April 2017 Page 1 of 34

VA/DoD CLINICAL PRACTICE GUIDELINE FOR 

THE MANAGEMENT OF TYPE 2 DIABETES 

MELLITUS IN PRIMARY CARE

Department of Veterans Affairs

Department of Defense

Clinician Summary

QUALIFYING STATEMENTS

The Department of Veterans Affairs and the Department of Defense guidelines are based upon the best 

information available at the time of publication. They are designed to provide information and assist 

decision-making. They are not intended to define a standard of care and should not be construed as one. 

Neither should they be interpreted as prescribing an exclusive course of management.

This Clinical Practice Guideline is based on a systematic review of both clinical and epidemiological 

evidence. Developed by a panel of multidisciplinary experts, it provides a clear explanation of the logical 

relationships between various care options and health outcomes while rating both the quality of the 

evidence and the strength of the recommendations.

Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of 

individual patients, available resources, and limitations unique to an institution or type of practice. Every 

healthcare professional making use of these guidelines is responsible for evaluating the appropriateness of 

applying them in the setting of any particular clinical situation. 

These guidelines are not intended to represent Department of Veterans Affairs or TRICARE policy. Further, 

inclusion of recommendations for specific testing and/or therapeutic interventions within these guidelines 

does not guarantee coverage of civilian sector care. Additional information on current TRICARE benefits 

may be found at www.tricare.mil or by contacting your regional TRICARE Managed Care Support 

Contractor. 

Version 5.0 – 2017
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April 2017 Page 2 of 34

Table of Contents

I. Introduction .................................................................................................................................. 3

II. Background................................................................................................................................... 3

A. Description of Diabetes Mellitus...................................................................................................... 3

B. Epidemiology and Impact................................................................................................................. 5

III. Scope of this CPG........................................................................................................................... 6

IV. Shared Decision-making and Patient-centered Care ...................................................................... 6

V. Guideline Work Group................................................................................................................... 8

VI. Algorithm...................................................................................................................................... 9

A. Module A: General Care and Treatment........................................................................................10

B. Module B: Diabetes Self-Management Education ........................................................................11

VII. Recommendations ...................................................................................................................... 12

VIII. Glycemic Control Targets and Monitoring.................................................................................... 14

IX. Pharmacological Therapy ............................................................................................................ 15

X. Methods...................................................................................................................................... 29

A. Strength of Recommendations ......................................................................................................29

B. Recommendation Categorization...................................................................................................31

References ............................................................................................................................................ 33
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I. Introduction

The Department of Veterans Affairs (VA) and Department of Defense (DoD) Evidence-Based Practice Work 

Group (EBPWG) was established and first chartered in 2004, with a mission to advise the “...Health 

Executive Council on the use of clinical and epidemiological evidence to improve the health of the 

population across the Veterans Health Administration and Military Health System,” by facilitating the 

development of clinical practice guidelines for the VA and DoD populations.[1] This clinical practice 

guideline (CPG) is intended to provide healthcare providers with a framework by which to evaluate, treat, 

and manage the individual needs and preferences of patients with diabetes mellitus (DM), thereby leading 

to improved clinical outcomes.

The first VA/DoD CPG for the Management of Diabetes Mellitus, based upon earlier iterations in 1997 and 

2000, was published in 2003.[2] It established a risk stratification approach for setting individualized target 

goals based upon life expectancy, comorbid conditions, patient preferences, and absolute benefits and 

potential risks of therapy.[2] It also emphasized the risks of hypoglycemia. In 2010, the VA and DoD 

published a CPG for the Management of Diabetes Mellitus (2010 DM CPG), which was based on evidence 

reviewed through June 2009. Since the release of that guideline, a growing body of research has expanded 

the general knowledge and understanding of DM. Follow-up of major clinical trials of intensive therapy, as 

well as advances in physiological, behavioral, nutritional, and pharmacological research have led to the 

emergence of new strategies to manage and treat patients with DM.

Consequently, a recommendation to update the 2010 DM CPG was made and the update to the 2010 

DM CPG was initiated in 2015. The updated CPG includes evidence-based recommendations and 

additional information on the management of DM. It is intended to assist healthcare providers in all 

aspects of patient care, including diagnosis, treatment, and follow-up. The system-wide goal of 

evidence-based guidelines is to improve the patient’s health and well-being by guiding health providers, 

especially in primary care, to the management pathways that are supported by evidence. The expected 

outcome of successful implementation of this guideline is to:

• Emphasize shared decision-making to establish patient goals

• Assess the patient’s situation and determine, in collaboration with the patient, the treatment

methods to achieve the goals.

• Reduce the risk of preventable complications while improving quality of life (QoL).

II. Background

A. Description of Diabetes Mellitus

Diabetes mellitus is a disease caused by an absolute or relative insulin deficiency resulting in

hyperglycemia. Type 1 DM (T1DM) is due to insulin secretion deficiency not resulting from insulin 

resistance, while type 2 DM (T2DM) is due to insulin resistance that can eventually also result in insulin 

secretion deficiency. The insulin resistance resulting in T2DM is thought to be due to excess adiposity, 

especially central distribution of adiposity, but can be due to other factors, such as corticosteroid 

treatment or Cushing’s syndrome. Gestational diabetes (GDM) is DM present during pregnancy. Other 
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more unusual types of DM also exist, such as maturity onset diabetes of the young (MODY), latent 

autoimmune diabetes of adult (LADA) and those related to pancreatic disease or acromegaly, but the 

current guideline is focused on T2DM.

Several criteria exist to diagnose T2DM and prediabetes based on biomarker levels. The criteria used by 

this Work Group are summarized in Table 1. Prediabetes is a condition where blood glucose levels are 

higher than normal but the patient does not meet the criteria for DM.[3] Hyperglycemia not sufficient to 

meet the diagnostic criteria for DM has historically been categorized as either impaired fasting glucose 

(IFG), or impaired glucose tolerance (IGT) depending on the methodology through which it is identified. 

