrinologists and American
College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues
in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to
achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to
be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.
Submitted for publication November 15, 2017 13Chairman, Grunberger Diabetes Institute, Clinical Professor, Internal
Accepted for publication December 7, 2017 Medicine and Molecular Medicine & Genetics, Wayne State University
From the 1Chair, Professor, Departments of Medicine, Biochemistry School of Medicine, Professor, Internal Medicine, Oakland University
and Molecular Biology, and Molecular and Cellular Biology, Baylor William Beaumont School of Medicine, Visiting Professor, Internal Medicine,
College of Medicine, Houston, Texas; 2Beth Israel Deaconess Medical First Faculty of Medicine, Charles University, Prague, Czech Republic, Past
Center, Department of Medicine and Harvard Medical School, Boston, President, American Association of Clinical Endocrinologists, President
Massachusetts; 3Division of Endocrinology Kaiser Permanente of Georgia Elect, American College of Endocrinology; 14Medical Director & Principal
and Professor, Division of Endocrinology, Emory University School of Investigator, Metabolic Institute of America, Chair, AACE Diabetes Scientific
Medicine, Atlanta, Georgia; 4Director, Ochsner Diabetes Clinical Research Committee, Tarzana, California; 15Professor of Medicine, University of
Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Washington School of Medicine, Seattle, Washington; 16Professor of Clinical
Ochsner Medical Center, New Orleans, Louisiana; 5Clinical Professor, Icahn Medicine, University of Miami, Miller School of Medicine, Miami, Florida,
School of Medicine at Mount Sinai, Editor, the Journal of Diabetes, New York, The Center for Diabetes & Endocrine Care, Hollywood, Florida; 17Professor
New York; 6Clinical Chief, Division of Endocrinology, Cedars-Sinai Medical of Medicine, Division of Endocrinology, Metabolism & Lipid Research,
Center, President, California AACE Chapter, Associate Clinical Professor Washington University, St. Louis, Missouri; 18Professor of Medicine, Medical
of Medicine, Geffen School of Medicine, UCLA, Los Angeles, California; Director, The Marie-Josee and Henry R. Kravis Center for Cardiovascular
7A.C. Mullins Professor & Director, Division of Endocrinology, Diabetes
Health at Mount Sinai Heart, Director, Metabolic Support, Divisions of
and Metabolism, University of Tennessee Health Science Center, Memphis, Cardiology and Endocrinology, Diabetes and Bone Disease, Icahn School
Tennessee; 8Professor of Medicine, Chief, Diabetes Division, University of Medicine at Mount Sinai; Immediate Past President, American College
of Texas Health Science Center at San Antonio, San Antonio, Texas; 9Past of Endocrinology, Past President, American Association of Clinical
President, American College of Endocrinology, Past President, American Endocrinology, Past President, American Board of Physician Nutrition
Association of Clinical Endocrinologists, Medical Director, Scripps Whittier Specialists, Editor-in-Chief Emeritus, President’s Council on Fitness; 19Clinical
Diabetes Institute, Clinical Professor of Medicine, UCSD, Associate Editor, Professor, Medicine, Division of Endocrinology, Diabetes, Metabolism,
Journal of Diabetes, President, Diabetes and Endocrine Associates, La Jolla, University California Irvine School of Medicine, Irvine, California,
California; 10Professor of Medicine and Pharmacology, Tullis Tulane Alumni Co-Director, Diabetes Out-Patient Clinic, UCI Medical Center, Orange,
Chair in Diabetes, Chief, Section of Endocrinology, Tulane University Health California; 20Professor of Medicine, Emory University School of Medicine,
Sciences Center, New Orleans, Louisiana; 11Endocrine Division, Harvard Director, Endocrinology Section, Grady Health System, Atlanta, Georgia.
Vanguard Medical Associates, Division of Endocrinology, Beth Israel Address correspondence to American Association of Clinical
Deaconess Medical Center, Boston, Massachusetts; 12Professor and Chair, Endocrinologists, 245 Riverside Avenue, Suite 200, Jacksonville, FL 32202.
Department of Nutrition Sciences, University of Alabama at Birmingham, E-mail: publications@aace.com. DOI: 10.4158/CS-2017-0153
Director, UAB Diabetes Research Center, Staff Physician and GRECC To purchase reprints of this article, please visit: www.aace.com/reprints.
Investigator, Birmingham VA Medical Center, Birmingham, Alabama; Copyright © 2018 AACE.
ENDOCRINE PRACTICE Vol 24 No. 1 January 2018 9192 2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1)
edition includes an updated section on lifestyle therapy,
Abbreviations: as well as discussion of all classes of obesity, antihyper-
A1C = hemoglobin A1C; AACE = American glycemic, lipid-lowering, and antihypertensive medica-
Association of Clinical Endocrinologists; ACCORD tions approved by the U.S. Food and Drug Administration
= Action to Control Cardiovascular Risk in Diabetes; (FDA) through December 2016.