The use of hemoglobin A1c (HbA1c) in the diagnosis of diabetes is derived from a study of the linear 

relationship between HbA1c values and microvascular complications, specifically retinopathy, with the 

diagnostic level occurring at the inflection point of rise in incidence. However, differences among 

laboratories in the acceptable variability of HbA1c test values, as well as evidence suggesting that there 

may be racial/ethnic differences, suggests that reliance upon HbA1c test results alone are not congruent 

with fasting blood glucose levels.[4,5] Racial differences were reported among participants in the 

Diabetes Prevention Program. Despite having comparable measures of glycemia, African Americans had 

significantly higher HbA1c levels (6.2%) than Whites (5.8%).[6] The VA/DoD DM CPG recommends that 

HbA1c values between 6.5%-7.0% be confirmed with fasting plasma glucose levels to improve diagnostic 

specificity. 

Table 1: Criteria for the diagnosis of diabetes mellitus and prediabetes [6] 

Status Fasting Plasma Glucose 1,2 or Hemoglobin A1c 3

Diabetes Mellitus

FPG ≥ 126 mg/dL (7.0 mmol/L) on two occasions

OR

HbA1c ≥ 6.5% with a confirmatory FPG ≥ 126 mg/dL (7.0 mmol/L)

OR

HbA1c ≥ 7.0% on two occasions

Prediabetes

FPG ≥ 100 mg/dL and < 126 mg/dL on two occasions

OR

HbA1c ≥ 5.7% and FPG ≥ 100 mg/dL and < 126 mg/dL (7.0 mmol/L)

OR

2-hr plasma glucose 140-199 mg/dL (7.8-11.0 mmol/L) (IGT)

Normal FPG < 100 mg/dL

HbA1c < 5.7%

Abbreviations: dL: deciliter; FPG: fasting plasma glucose; HbA1c: hemoglobin A1c; hr: hour; IGT: impaired glucose tolerance; 

L: liter; mg: milligram; mmol: millimole 

1 Fasting is defined as no caloric intake for at least eight hours. 

2 FPG is the preferred test for diagnosis, but either of the two listed is acceptable. In the absence of unequivocal hyperglycemia 

with acute metabolic decompensation, one of these two tests should be done on different days.

3 Using a clinical laboratory (not a point-of-care) methodology standardized to the National Glycohemoglobin Standardization 

Program (NGSP)

An oral glucose tolerance testing (OGTT) is most commonly done to diagnose gestational diabetes. 
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Patients with one or more of the following risk factors are at higher risk for T2DM: 

• Age ≥ 45 years

• Family history (first-degree relative with DM)

• Member of a high-prevalence population (e.g., African American, Hispanic American, Native

American, Asian American, Pacific Islander)

• Prediabetes (HbA1c ≥ 5.7% [39 mmol/mol], fasting blood glucose 100-125 mg/dl IGT [7], or IFG 

on previous testing)

1

• Hypertension (blood pressure ≥ 140/90 mmHg or on therapy for hypertension)

1

• High-density lipoprotein cholesterol (HDL-C) level < 35 mg/dL (0.90 mmol/L) and/or a triglyceride

(TG) level > 250 mg/dL (2.82 mmol/L)1

• History of cardiovascular disease (CVD)1

• Overweight (body mass index [BMI] ≥ 25 kg/m2 or ≥ 23 kg/m2 in Asian Americans)

1

• Abdominal obesity1

• Women with polycystic ovary syndrome (PCOS)1

• History of GDM or history of delivering babies weighing > 9 lbs (about 4 kg)

• Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis

nigricans)

• Physical inactivity/sedentary lifestyle

• Patients using antipsychotics or statins

B. Epidemiology and Impact

The prevalence of diabetes is increasing around the world, mostly due to the increase in obesity and 

sedentary lifestyles.[8] The number of Americans with diagnosed DM has increased four-fold between 

1980 and 2014.[9] In the United States (U.S.), a total of 29.1 million people, or 9.3% of the population, 

have DM (type 1 or type 2), of which 21 million are diagnosed and 8.1 million are undiagnosed.[10]

In the military population enrolled in the Military Health System (MHS), the prevalence of diagnosed DM 

ranged from 7.3% to 11.2% in 2006 and from 8.3% to 13.6% in 2010.[11] Although the prevalence among 

Active Duty Service Members remained stable, a significant increase was observed over time among NonActive Duty Service Members.[11] In 2010, the prevalence among Non-Active military men and women 

were 15.0% and 13.3% respectively for those aged 45-64 years, 32.9% and 26.9% respectively for those 

aged 65-74 years, and 31.5% and 25.7% respectively for those aged 75 years and older.[11]According to 

the Veterans Health Administration (VHA), nearly one in four Veterans (1.6 million individuals) who are 

receiving care from the VA has DM. Veterans 65 years and older comprise 70% of those with diabetes, 

reflecting the older age distribution of this population.[12]

 1 Associated with insulin resistance
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DM can cause microvascular complications such as retinopathy, nephropathy, and neuropathy as well as 

macrovascular complications, including ischemic heart disease, stroke, and peripheral vascular disease.[13] 

In addition to the complications of T2DM, conditions such as chronic obstructive pulmonary disease 

(COPD), substance use disorder (SUD), and depression can affect the management of DM. For guidance on 

how to address those comorbidities, see the respective VA/DoD Clinical Practice Guidelines for the 

Management of COPD, SUD and Major Depressive Disorder (MDD).2,3,4 DM is a major cause of morbidity 

and mortality in the U.S. It is associated with a two-fold to four-fold increased risk for atherosclerotic CVD, 

resulting in substantial morbidity and mortality from coronary events. For the management of CVD risk 

factors, refer to the VA/DoD Clinical Practice Guidelines for the Management of Hypertension, Chronic 

Kidney Disease (CKD), and Dyslipidemia.5,6,7 The total costs of diagnosed DM in the U.S. were $245 billion 

in 2012, including $176 billion for direct medical costs and $69 billion in reduced productivity.[14] Direct 

costs in the VHA and MHS are not known.