ACCORD BP = Action to Control Cardiovascular This algorithm supplements the American Association
Risk in Diabetes Blood Pressure; ACEI = angiotensin- of Clinical Endocrinologists (AACE) and American College
converting enzyme inhibitor; ADVANCE = Action in of Endocrinology (ACE) 2015 Clinical Practice Guidelines
Diabetes and Vascular Disease: Preterax and Diamicron for Developing a Diabetes Mellitus Comprehensive Care
MR Controlled Evaluation; AGI = alpha-glucosi- Plan (2) and is organized into discrete sections that address
dase inhibitor; apo B = apolipoprotein B; ASCVD = the following topics: the founding principles of the algo-
atherosclerotic cardiovascular disease; BAS = bile acid rithm, lifestyle therapy, obesity, prediabetes, glucose
sequestrant; BCR-QR = bromocriptine quick release; control with noninsulin antihyperglycemic agents and
BMI = body mass index; BP = blood pressure; CCB insulin, and management of hypertension and dyslipid-
= calcium channel blocker; CHD = coronary heart emia. In the accompanying algorithm, a chart summariz-
disease; CKD = chronic kidney disease; CVD = cardio- ing the attributes of each antihyperglycemic class and the
vascular disease; DASH = Dietary Approaches to Stop principles of the algorithm appear at the end.
Hypertension; DPP4 = dipeptidyl peptidase 4; eGFR
= estimated glomerular filtration rate; ER = extended Principles
release; FDA = Food and Drug Administration; GLP1 The founding principles of the Comprehensive Type
= glucagon-like peptide 1; HDL-C = high-density 2 Diabetes Management Algorithm are as follows (see
lipoprotein cholesterol; IMPROVE-IT = Improved Comprehensive Type 2 Diabetes Management Algorithm—
Reduction of Outcomes: Vytorin Efficacy International Principles):
Trial; LDL-C = low-density lipoprotein cholester- 1. Lifestyle optimization is essential for all patients
ol; LDL-P = low-density lipoprotein particle; Look with diabetes. Lifestyle optimization is multifaceted,
AHEAD = Look Action for Health in Diabetes; NPH = ongoing, and should engage the entire diabetes team.
neutral protamine Hagedorn; OSA = obstructive sleep However, such efforts should not delay needed phar-
apnea; RCT = randomized controlled trial; SU = sulfo- macotherapy, which can be initiated simultaneously
nylurea; SGLT2 = sodium glucose cotransporter-2; and adjusted based on patient response to lifestyle
SMBG = self-monitoring of blood glucose; T2D = type efforts. The need for medical therapy should not be
2 diabetes; TZD = thiazolidinedione; VADT = Veterans interpreted as a failure of lifestyle management but as
Affairs Diabetes Trial an adjunct to it.
2. Weight loss should be considered in all patients with
prediabetes and T2D who also have overweight or
EXECUTIVE SUMMARY obesity. Weight-loss therapy should consist of lifestyle
prescription that includes a reduced-calorie healthy
This algorithm for the comprehensive management meal plan, physical activity, and behavioral interven-
of persons with type 2 diabetes (T2D) was developed to tions. Weight-loss medications approved for the chron-
provide clinicians with a practical guide that considers the ic management of obesity should also be considered if
whole patient, his or her spectrum of risks and complica- needed to obtain the degree of weight loss required
tions, and evidence-based approaches to treatment. It is to achieve therapeutic goals in prediabetes and T2D.
now clear that the progressive pancreatic beta-cell defect Obesity is a chronic disease, and a long-term commit-
that drives the deterioration of metabolic control over time ment to therapy is necessary.
begins early and may be present before the diagnosis of 3. The hemoglobin A1C (A1C) target should be individ-
diabetes (1). In addition to advocating glycemic control to ualized based on numerous factors such as age, life
reduce microvascular complications, this document high- expectancy, comorbid conditions, duration of diabetes,
lights obesity and prediabetes as underlying risk factors risk of hypoglycemia or adverse consequences from
for the development of T2D and associated macrovascular hypoglycemia, patient motivation, and adherence. An
complications. In addition, the algorithm provides recom- A1C level of ≤6.5% is considered optimal if it can be
mendations for blood pressure (BP) and lipid control, achieved in a safe and affordable manner, but higher
the two most important risk factors for cardiovascular targets may be appropriate for certain individuals and
disease (CVD). may change for a given individual over time.
Since it was originally drafted in 2013, the algorithm 4. Glycemic control targets include fasting and post-
has been updated as new therapies, management approach- prandial glucose as determined by self-monitoring of
es, and important clinical data have emerged. The 2018 blood glucose (SMBG).2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1) 93
5. The choice of diabetes therapies must be individual- Lifestyle therapy begins with nutrition counseling and
ized based on attributes specific to both patients and education. All patients should strive to attain and main-
the medications themselves. Medication attributes that tain an optimal weight through a primarily plant-based
affect this choice include antihyperglycemic efficacy; meal plan high in polyunsaturated and monounsaturated
mechanism of action; risk of inducing hypoglycemia; fatty acids, with limited intake of saturated fatty acids and
risk of weight gain; other adverse effects; tolerability; avoidance of trans fats. Patients with overweight (body
ease of use; likely adherence; cost; and safety or risk mass index [BMI] 25-29.9 kg/m2) or obesity (BMI ≥30 kg/
reduction in heart, kidney, or liver disease. m2, see Obesity section) should also restrict their caloric
6. Minimizing the risk of both severe and nonsevere intake with the goal of reducing body weight by at least 5
hypoglycemia is a priority. It is a matter of safety, to 10%. As shown in the Look AHEAD (Action for Health
adherence, and cost. in Diabetes) and Diabetes Prevention Program (DPP) stud-
7. Minimizing risk of weight gain is also a priority. This ies, lowering caloric intake is the main driver for weight
is important for long-term health, in addition to safety, loss (3-6). The clinician, a registered dietitian, or a nutri-
adherence, and cost. tionist (i.e., a healthcare professional with formal train-
8. The initial acquisition cost of medications is only a ing in the nutritional needs of individuals with diabetes)
part of the total cost of care, which includes moni- should discuss recommendations in plain language at the
toring requirements and risks of hypoglycemia and initial visit and periodically during follow-up office visits.
weight gain. Safety and efficacy should be given high- Discussion should focus on foods that promote health,
er priority than medication cost. including information on specific foods, meal planning,
9. This algorithm stratifies choice of therapies based grocery shopping, and dining-out strategies. Clinicians
on initial A1C level. It provides guidance as to what should be sensitive to patients’ ethnic and cultural back-
therapies to initiate and add but respects individual grounds and their associated food preferences. In addition,
circumstances that could lead to different choices. education on medical nutrition therapy for patients with
10. Combination therapy is usually required and should diabetes should also address the need for consistency in
involve agents with complementary mechanisms day-to-day carbohydrate intake, limiting sucrose-contain-
of action. ing, high fructose-containing, or other or high-glycemic
11. Comprehensive management includes lipid and BP index foods, and adjusting insulin doses to match carbo-
therapies and treatment of related comorbidities. hydrate intake (e.g., use of carbohydrate counting with
12. Therapy must be evaluated frequently (e.g., every 3 glucose monitoring) (2,7). Carbohydrate counting was not
months) until stable using multiple criteria, includ- more effective than a simplified bolus insulin dosage algo-
ing A1C, SMBG records (fasting and postprandial) or rithm based on premeal and bedtime glucose patterns (8).
continuous glucose monitoring tracings, documented Structured counseling (e.g., weekly or monthly sessions
and suspected hypoglycemia events, lipid and BP with a specific weight-loss curriculum) and meal replace-
values, adverse events (weight gain, fluid retention, ment programs have been shown to be more effective than
hepatic or renal impairment, or CVD), comorbidi- standard in-office counseling (3,6,9-16). Additional nutri-
ties, other relevant laboratory data, concomitant drug tion recommendations can be found in the 2013 Clinical
administration, complications of diabetes, and psycho- Practice Guidelines for Healthy Eating for the Prevention
social factors affecting patient care. Less frequent and Treatment of Metabolic and Endocrine Diseases in
monitoring is acceptable once targets are achieved. Adults from the AACE/ACE and The Obesity Society (17).
13. The therapeutic regimen should be as simple as possi- After nutrition, physical activity is the main compo-
ble to optimize adherence. nent in weight loss and maintenance programs. Regular
14. This algorithm includes every FDA-approved class of physical activity—both aerobic exercise and strength
medications for T2D (as of December 2016). training—improves glucose control, lipid levels, and BP;
decreases the risk of falls and fractures; and improves
Lifestyle Therapy functional capacity and sense of well-being (18-25). In
The key components of lifestyle therapy include Look AHEAD, which had a weekly goal of ≥175 minutes
medical nutrition therapy, regular physical activity, suffi- per week of moderately intense activity, minutes of physi-
cient amounts of sleep, behavioral support, and smok- cal activity were significantly associated with weight loss,
ing cessation and avoidance of all tobacco products (see suggesting that those who were more active lost more
Comprehensive Type 2 Diabetes Management Algorithm— weight (3). The physical activity regimen should involve
Lifestyle Therapy). In the algorithm, recommendations at least 150 minutes per week of moderate-intensity physi-
appearing on the left apply to all patients. Patients with cal activity such as brisk walking (e.g., 15- to 20-minute
increasing burden of obesity or related comorbidities may miles) and strength training; patients should start any new
also require the additional interventions listed in the middle activity slowly and gradually increase intensity and dura-
and right side of the Lifestyle Therapy algorithm panel. tion as they become accustomed to the exercise. Structured94 2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1)
programs can help patients learn proper technique, estab- in patients having difficulty with smoking cessation.
lish goals, and stay motivated. Wearable technologies such Structured programs should be recommended for patients
as pedometers or accelerometers can provide valuable unable to stop smoking on their own (2).
information to motivate, as well as guide healthy amounts
of physical activity. Patients with diabetes and/or severe Obesity
obesity or complications should be evaluated for contrain- Obesity is a progressive chronic disease with genetic,
dications and/or limitations to increased physical activity, environmental, and behavioral determinants that result in
and an activity prescription should be developed for each excess adiposity associated with an increase in morbidity
patient according to both goals and limitations. More detail and mortality (39,40). An evidence-based approach to the
on the benefits and risks of physical activity and the practi- treatment of obesity incorporates lifestyle, medical, and
cal aspects of implementing a training program in people surgical options, balances risks and benefits, and empha-
with T2D can be found in a joint position statement from sizes medical outcomes that address the complications of
the American College of Sports Medicine and American obesity. Weight loss should be considered in all patients
Diabetes Association (26). with overweight or obesity who have prediabetes or T2D,
Adequate rest is important for maintaining energy given the known therapeutic effects of weight loss to lower
levels and well-being, and all patients should be advised to glycemia, improve the lipid profile, reduce BP, prevent or
sleep approximately 7 hours per night. Evidence supports delay the progression to T2D in patients with prediabetes,
an association of 6 to 9 hours of sleep per night with a and decrease mechanical strain on the lower extremities
reduction in cardiometabolic risk factors, whereas sleep (hips and knees) (2,39).