III. Scope of this CPG

This CPG is designed to assist providers in managing or co-managing patients with T2DM. Moreover, the 

patient population of interest for this CPG is adults who are eligible for care in the VA and DoD healthcare

delivery systems, which includes Veterans, deployed and non-deployed Active Duty Service Members, and 

their adult family members, and retirees and their beneficiaries or dependents. This CPG does not provide 

recommendations for the management of DM in children, adolescents, or pregnant/nursing women. 

IV. Shared Decision-making and Patient-centered Care

Throughout this VA/DoD CPG, the authors encourage clinicians to focus on shared decision-making (SDM). 

The SDM model was introduced in Crossing the Quality Chasm, an Institute of Medicine (now the National 

Academy of Medicine) report, in 2001.[15] It is readily apparent that patients with DM, together with their 

clinicians, make decisions regarding their plan of care and target glycemic range; however, these patients 

require sufficient information to be able to make informed decisions. Clinicians must be skilled at 

presenting their patients with understandable and actionable information regarding both individual 

treatments and levels and locations of care. 

Therefore, the VA/DoD CPG recommendations are intended to promote SDM and be patient-centered. 

VA/DoD CPGs encourage clinicians to use SDM to individualize treatment goals and plans based on patient 

capabilities, needs, goals, prior treatment experience, and preferences. Good communication between 

2 See the VA/DoD Clinical Practice Guideline for the Management of Chronic Obstructive Pulmonary Disease (COPD). Available 

at: http://www.healthquality.va.gov/guidelines/CD/copd/

3 See the VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders (SUD). Available at: 

http://www.healthquality.va.gov/guidelines/MH/sud/

4 See the VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder (MDD). Available at: 

http://www.healthquality.va.gov/guidelines/MH/mdd/

5 See the VA/DoD Clinical Practice Guideline for the Diagnosis and Management of Hypertension in Primary Care. Available at: 

http://www.healthquality.va.gov/guidelines/CD/htn/

6 See the VA/DoD Clinical Practice Guideline for the Management of Chronic Kidney Disease in Primary Care (CKD). Available at: 

http://www.healthquality.va.gov/guidelines/CD/ckd/

7 See the VA/DoD Clinical Practice Guideline for the Management of Dyslipidemia for Cardiovascular Risk Reduction. Available at: 

http://www.healthquality.va.gov/guidelines/CD/lipids/
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healthcare professionals and the patient is essential and should be supported by evidence-based 

information tailored to the patient’s needs. Use of an empathetic and non-judgmental (versus a 

confrontational) approach facilitates discussions sensitive to gender, culture, and ethnic differences. The 

information that patients are given about treatment and care should be culturally appropriate and also 

available to people with limited literacy skills. It should also be accessible to people with additional needs 

such as physical, sensory, or learning disabilities. Family involvement should be considered if appropriate, 

especially in elderly patients.[16] When properly executed, SDM [17,18] may decrease patient anxiety, 

increase trust in clinicians,[19] and improve treatment adherence.[20] Improved patient-clinician 

communication can be used to convey openness to discuss any future concerns. 

As part of the patient-centered care approach, clinicians should review the outcomes of previous selfchange efforts, past treatment experiences, and outcomes (including reasons for treatment drop-out) with 

the patient. Lastly, they should involve the patient in prioritizing problems to be addressed and in setting 

specific goals regardless of the selected setting or level of care.
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V. Guideline Work Group

Guideline Work Group

Department of Veterans Affairs Department of Defense

Leonard Pogach, MD, MBA, FACP (Champion) Maj Jeffrey A. Colburn, MD, FACP (Champion)

David C. Aron, MD, MS Elizabeth Rees Atayde, RN, MSN, FNP, CCM, CPHM

Paul R. Conlin, MD Amy M. Lugo, PharmD, BCPS, BC-ADM, FAPhA

Mercedes Falciglia, MD, FACP Susan McReynolds, RD, CDE

Chester B. Good, MD, MPH, FACP Maj Tracy L. Snyder, MS, RD

Mary M. Julius, RDN, CDE Evan N. Steil, MD, MBA, MHA

Deborah Khachikian, PharmD Elaine P. Stuffel, RN, BSN, MHA

Rose Mary Pries, DrPH COL Gwendolyn H. Thompson, PharmD

Sharon A. Watts, DNP, FNP-BC, CDE LCDR Mark P. Tschanz, DO, MACM, FACP

Nina A. Watson, MSN, RN, CDE

Office of Quality, Safety and Value

Veterans Health Administration

Office of Evidence Based Practice

U.S. Army Medical Command

Eric Rodgers, PhD, RNP-BC

James L. Sall, PhD, FNP-BC

Rene Sutton, BS, HCA

Corinne K. B. Devlin, MSN, RN, FNP-BC

Elaine P. Stuffel, RN, BSN, MHA

Lewin Group ECRI Institute

Clifford Goodman, PhD

Christine Jones, MS, MPH, PMP

Raksha Adhikari, MSPH, CPH

Nicolas Stettler-Davis, MD, MSCE

Kristen E. D’Anci, PhD

Jane S. Jue, MD

Nancy M. Sullivan, BA

Edmond Baganizi, MPH

Oluwasean Akinyede, MPH

Eileen Erinoff, MSLIS

Sigma Health Consulting, LLC Duty First Consulting

Frances Murphy, MD, MPH Megan McGovern, BA

Anita Ramanathan, BA
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VI. Algorithm