deprivation aggravates insulin resistance, hypertension, The AACE Clinical Practice Guidelines for
hyperglycemia, and dyslipidemia and increases inflamma- Comprehensive Medical Care of Patients with Obesity and
tory cytokines (27-32). Daytime drowsiness—a frequent Treatment Algorithm (41) provide evidence-based recom-
symptom of sleep disorders such as sleep apnea—is asso- mendations for obesity care including screening, diagnosis,
ciated with increased risk of accidents, errors in judgment, clinical evaluation and disease staging, therapeutic deci-
and diminished performance (33). Basic sleep hygiene sion-making, and follow-up. Rather than a BMI-centric
recommendations should be provided to all patients with approach for the treatment of patients who have obesity
diabetes. The most common type of sleep apnea, obstruc- or are overweight, the AACE has emphasized a complica-
tive sleep apnea (OSA), is caused by physical obstruc- tions-centric model that incorporates 3 disease stages: Stage
tion of the airway during sleep. The resulting lack of 0 (elevated BMI with no obesity complications), Stage 1 (1
oxygen causes the patient to awaken and snore, snort, and or 2 mild to moderate obesity complications), and Stage 3
grunt throughout the night. The awakenings may happen (>2 mild to moderate obesity complications, or ≥1 severe
hundreds of times per night, often without the patient’s complications) (41,42). The patients who will benefit
awareness. OSA is more common in males, the elderly, and most from medical and surgical intervention have obesity-
persons with obesity (34,35). Individuals with suspected related complications that can be classified into 2 general
OSA should be referred for a home study in lower risk categories: insulin resistance/cardiometabolic disease and
settings or to a sleep specialist for formal evaluation and biomechanical consequences of excess body weight (43).
treatment in higher risk settings (2). Clinicians should evaluate patients for the risk, presence,
Behavioral support for lifestyle therapy includes the and severity of complications, regardless of BMI, and these
structured weight loss and physical activity programs factors should guide treatment planning and further evalu-
mentioned above, as well as support from family and ation (44,45). Once these factors are assessed, clinicians
friends. Patients should be encouraged to join commu- can set therapeutic goals and select appropriate types and
nity groups dedicated to a healthy lifestyle for emotional intensities of treatment that will help patients achieve their
support and motivation. In addition, obesity and diabetes weight-loss goals linked to the prevention or amelioration
are associated with high rates of anxiety and depression, of weight-related complications. The primary clinical goal
which can adversely affect outcomes (36,37). Alcohol of weight-loss therapy is to prevent progression to T2D
moderation and substance abuse counseling should be in patients with prediabetes and to achieve the target for
provided where appropriate. Healthcare professionals A1C in patients with T2D, in addition to improvements in
should assess patients’ mood and psychological well-being lipids and BP. Patients should be periodically reassessed to
and refer patients with mood disorders to mental healthcare determine if targets for improvement have been reached; if
professionals. Cognitive behavioral therapy may be benefi- not, weight-loss therapy should be changed or intensified.
cial. A recent meta-analysis of psychosocial interventions Lifestyle therapy can be recommended for all patients with
provides insight into successful approaches (38). overweight or obesity, and more intensive options can be
Smoking cessation is the final component of life- prescribed for patients with complications. For example,
style therapy and involves avoidance of all tobacco prod- weight-loss medications can be used to intensify therapy
ucts. Nicotine replacement therapy should be considered in combination with lifestyle therapy for all patients with a2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1) 95
BMI ≥27 kg/m2 having complications and for patients with water retention and potentially heart failure, in susceptible
BMI ≥30 kg/m2 whether or not complications are present. patients (i.e., those with pre-existing ventricular dysfunc-
As of 2016, the FDA has approved 8 drugs as adjuncts to tion). In addition, there is an increased risk of distal limb
lifestyle therapy in patients with overweight or obesity. bone fractures (70-72). More importantly cardiovascular
Diethyproprion, phendimetrazine, and phentermine may benefits, as reduced major adverse cardiac event risk, have
be used for short-term (≤3 months) use, whereas orlistat, been documented in T2D (73) and in patients with predia-
phentermine/topiramate extended release (ER), lorcaserin, betes with a history of stroke (74).
naltrexone ER/bupropion ER, and liraglutide 3 mg have Glucagon-like peptide 1 (GLP1) receptor agonists
been approved for long-term weight reduction therapy. may be equally effective, as demonstrated by the profound
In clinical trials, the 5 drugs approved for long-term use effect of liraglutide 3 mg in safely preventing diabetes and
were associated with statistically significant weight loss restoring normoglycemia in the vast majority of subjects
(placebo-adjusted decreases ranged from 2.9% with orli- with prediabetes (62,63,75,76). However, owing to the
stat to 9.7% with phentermine/topiramate ER) after 1 year lack of long-term safety data on GLP1 receptor agonists
of treatment. These agents improve BP and lipids, prevent and the known adverse effects of TZDs, these agents
progression to diabetes during trial periods, and improve should be considered only for patients at the greatest
glycemic control and lipids in patients with T2D (46-63). risk of developing future diabetes and those failing more
Bariatric surgery should be considered for adult patients conventional therapies.
with a BMI ≥35 kg/m2 and comorbidities, especially As with diabetes, prediabetes increases the risk for
if therapeutic goals have not been reached using other atherosclerotic cardiovascular disease (ASCVD). Patients
modalities (2,64). with prediabetes should be offered lifestyle therapy and
pharmacotherapy to achieve lipid and BP targets that will
Prediabetes reduce ASCVD risk.
Prediabetes reflects failing pancreatic islet beta-cell
compensation for an underlying state of insulin resis- T2D Pharmacotherapy
tance, most commonly caused by excess body weight or In patients with T2D, achieving the glucose and A1C
obesity. Current criteria for the diagnosis of prediabe- targets requires a nuanced approach that balances age,
tes include impaired glucose tolerance, impaired fasting comorbidities, and hypoglycemia risk (2). The AACE
glucose, or insulin resistance (metabolic) syndrome (see supports an A1C goal of ≤6.5% for most patients or
Comprehensive Type 2 Diabetes Management Algorithm— >6.5% (up to 8%; see below) if the lower target cannot be
Prediabetes Algorithm). Any one of these factors is associ- achieved without adverse outcomes (see Comprehensive
ated with a 5-fold increase in future T2D risk (65). Type 2 Diabetes Management Algorithm—Goals for
The primary goal of prediabetes management is Glycemic Control). Significant reductions in the risk or
weight loss. Whether achieved through lifestyle therapy progression of nephropathy were seen in the Action in
alone or a combination of lifestyle therapy with phar- Diabetes and Vascular Disease: Preterax and Diamicron
macotherapy and/or surgery, weight loss reduces insu- MR Controlled Evaluation (ADVANCE) study, which
lin resistance and can effectively prevent progression to targeted an A1C 8.5%, patients randomized to intensive glucose-
the management of prediabetes and/or prevention of T2D. lowering therapy (A1C target of 7% despite intensive ther-
patients with prediabetes by 25 to 30%. Both medications apy, while in the standard therapy group (A1C target 7 to
are relatively well-tolerated and safe, and they may confer 8%), mortality followed a U-shaped curve with increasing
a cardiovascular risk benefit (66-69). In clinical trials, death rates at both low (8%) A1C levels
insulin sensitizers (thiazolidinediones [TZDs]) prevented (81). In contrast, in the Veterans Affairs Diabetes Trial
future development of diabetes in 60 to 75% of subjects (VADT), which had a higher A1C target for intensively
with prediabetes (70-72), but this class of drugs has been treated patients (1.5% lower than the standard treatment
associated with adverse outcomes including subcutane- group), there were no between-group differences in CVD
ous fat weight gain, despite visceral adiposity reduction, endpoints, cardiovascular death, or overall death during the96 2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1) 5.6-year study period (80,82). Cardiovascular autonomic lar safety relative to SUs (88-90). The FDA recently neuropathy may be another useful predictor of cardio- changed the package label for metformin use in chron- vascular risk. Moreover, a combination of cardiovascular ic kidney disease (CKD) patients lifting the previous autonomic neuropathy (83) and symptoms of peripheral contraindication in males with serum creatinine >1.5 neuropathy increase the odds ratio to 4.55 for CVD and mg/dL and females with serum creatinine >1.4 mg/ mortality (84). After approximately 10 years, however, dL (91,92). Newer CKD guidelines are based on esti- VADT patients participating in an observational follow-up mated glomerular filtration rate (eGFR), not on serum study were 17% less likely to have a major cardiovascu- creatinine. Metformin can be used in patients with lar event if they received intensive therapy during the trial stable eGFR >30 mL/min/1.73 m2; however, it should (P
2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1) 97
• Sodium glucose cotransporter 2 (SGLT2) inhibitors secretion. DPP4 inhibitors have modest A1C-lowering
have a glucosuric effect that results in decreased A1C, properties; are weight-neutral; and are available
weight, and systolic BP. Empagliflozin was associ- in combination tablets with metformin, an SGLT2
ated with significantly lower rates of all-cause and inhibitor, and a TZD. The risk of hypoglycemia with
cardiovascular death and lower risk of hospitaliza- DPP4 inhibitors is low (117,118). The DPP4 inhibi-
tion for heart failure in the cardiovascular outcome tors, except linagliptin, are excreted by the kidneys;
trial EMPA-REG OUTCOME trial (Empagliflozin, therefore, dose adjustments are advisable for patients
Cardiovascular Outcomes, and Mortality in Type 2 with renal dysfunction. These agents should be used
Diabetes) (106). Treatment with canagliflozin signifi- with caution in patients with a history of pancreatitis
cantly reduced the risk of the combined cardiovascular (and stopped if pancreatitis occurs), although a caus-
outcomes of cardiovascular death, myocardial infarc- ative association has not been established (105). DPP4
tion, or nonfatal stroke, but increased the risk of ampu- inhibitors have been shown to have neutral effects on
tation in the CANVAS (Canagliflozin Cardiovascular cardiovascular outcomes (119-121). An increased risk
Assessment Study), and hospitalization for heart fail- of heart failure with saxagliptin and alogliptin was
ure was also reduced in CANVAS (107). Both empa- found in the respective cardiovascular outcome trials
gliflozin and canagliflozin reduced secondary renal (122,123).
endpoints (106,107). Heart failure-related endpoints • The TZDs, the only antihyperglycemic agents to
appeared to account for most of the observed benefits directly reduce insulin resistance, have relatively
in this study. Empagliflozin recently received FDA potent A1C-lowering properties, a low risk of hypo-
approval for indication of reducing cardiac mortal- glycemia, and durable glycemic effects (73,89,124).