This CPG includes an algorithm which is designed to facilitate understanding of the clinical pathway and 

decision-making process used in management of DM. The use of the algorithm format as a way to 

represent patient management was chosen based on the understanding that such a format may 

promote more efficient diagnostic and therapeutic decision making and has the potential to change 

patterns of resource use. Recognizing that some clinical care processes are non-linear, the algorithm 

format allows the provider to follow a simplified linear approach in assessing the critical information 

needed at the major decision points in the clinical process, and includes:

• An ordered sequence of steps of care

• Relevant observations and examinations

• Decisions for consideration

• Actions to be taken

A clinical algorithm diagrams a guideline into a step-by-step decision tree. Standardized symbols are 

used to display each step in the algorithm and arrows connect the numbered boxes indicating the order 

in which the steps should be followed.[21] 
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A. Module A: General Care and Treatment

Abbreviations: T2DM: Type 2 diabetes mellitus

*For sequential treatment of DM, see Figure 1

†Target range incorporates the known variation in the HbA1c test from the laboratory used by the patient

^Use the Teach-Back Method: Tool #5. Content last reviewed February 2015. Agency for Healthcare Research and Quality, Rockville, MD. 

http://www.ahrq.gov/professionals/quality-patient-safety/quality-resources/tools/literacy-toolkit/healthlittoolkit2-tool5.html
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B. Module B: Diabetes Self-Management Education 
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VII. Recommendations

The following recommendations were made based on a systematic evidence review and consideration 

of four decision domains as per the Grading of Recommendations Assessment, Development and 

Evaluation (GRADE) approach as detailed in the section on Methods. These domains include: confidence 

in the quality of the evidence, balance of desirable and undesirable outcomes (i.e., benefits and harms), 

patient or provider values and preferences, and other implications, as appropriate (e.g., resource use, 

equity, acceptability).

# Recommendation Strength Category

A. General Approach to T2DM Care

1. We recommend shared decision-making to enhance patient knowledge and 

satisfaction.

Strong for Reviewed, 

New-added

2. We recommend that all patients with diabetes should be offered ongoing 

individualized diabetes self-management education via various modalities 

tailored to their preferences, learning needs and abilities based on available 

resources.

Strong for Reviewed, 

New-replaced

3. We suggest offering one or more types of bidirectional telehealth interventions 

(typically health communication via computer, telephone or other electronic 

means) involving licensed independent practitioners to patients selected by 

their primary care provider as an adjunct to usual patient care.

Weak for Reviewed, 

New-replaced

B. Glycemic Control Targets and Monitoring

4. We recommend setting an HbA1c target range based on absolute risk 

reduction of significant microvascular complications, life expectancy, patient 

preferences and social determinants of health.

Strong for Reviewed, 

New-added

5. We recommend developing an individualized glycemic management plan, 

based on the provider’s appraisal of the risk-benefit ratio and patient 

preferences.

Strong for Reviewed, 

Amended

6. We recommend assessing patient characteristics such as race, ethnicity, 

chronic kidney disease, and non-glycemic factors (e.g., laboratory 

methodology and assay variability) when interpreting HbA1c, fructosamine 

and other glycemic biomarker results.

Strong for Reviewed, 

New-added

7. We recommend an individualized target range for HbA1c taking into account 

individual preferences, presence or absence of microvascular complications, 

and presence or severity of comorbid conditions (See Table 2).

Strong for Reviewed, 

New-replaced

8. We suggest a target HbA1c range of 6.0-7.0% for patients with a life 

expectancy greater than 10-15 years and absent or mild microvascular 

complications, if it can be safely achieved (See Table 2).

Weak for Reviewed, 

New-replaced

9. We recommend that in patients with type 2 diabetes, a range of HbA1c 7.0-

8.5% is appropriate for most individuals with established microvascular or 

macrovascular disease, comorbid conditions, or 5-10 years life expectancy, if 

it can be safely achieved (See Table 2).

Strong for Reviewed, 

New-added

10. We suggest a target HbA1c range of 8.0-9.0% for patients with type 2 

diabetes with life expectancy <5 years, significant comorbid conditions, 

advanced complications of diabetes, or difficulties in self-management 

attributable to e.g., mental status, disability or other factors such as food 

insecurity and insufficient social support. (See Table 2).

Weak for Reviewed, 

New-replaced

11. We suggest that providers be aware that HbA1c variability is a risk factor for 

microvascular and macrovascular outcomes.

Weak for Reviewed, 

New-added
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# Recommendation Strength Category

C. Non-pharmacological Treatments

12. We recommend offering therapeutic lifestyle changes counseling that

includes nutrition, physical activity, cessation of smoking and excessive use of

alcohol, and weight control to patients with diabetes (See VA/DoD CPGs for 

obesity, substance use disorders, and tobacco use cessation). 

Strong for Not Reviewed, 

Amended

13. We recommend a Mediterranean diet if aligned to patient’s values and 

preferences.

Strong for Reviewed, 

New-added

14. We recommend a nutrition intervention strategy reducing percent of energy 

from carbohydrate to 14-45% per day and/or foods with lower glycemic index 

in patients with type 2 diabetes who do not choose the Mediterranean diet. 

Strong for Reviewed, 

New-added

D. Inpatient Care

15. We recommend against targeting blood glucose levels <110 mg/dL for all 

hospitalized patients with type 2 diabetes receiving insulin.

Strong 

against

Reviewed, 

Amended

16. We recommend insulin be adjusted to maintain a blood glucose level 

between 110 and 180 mg/dL for patients with type 2 diabetes in critically ill 

patients or those with acute myocardial infarction.

Strong for Reviewed, 

Amended

17. We recommend against the use of split mixed insulin regimen for all 

hospitalized patients with type 2 diabetes.

Strong 

against

Reviewed, 

New-added

18. We suggest a regimen including basal insulin and short-acting meal time or 

basal insulin and correction insulin for non-critically ill hospitalized patients 

with type 2 diabetes.

Weak for Reviewed, 

New-added

19. We suggest providing medication education and diabetes survival skills to 

patients before hospital discharge.