ity in adults with T2D and established CVD (108). Pioglitazone may confer CVD benefits (73,74,125),
SGLT2 inhibitors are associated with increased risk of while rosiglitazone has a neutral effect on CVD risk
mycotic genital infections and slightly increased low- (126,127). Side effects that have limited TZD use
density lipoprotein cholesterol (LDL-C) levels, and include weight gain, increased bone fracture risk
because of their mechanism of action, they have limit- in postmenopausal females and elderly males, and
ed efficacy in patients with an estimated glomerular elevated risk for chronic edema or heart failure (128-
filtration rate98 2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1)
decreases LDL-C. A perceived modest efficacy for Certain patient populations are at higher risk for
both A1C and LDL-C lowering, as well as gastrointes- adverse treatment-related outcomes, underscoring the need
tinal intolerance (constipation and dyspepsia, which for individualized therapy. Although several antihypergly-
occurs in 10% of users), may contribute to limited cemic drug classes carry a low risk of hypoglycemia (e.g.,
use. In addition, colesevelam can increase triglycer- metformin, GLP1 receptor agonists, SGLT2 inhibitors,
ide levels in individuals with pre-existing triglycer- DPP4 inhibitors, and TZDs), significant hypoglycemia
ide elevations, but this is preventable by concomitant can still occur when these agents are used in combination
statin use (138). with an insulin secretagogue or exogenous insulin. When
• The quick-release sympatholytic dopamine receptor such combinations are used, one should consider lowering
agonist bromocriptine mesylate has slight glucose- the dose of the insulin secretagogue or insulin to reduce
lowering properties (139) and does not cause hypogly- the risk of hypoglycemia. Many antihyperglycemic agents
cemia. It can cause frequent nausea and orthostasis, (e.g., metformin, GLP1 receptor agonists, SGLT2 inhibi-
which may be mitigated by limiting use to less than tors, some DPP4 inhibitors, AGIs, SUs) have limitations in
maximal recommended doses, and should not be used patients with impaired renal function and may require dose
in patients taking antipsychotic drugs. Bromocriptine adjustments or special precautions (see Comprehensive
mesylate may be associated with reduced cardiovascu- Type 2 Diabetes Management Algorithm—Profiles of
lar event rates (140,141). Antidiabetic Medications). In general, diabetes thera-
py does not require modification for mild to moderate
For patients with recent-onset T2D or mild hypergly- liver disease, but the risk of hypoglycemia increases in
cemia (A1C 7.5% should be started on metformin plus another agent all health status, as well as cost considerations. Patients
in addition to lifestyle therapy (136) (see Comprehensive taking 2 oral antihyperglycemic agents who have an A1C
Type 2 Diabetes Management Algorithm—Glycemic >8.0% and/or long-standing T2D are less likely to reach
Control Algorithm). In metformin-intolerant patients, 2 their target A1C with a third oral antihyperglycemic agent.
drugs with complementary mechanisms of action from Although adding a GLP1 receptor agonist as the third agent
other classes should be considered. Fixed-dose (single- may successfully lower glycemia, eventually many patients
pill) combinations of oral agents including metformin and/ will still require insulin (142,143). When insulin becomes
or SGLT2 inhibitors, DPP4 inhibitors, TZDS, and SUs necessary, a single daily dose of basal insulin should be
are available for the treatment of T2D. Fixed-ratio combi- added to the regimen. The dosage should be adjusted at
nations of GLP1 receptor agonists and basal insulin are regular and fairly short intervals to achieve the targeted
also available. glycemic goal while avoiding hypoglycemia. Recent stud-
The addition of a third agent may safely enhance ies (144,145) have shown that titration is equally effective
treatment efficacy (see Comprehensive Type 2 Diabetes whether it is guided by the healthcare professional or a
Management Algorithm—Glycemic Control Algorithm), patient who has been instructed in SMBG.
although any given third-line agent is likely to have some- Basal insulin analogs are preferred over neutral prot-
what less efficacy than when the same medication is used amine Hagedorn (NPH) insulin because a single basal
as first- or second-line therapy. Patients with A1C >9.0% analog dose provides a relatively flat serum insulin concen-
who are symptomatic would derive greater benefit from tration for 24 hours or longer. Although basal insulin
the addition of insulin, but if presenting without signifi- analogs and NPH have been shown to be equally effective
cant symptoms, these patients may initiate therapy with in reducing A1C in clinical trials, insulin analogs caused
maximum doses of 2 other medications. Doses may then significantly less hypoglycemia (144-148), especially
be decreased to maintain control as glucose falls. Therapy newer ultra long-acting analogs that demonstrate minimal
intensification should include intensified lifestyle therapy variability (149).
and anti-obesity treatment (when indicated).2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1) 99
These newer basal insulin formulations—glargine insulin later, if needed. Several RCTs have shown that the
U300 and degludec U100 and U200—have more prolonged stepwise addition of prandial insulin to basal insulin is safe
and stable pharmacokinetic (PK) and pharmacodynam- and effective in achieving target A1C with a low rate of
ics (PD) characteristics than glargine U100 and detemir hypoglycemia (170-172). A full basal-bolus program is the
(149,150). Degludec may have more stable day-to-day most effective insulin regimen and provides greater flex-
variability than glargine U300 (151). RCTs have report- ibility for patients with variable mealtimes and meal carbo-
ed equivalent glycemic control and lower rate of severe hydrate content, although this type of program has been
or confirmed hypoglycemia, particularly nocturnal hypo- associated with weight gain (172).
glycemia compared to glargine U100 and detemir insulin Pramlintide is indicated for use with basal-bolus insu-
(149,152-157). Cardiovascular outcomes were equivalent lin regimens. Pioglitazone is indicated for use with insulin
in the DEVOTE (Trial Comparing Cardiovascular Safety at doses of 15 and 30 mg, but this approach may aggravate
of Insulin Degludec versus Insulin Glargine in Patients with weight gain. There are no specific approvals for the use of
Type 2 Diabetes at High Risk of Cardiovascular Events) SUs with insulin, but when they are used together, the risks
trial comparing insulin degludec to insulin glargine (149). of both weight gain and hypoglycemia increase (173,174).
Premixed insulins provide less dosing flexibility and It is important to avoid hypoglycemia. Approximately
have been associated with a higher frequency of hypo- 7 to 15% of insulin-treated patients in the United Kingdom
glycemic events compared to basal and basal-bolus regi- Prospective Diabetes Study (UKPDS) experienced at least
mens (158-160). Nevertheless, there are some patients for 1 annual episode of hypoglycemia (175), and based on other
whom a simpler regimen using these agents is a reason- studies, 1 to 2% have severe hypoglycemia (176,177). In
able compromise, in which case premixed analog insulin a study using CGM, 49% of patients experienced at least
may be preferred over premixed human due to lower rates 1 blood glucose100 2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1)
vascular outcomes or all-cause mortality between stan- (197,201-203). Patients with heart failure could bene-
dard therapy (which achieved a mean BP of 133/71 mm fit from beta blockers, those with prostatism from alpha
Hg) and intensive therapy (mean BP of 119/64 mm Hg). blockers, and those with coronary artery disease (CAD)
Intensive therapy did produce a comparatively significant from beta blockers or CCBs. In patients with BP >150/100
reduction in stroke and microalbuminuria, but these reduc- mm Hg, 2 agents should be given initially because it is
tions came at the cost of requiring more antihypertensive unlikely any single agent would be sufficient to achieve the
medications and produced a significantly higher number BP target. An ARB/ACEI combination more than doubles
of serious adverse events (SAEs). In particular, a greater the risk of renal failure and hyperkalemia and is therefore
likelihood of decline in renal function was observed in the not recommended (204,205). A CCB or other agent may be
intensive arm of ACCORD-BP (185). A meta-analysis of used based on the clinical characteristics of the patient.
antihypertensive therapy in patients with T2D or impaired
fasting glucose demonstrated similar findings. Systolic BP Lipids
≤135 mm Hg was associated with decreased nephropathy Compared to those without diabetes, patients with
and a significant reduction in all-cause mortality compared T2D have a significantly increased risk of ASCVD (206).
with systolic BP ≤140 mm Hg. Below 130 mm Hg, stroke Whereas blood glucose control is fundamental to preven-
and nephropathy, but not cardiac events, declined further, tion of microvascular complications, controlling athero-
but SAEs increased by 40% (182). genic cholesterol particle concentrations is fundamental
Lifestyle therapy can help T2D patients reach their to prevention of macrovascular disease (i.e., ASCVD).
BP goal: To reduce the significant risk of ASCVD, including
• Weight loss can improve BP in patients with T2D. coronary heart disease (CHD), in T2D patients, early
Compared with standard intervention, the results of intensive management of dyslipidemia is warranted (see
the Look AHEAD trial found that significant weight Comprehensive Type 2 Diabetes Management Algorithm—
loss is associated with significant reduction in BP, ASCVD Risk Factor Modifications Algorithm).
without the need for increased use of antihypertensive The classic major risk factors that modify the LDL-C
medications (4). goal for all individuals include cigarette smoking, hyper-
• Sodium restriction is recommended for all patients tension (BP ≥140/90 mm Hg or use of antihypertensive
with hypertension. Clinical trials indicate that potas- medications), high-density lipoprotein cholesterol (HDL-
sium chloride supplementation is associated with C)2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1) 101
Table 1
AACE Lipid Targets for Patients with T2D (188,189,197,200,240-251)
Treatment goals
Risk LDL-C Non-HDL-C Apo B
category Risk factorsa/10-year riskb (mg/dL) (mg/dL) (mg/dL)
Extreme risk – Progressive ASCVD including unstable angina in102 2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1)
atherogenic cholesterol particles (primarily LDL-C) and with an ASCVD event relative risk reduction trend of
the risk of ASCVD events (221), some residual risk will 42% (235).
remain (222). Data from several studies have shown that • The highly selective BAS colesevelam increases
even when LDL-C reaches an optimal level (20th percen- hepatic bile acid production by increasing elimination
tile), non-HDL-C, apo B, and LDL-P levels can remain of bile acids, thereby decreasing hepatic cholesterol
suboptimal (223). Furthermore, statin intolerance (usually stores. This leads to an upregulation of LDL recep-
muscle-related adverse effects) can limit the use of inten- tors; a reduction in LDL-C, non-HDL-C, apo B, and
sive statin therapy in some patients (224). LDL-P; and improved glycemic status. There is a
Other lipid-modifying agents should be utilized in small compensatory increase in de novo cholesterol
combination with maximally tolerated statins when ther- biosynthesis, which can be suppressed by the addition
apeutic levels of LDL-C, non-HDL-C, apo B, or LDL-P of statin therapies (236-238). Additionally, BAS cole-
have not been reached: sevelam may worsen hypertriglyceridemia (239).
• Ezetimibe inhibits intestinal absorption of cholesterol, • Fibrates have only small effects on lowering athero-
reduces chylomicron production, decreases hepatic genic cholesterol (5%) and are used mainly for lower-
cholesterol stores, upregulates LDL receptors, and ing triglycerides. By lowering triglycerides, fibrates
lowers apo B, non-HDL-C, LDL-C, and triglycerides unmask residual atherogenic cholesterol in triglyc-
(225). In IMPROVE-IT, the relative risk of ASCVD eride-rich remnants (i.e., very low density lipopro-
was reduced by 6.4% (P = .016) in patients taking tein cholesterol [VLDL-C]). In progressively higher
simvastatin plus ezetimibe for 7 years (mean LDL-C: triglyceride settings, as triglycerides decrease, LDL-C
54 mg/dL) compared to simvastatin alone (LDL-C: 70 increases, thus exposing the need for additional lipid
mg/dL). The ezetimibe benefit was almost exclusively therapies. As monotherapy, fibrates have demonstrat-
noted in the prespecified diabetes subgroup, which ed significantly favorable outcomes in populations
comprised 27% of the study population and in which with high non-HDL-C (240) and low HDL-C (241).