Weak for Reviewed, 

Amended

E. Selected Complications and Conditions

20. We recommend performing a comprehensive foot risk assessment annually. Strong for Not Reviewed, 

Amended

21. We recommend referring patients with limb-threatening conditions to the 

appropriate level of care for evaluation and treatment.

Strong for Not Reviewed, 

Amended

22. We recommend a retinal examination (e.g., dilated fundus examination by an 

eye care professional or retinal imaging with interpretation by a qualified, 

experienced reader) be used to detect retinopathy. 

Strong for Not Reviewed, 

Amended

23. We suggest screening for retinopathy at least every other year (biennial 

screening) for patients who have had no retinopathy on all previous 

examinations. More frequent retinal examinations in such patients should be 

considered when risk factors associated with an increased rate of progression 

of retinopathy are present. Patients with existing retinopathy should be 

managed in conjunction with an eye care professional and examined at 

intervals deemed appropriate for the level of retinopathy.

Weak for Not Reviewed, 

Amended

24. We recommend that all females with pre-existing diabetes or personal 

history of diabetes and who are of reproductive potential be provided 

contraceptive options education and education on the benefit of optimizing 

their glycemic control prior to attempting to conceive.

Strong for Not Reviewed, 

Amended

25. We recommend that all females with pre-existing diabetes or personal 

history of diabetes who are planning pregnancy be educated about the safest

options of diabetes management during the pregnancy and referred to a 

maternal fetal medicine provider (when available) before, or as early as 

possible, once pregnancy is confirmed. 

Strong for Not Reviewed, 

Amended
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VIII. Glycemic Control Targets and Monitoring

Setting HbA1c target levels with patients is often the major treatment goal in the management of T2DM. 

Table 2 provides general guidance for target ranges, based on patient’s comorbidities and life expectancy 

that are consistent with Recommendations 7-10. 

Table 2: Determination of average target HbA1c level over time 1,2,3,4,5,12

Major Comorbidity6 or 

Physiologic Age

Microvascular Complications

Absent or Mild 7 Moderate 8 Advanced 9

Absent*

> 10-15 years of life expectancy 6.0-7.0%† 7.0-8.0% 7.5-8.5%‡

Present 10

5-10 years of life expectancy 7.0-8.0%† 7.5-8.5% 7.5-8.5%‡

Marked 11

<5 years of life expectancy 8.0-9.0%‡ 8.0-9.0%‡ 8.0-9.0%‡

*Progression to major complications of diabetes is likely to occur in individuals with longer than 15-20 years of life expectancy.

Therefore, goal ranges are more beneficial early in disease in younger individuals, or healthier older adults with a longer life 

expectancy.

†Without significant side effects, including but not limited to hypoglycemia.

‡Further reductions may be appropriate, balancing safety and tolerability of therapy. 

HbA1c laboratory considerations:

1 Based upon the NGSP reference standard. Clinicians need to obtain information regarding the coefficient of variation (CV)

from the methodology used at their site. As an example, an HbA1c of 8.0% from a laboratory with a CV of 3% would be within 

a 7.76-8.24% range 13 out of 20 times (1 standard deviation), and would be between a 7.53-8.47% range 19 out of 20 times (2 

standard deviations).

2 The HbA1c range reflects an “HbA1c average goal” over time. Intensification or relaxation of therapy should be undertaken

based upon individual clinical circumstances and treatment options. 

3 A medication change in response to a single HbA1c test that encompasses the "goal" is discouraged, especially if it is 

discordant with self-monitoring of blood glucose (SMBG) results. 

4 African Americans, on average, have higher HbA1c levels than Whites and this difference cannot be explained by measured 

differences in glycemia. Caution is recommended in changing medication therapy based upon HbA1c results, especially for 

patients on insulin therapy, without correlation with SMBG results.

5 For all of the above reasons, the VA/DoD DM CPG does not recommend the use of estimated average glucose.

Comorbid illness considerations: 

6 Major comorbidity includes, but is not limited to, any or several of the following active conditions: significant CVD, severe CKD, 

severe COPD, severe chronic liver disease, recent stroke, and life-threatening malignancy.

7 Mild microvascular disease is defined by early background retinopathy, and/or microalbuminuria, and/or mild neuropathy.

8 Moderate microvascular disease is defined by pre-proliferative (without severe hemorrhage, intra-retinal microvascular 

anomalies [IRMA], or venous bleeding) retinopathy or persistent, fixed proteinuria (macroalbuminuria), and/or demonstrable 

peripheral neuropathy (sensory loss).

9 Advanced microvascular disease is defined by severe non-proliferative (with severe hemorrhage, IRMA, or venous bleeding), 

or proliferative retinopathy and/or renal insufficiency (serum creatinine level > 2.0 mg/dL), and/or insensate extremities or

autonomic neuropathy (e.g., gastroparesis, impaired sweating, orthostatic hypotension).

10 Major comorbidity is present, but is not end-stage and management is achievable.

11 Major comorbidity is present and is either end-stage or management is significantly challenging. This can include mental 

health conditions and substance/opioid use.

Social determinant considerations:

12 Social determinants of health, including social support, ability to self-monitor on insulin, food insufficiency, and cognitive 

impairment need to be considered. Additionally, side effects of medications and patient preferences need to be considered in 

a process of shared decision-making.
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IX. Pharmacological Therapy

When individualized glycemic goals are not achieved with nonpharmacological therapy such as diet

and physical activity, adjunctive therapy with medications is indicated (see Recommendation 5). The 

magnitude of the reduction in HbA1c necessary to achieve goals should be considered when choosing 

medications and when assessing hypoglycemia risk, weight gain, patient preferences, administration 

burden, and cost (see Recommendations 4 and 7). 

For treatment of DM in obese patients, see the VA/DoD Obesity CPG.