the relative risk of ASCVD was reduced by 14.4% (P The addition of fenofibrate to statins in the ACCORD
= .023) (209). study showed no benefit in the overall cohort in which
• Monoclonal antibody inhibitors of proprotein conver- mean baseline triglycerides and HDL-C were within
tase subtilisin-kexin type 9 serine protease (PCSK9), normal limits (242). Subgroup analyses and meta-
a protein that regulates the recycling of LDL recep- analyses of major fibrate trials, however, have shown
tors, have recently been approved by the FDA for a relative risk reduction for CVD events of 26 to 35%
primary prevention in patients with hetero- and homo- among patients with moderate dyslipidemia (triglycer-
zygous familial hypercholesterolemia (HeFH and ides >200 mg/dL and HDL-C2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1) 103
levels and those with metabolic syndrome (253). As ACKNOWLEDGMENT
a result, it is particularly important to closely monitor
glycemia in individuals with diabetes or prediabetes Amanda M. Justice, BA, provided editorial support
who are not receiving glucose-lowering treatment and and medical writing assistance in the preparation of
taking niacin. this document.
• Dietary intake of fish and omega-3 fish oil is associated
with reductions in the risks of total mortality, sudden DISCLOSURES
death, and CAD through various mechanisms of
action other than lowering of LDL-C. In a large clini- Dr. Alan J. Garber reports that he is a consultant for
cal trial, highly purified, prescription-grade, moderate- Novo Nordisk and Intarcia.
dose (1.8 g) eicosapentaenoic acid (EPA) added to a Dr. Martin Julian Abrahamson reports that he is a
statin regimen was associated with a significant 19% consultant for Novo Nordisk, and WebMD Health Services.
reduction in risk of any major coronary event among Dr. Joshua I. Barzilay reports that he does not
Japanese patients with elevated total cholesterol have any relevant financial relationships with any
(254) and a 22% reduction in CHD in patients with commercial interests.
impaired fasting glucose or T2D (255). Among those Dr. Lawrence Blonde reports that he is a consul-
with triglycerides >150 mg/dL and HDL-C 50% LDL-C and Novartis.
lowering), drugs such as ezetimibe, BASs, fibrates, and Dr. Michael A. Bush reports that he is a consultant for
niacin have lesser LDL-C–lowering effects (7 to 20%) Janssen and AstraZeneca. He is also a speaker for Eli Lilly,
and ASCVD reduction (259). However, these agents can Novo Nordisk, Janssen, AstraZeneca, and Boehringer
significantly lower LDL-C when utilized in various combi- Ingelheim.
nations, either in statin-intolerant patients or as add-on to Dr. Samuel Dagogo-Jack reports that he is a consul-
maximally tolerated statins. Triglyceride-lowering agents tant for Merck, Janssen, AstraZeneca, and Sanofi. He owns
such as prescription-grade omega-3 fatty acids, fibrates, stock with Dance Pharma and Janacare. He has also received
and niacin are important agents that expose the athero- research grant support to the University of Tennessee from
genic cholesterol within triglyceride-rich remnants, which AstraZeneca, Novo Nordisk, and Boehringer Ingelheim.
require additional cholesterol lowering. PCSK9 inhibitors Dr. Ralph A. DeFronzo reports that he is a consultant
are currently indicated for adult patients with HeFH or for Boehringer Ingelheim, AstraZeneca, Novo Nordisk,
HoFH or clinical ASCVD as an adjunct to a lipid manage- Janssen, Intarcia, and Elcelyx. He is a speaker for Novo
ment meal plan and maximally tolerated statin therapy, who Nordisk, AstraZeneca, and Merck. He has also received
require additional LDL-C lowering. Patients with diabetes grant research support from Bristol Myers Squibb,
and characteristics consistent with ASCVD risk equiva- Boehringer Ingelheim, Janssen, and AstraZeneca.
lents are not currently candidates in the United States. Dr. Daniel Einhorn reports that he is a consul-
If triglyceride levels are severely elevated (>500 tant for Lilly, Novo Nordisk, Sanofi, Takeda, Halozyme,
mg/dL), begin treatment with a very low-fat meal plan AstraZeneca, Adocia, Epitracker, GlySens, and Janssen.
and reduced intake of simple carbohydrates and initiate He is a speaker for Abbott. He owns stock with Halozyme
combinations of a fibrate, prescription-grade omega-3-fat- and has options with Nexus BioPharma, Epitracker, and
ty acid, and/or niacin to reduce triglyceride levels and to GlySens. He has also received research grant support from
prevent pancreatitis. While no large clinical trials have Novo Nordisk, Lilly, AstraZeneca, Janssen, and Sanofi.
been designed to test this objective, observational data Dr. Vivian A. Fonseca reports that he is a consultant
and retrospective analyses support long-term dietary and for Takeda, Novo Nordisk, Eli Lilly, Pamlab, AstraZeneca,
lipid management of hypertriglyceridemia for prophylaxis Abbott, Boehringer Ingelheim, Janssen, Intarcia, and Ashi
against or treatment of acute pancreatitis (260,261). Pharmaceuticals. He is a speaker for Sanofi and Takeda.104 2018 AACE/ACE T2D Management, Endocr Pract. 2018;24(No. 1)
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