8

Considerations 

The evidence for pharmacological treatment options for T2DM was not systematically reviewed as part 

of this guideline update; therefore, formal recommendations could not be made. The rationale to not 

systematically review the evidence for pharmacotherapy was that the evidence in this area is rapidly 

evolving and therefore any recommendations made may be outdated during the lifetime of this 

guideline. In lieu of recommendations, the following considerations are offered based on usual care and 

recent SRs performed by other groups. Where applicable, users of this guideline are asked to refer to 

their respective agencies for guidance/criteria on the use of pharmacotherapy for T2DM that are based 

on the most current evidence. 

The following considerations are based on usual care and SRs performed by other groups: 

1. When selecting an agent, consideration must be given to efficacy, contraindications, drug 

interactions, comorbidities, and potential side effects. Discuss with patients the various treatment 

options and arrive at a shared treatment plan.

2. Insulin should be considered as initial therapy in any patient with hyperglycemia with significant 

symptoms, if ketosis is present, and in newly diagnosed or previously unrecognized T1DM. 

3. Metformin should be given as the first-line agent unless there are contraindications.

4. In patients with metformin intolerance or contraindications, other drug classes can be 

considered. These include (not in order of preference): alpha-glucosidase inhibitors (AGIs), 

dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, insulin, 

meglitinides, sodium glucose co-transporter 2 (SGLT2) inhibitors, sulfonylureas (SU), and 

thiazolidinediones (TZDs).

5. When initial therapy no longer provides adequate glycemic control, addition of a second-line 

agent from another class rather than substitution is usually necessary. Substitution can be 

reserved for intolerance/adverse effect to a drug. Combination of two anti-hyperglycemic drugs 

has the benefit of reducing hyperglycemia by working on different mechanisms that cause 

hyperglycemia (refer to Figure 1). Some agents are not generally used in combination or have not

been studied in combination (refer to Table 14). Although the evidence is clear on the relative 

efficacy of the various medications, their usage needs to be guided by clinical considerations. 

 8 See the VA/DoD Clinical Practice Guideline for Screening and Management of Overweight and Obesity. Available at: 

http://www.healthquality.va.gov/guidelines/CD/obesity/
VA/DoD Clinical Practice Guideline for the Management of Type 2 Diabetes Mellitus in Primary Care

April 2017 Page 16 of 34

6. Addition of basal insulin to existing regimen should be considered, particularly if the desired 

decrease in HbA1c is not likely to be achieved by use of combination therapy. 

7. Patients and their families should be instructed to recognize and confirm their understanding of 

signs and symptoms of hypoglycemia and its management.

8. Given that new studies and FDA alerts will be published subsequent to the release of this 

guideline, clinicians should refer to the criteria for use published by the VA Pharmacy Benefits 

Management program (VA PBM) and the Department of Defense Pharmacy and Therapeutics 

Committee (DoD P&T).

Figure 1: Sequential Treatment of Type 2 Diabetes*

Abbreviations: DPP-4: dipeptidyl peptidase-4; DSME: diabetes self-management and education; GLP-1: glucagon-like peptide-1; 

SGLT2: sodium glucose co-transporter 2

*Bile acid sequestrants, bromocriptine quick release, and pramlintide are uncommonly used agents in the management of diabetes 

and are not included in this guideline.

†Consider a trial of metformin extended-release in those with persistent adverse gastrointestinal effects from metformin 

immediate-release

†Second-line agentslisted alphabetically; not in order of preference ‡If applicable, refer to VA (http://www.pbm.va.gov/) or DoD (http://www.health.mil/PandT) guidance/criteria for further

recommendations on use of these agents.
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April 2017 Page 17 of 34 

Table 3: Alpha-glucosidase inhibitors

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact 

on 

Weight Clinical Considerations

Adverse 

Events/Side Effects Cost

Acarbose

Miglitol

0.5 - 1% Low Weight 

neutral

 Administer at the start of each main meal

 Titrate dose gradually to minimize GI effects

 GI side effects may be intensified in patients

consuming large amounts of simple

carbohydrates

 Reduces postprandial glucose values

 Not recommended in patients with significant

renal impairment (SCr >2 mg/dL)

 Use with caution in hepatic impairment

 Contraindications: DKA, inflammatory bowel

disease, colonic ulceration, partial intestinal

obstruction, marked disorders of digestion or

absorption conditions, cirrhosis (acarbose)

 Prevents breakdown of table sugar; therefore,

a source of glucose (dextrose, D-glucose)

should be readily available to treat symptoms

of hypoglycemia

 Flatulence; tend to

abate with time

 Diarrhea and

abdominal pain

 Dose-related

increase in serum

transaminases,

usually

asymptomatic,

reversible

(acarbose)

 Inexpensive

(acarbose)

 Moderately

expensive

(miglitol)

Abbreviations: DKA: diabetic ketoacidosis; dL: deciliter; GI: gastrointestinal; HbA1c: hemoglobin A1c; mg: milligram; SCr: serum creatinine
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Table 4: Amylin analog

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact on 

Weight Clinical Considerations

Adverse Events/Side 

Effects Cost

Pramlintide 0.5 - 1% High (especially 

in those with 

T1DM)

↓Weight  Indicated to be co-administered with mealtime 

insulin 

 Reduces postprandial glucose values

 Requires frequent pre- and post-meal and 

bedtime glucose monitoring

 When initiating pramlintide, reduce mealtime 

insulin (including premixed insulin) dose by 50%; 

individualize subsequent insulin doses 

thereafter

 Contraindicated in those with hypoglycemia 

unawareness and confirmed gastroparesis 

 Patients that should NOT be considered for 

pramlintide therapy:

• Poor compliance with current insulin 

regimen

• Poor compliance with prescribed SMBG

• HbA1c >9%

• Recurrent severe hypoglycemic requiring 

assistance during the past 6 months

• Require the use of drugs that stimulate GI 

motility

• pediatric patients

 Injectable

 GI effects (nausea, 

vomiting, anorexia)

Expensive

Abbreviations: GI: gastrointestinal; HbA1c: hemoglobin A1c; SMBG: self-monitoring of blood glucose; T1DM: type 1 diabetes mellitus
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Table 5: Biguanides

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact 

on 

Weight Clinical Considerations

Adverse Events /Side 

Effects Cost

Metformin 1 - 1.5% Low Weight 

neutral

 Use well established

 Before starting metformin, obtain the 

patient’s eGFR

 Metformin is contraindicated in patients 

with an eGFR below 30 mL/min/1.73 m2

 Starting metformin in patients with an 

eGFR between 30-45 mL/min/1.73 m2 is 

not recommended

 Obtain an eGFR at least annually in all 

patients taking metformin; in patients at 

increased risk for the development of 

renal impairment such as the elderly, renal 

function should be assessed more 

frequently

 In patients taking metformin whose eGFR 

later falls below 45 mL/min/1.73 m2

, 

assess the benefits and risks of continuing 

treatment; discontinue metformin if the 

patient’s eGFR later falls below 30 

mL/min/1.73 m2

 Titrate dose gradually to minimize GI 

symptoms; a trial of metformin extendedrelease should be offered to patients 

experiencing continued GI effects

 Likely reduces CV events (UKPDS)

 GI effects (diarrhea, 

nausea, abdominal 

cramping)

 Rare risk of lactic 

acidosis (risk is 

increased in patients 

with acute CHF, 

dehydration, excessive 

alcohol intake, renal 

impairment or sepsis) 

 May impair vitamin 

B12 absorption; rarely 

associated with

anemia

Inexpensive

Abbreviations: CHF: congestive heart failure; CV: cardiovascular; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; HbA1c: hemoglobin A1c; m2: square meter; 

min: minute; mL: milliliter; UKPDS: United Kingdom Prospective Diabetes Study
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Table 6: Dipeptidyl-Peptidase 4 Inhibitors

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact 

on 

Weight Clinical Considerations Adverse Events/Side Effects Cost

Sitagliptin

Saxagliptin

Linagliptin

Alogliptin

0.5 - 1% Low 

(↑ risk when 

combined with

SU or insulin)

Weight 

neutral

 May require dosage

adjustment for renal

impairment or concomitant

use of strong CYP3A4/5

inhibitors (varies by

product)

 Use of CYP3A4 or P-gp

inducers with linagliptin is

not recommended

 No cardiovascular benefits

compared to placebo

 Not studied in patients with

history of pancreatitis

 Hypersensitivity reactions (e.g., urticaria,

facial edema); post-marketing reports of

serious hypersensitivity reactions such as

anaphylaxis, angioedema, and exfoliative

skin conditions

 Acute pancreatitis has been reported;

discontinue if pancreatitis is suspected

 Severe and disabling arthralgia has been

reported

 May increase risk for hospitalization for

heart failure (saxagliptin and alogliptin)

Expensive

Abbreviations: CYP3A4/5: Cytochrome P450 3A4; HbA1c: hemoglobin A1c; P-gp: P-glycoprotein; SU: sulfonylurea
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Table 7: Glucagon-like 1 peptide receptor agonists

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact on 

Weight Clinical Considerations

Adverse Events/Side 

Effects Cost

Exenatide

Liraglutide

Lixisenatide

Once weekly 

agents

Exenatide

Albiglutide

Dulaglutide

1 - 1.5% Low 

(↑ risk when 

combined with

SU or insulin)

↓ Weight  Reduces postprandial glucose values

 Contraindicated in patients with a 

personal or family history of 

medullary thyroid carcinoma or in 

patients with multiple endocrine 

neoplasia syndrome type 2

 Consider other antidiabetic 

therapies in patients with a history 

of pancreatitis

 Use with caution in patients 

receiving oral medications that 

require rapid GI absorption

 Avoid use if patient has severe GI 

disease, including severe 

gastroparesis

 May require dosage adjustment for 

renal impairment (varies by 

product); exenatide should not be 

used if eGFR <30 mL/minute/1.73 m2

 Injectable 

 Liraglutide was shown to reduce the 

risk of cardiovascular events

 GI effects (nausea, 

vomiting, diarrhea)

 Reports of renal 

impairment usually in 

association with nausea, 

vomiting, diarrhea

 Injection site reactions 

 Post-marketing reports, 

including fatal and nonfatal hemorrhagic or 

necrotizing pancreatitis.

 Post-marketing reports 

of serious 

hypersensitivity 

reactions (e.g., 

anaphylactic reactions 

and angioedema).

 Unconfirmed association 

with medullary cell 

carcinoma

Expensive

Abbreviations: CYP3A4/5: Cytochrome P450 3A4; eGFR: estimated glomerular filtration rate; GI: gastrointestinal; HbA1c: hemoglobin A1c; m2: square meter; mL: milliliter; SU: 

sulfonylurea
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Table 8: Insulin

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact on 

Weight Clinical Considerations

Adverse Events /

Side Effects Cost

Insulin (prandial) 

Short-acting

Regular

Rapid-acting analog

Lispro 

Aspart 

Glulisine 

Insulin (basal)

Intermediate-acting

NPH

Long-acting analogs

Glargine

Detemir

Degludec

Premixed

NPH/Regular 

Biphasic insulin aspart 

Insulin lispro

protamine/lispro 

Insulin degludec/aspart

Variable Moderate-high ↑ Weight  Use well established

 Most effective at lowering

elevated glucose

 Dosing can be individualized

 Beneficial effect on

triglycerides and HDL-C 

 Lower doses may be needed

for renal and hepatic 

impairment

 Patient training needed

 Hypersensitivity

reactions

 Injection site

reactions

 Anaphylaxis has 

been reported 

(rare)

 Inexpensive 

(human

insulin)

 Moderate to 

expensive 

(analogs)

Abbreviations: HbA1c: hemoglobin A1c; HDL-C: high-density lipoprotein cholesterol; NPH: neutral protamine Hagedorn
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Table 9: Meglitinides

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact on 

Weight Clinical Considerations

Adverse Events/Side 

Effects Cost

Nateglinide

Repaglinide

0.5 - 1% Moderate ↑ Weight  Administer with meals; scheduled 

dose should not be administered if a 

meal is missed to avoid hypoglycemia

 Reduces postprandial glucose values

 Use with caution in patients with 

moderate to severe hepatic 

impairment and severe renal 

impairment

 Use with caution in the elderly, 

debilitated, and malnourished 

patients; may be more susceptible to 

glucose-lowering effects 

 Combination therapy with SU is not 

recommended, no additional benefit 

 Upper respiratory 

infection 

 Flu-like symptoms

 Inexpensive 

(repaglinide)

 Moderately 

expensive 

(nateglinide)

Abbreviations: HbA1c: hemoglobin A1c; SU: sulfonylureas
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Table 10: Sodium glucose co-transporter 2 (SGLT2) inhibitors

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact on 

Weight Clinical Considerations Adverse Events/Side Effects Cost

Canagliflozin

Dapagliflozin

Empagliflozin

0.5 – 1% Low ↓ Weight  Do not use if eGFR <45 mL/min/1.73 

m2 (empagliflozin/canagliflozin) or 

<60 mL/min/1.73 m2 (dapagliflozin)

 Empagliflozin was shown to reduce 

the risk of cardiovascular events 

compared to placebo

 Decrease triglycerides

 Increase HDL-C 

 Increase LDL-C 

 Urinary tract 

infections/urosepsis

 Genital mycotic infections 

(higher incidence in females 

and uncircumcised males)

 Increased risk for 

hypotension, orthostasis, 

volume depletion in elderly, 

those taking diuretics, or antihypertensives

 Decreased eGFR or increased 

serum creatinine may occur; 

elderly and those with 

preexisting renal impairment 

may be at greater risk

 Decrease in systolic blood 

pressure (~4-6 mmHg)

 DKA rare (presenting blood 

glucose levels may be below 

those typically expected for 

diabetic ketoacidosis (often 

<250 mg/dL). 

 Decreased bone density and 

increased risk of bone 

fractures reported with 

canagliflozin

Expensive

Abbreviations: DKA: diabetic ketoacidosis; dL: deciliter; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; HDL-C: high density lipoprotein-cholesterol; LDL-C: low 

density lipoprotein-cholesterol; m2:square meter; mg: milligram; min: minute; mL: milliliter; mmHg: millimeter of mercury
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Table 11: Sulfonylureas

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact on 

Weight Clinical Considerations

Adverse Events/Side 

Effects Cost

Second 

Generation

Glimepiride

Glipizide

Glyburide

First generation 

agents seldom 

used

Chlorpropamide 

Tolazamide 

Tolbutamide

1 -1.5% Moderate ↑ Weight  Effectiveness diminishes with 

progression of T2DM due to continued 

beta cell destruction

 Use with caution in elderly and 

patients with hepatic or renal 

impairment 

 Patients with G6PD may be at an 

increased risk of SU-induced hemolytic 

anemia

 Allergic skin reactions 

 SIADH has been 

reported 

 Dose-related GI effects 

(nausea, diarrhea, 

constipation)

Inexpensive

Abbreviations: G6PD: glucose-6-phosphate dehydrogenase deficiency; GI: gastrointestinal; HbA1c: hemoglobin A1c; SIADH: syndrome of inappropriate antidiuretic hormone 

secretion; SU: sulfonylurea; T2DM: type 2 diabetes mellitus
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Table 12: Thiazolidinediones

Drug Class

Average 

HbA1c 

Reduction

Potential for 

Hypoglycemia

Impact 

on 

Weight Clinical Considerations

Adverse Events/Side 

Effects Cost

Pioglitazone

Rosiglitazone

1 – 1.5% Low 

(↑ risk when 

combined with

SU or insulin)

↑ Weight  Contraindicated in those with NYHA 

Class III or IV heart failure

 Use with caution in patients with 

NYHA Class I/II heart failure or 

patients with risk factors for heart 

failure 

 Not recommended in symptomatic 

heart failure 

 Do not use in patients with active 

bladder cancer; consider risk versus 

benefits of using pioglitazone in 

those with a history of bladder 

cancer

 Use with caution in premenopausal, 

anovulatory women; may result in 

resumption of ovulation, increasing 

risk of pregnancy

 Administer cautiously in those with 

abnormal liver function tests

 Pioglitazone may reduce CV events 

 Edema usually doserelated

 Cause or exacerbate 

heart failure 

(greater risk if used 

with insulin)

 Macular edema has 

been reported (may 

present with blurred 

vision or decreased 

visual acuity) 

 Increased incidence 

of bone fractures in 

females occurring in 

the upper arm, hand 

and foot 

 Liver injury has been 

reported; if ALT >3x 

ULN do not 

reinitiate therapy 

without another 

explanation for the 

liver test 

abnormalities

 Inexpensive 

(pioglitazone) 

 Moderately 

expensive 

(rosiglitazone)

Abbreviations: ALT: alanine aminotransferase; CV: cardiovascular; HbA1c: hemoglobin A1c; NYHA: New York Heart Association; SU: sulfonylurea; ULN: upper limit of normal
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Table 13: Insulin: Summary of Pharmacokinetics [22-28] 

Insulin Onset Peak Duration Half-life Comments

Prandial (bolus) Insulin

Rapid-Acting 

Insulin aspart NovoLog: 0.2 to 0.3 hr 

NovoLog Mix 70/30: 10 to 

20 mins 

NovoLog: 1 to 3 hrs

NovoLog Mix 70/30: 1 to 

4 hrs

NovoLog: 3 to 5 hrs

NovoLog Mix 70/30: 18 to 

24 hrs

Subcutaneous: 81 min 

(NovoLog); ≈ 8 to 9 hrs

(NovoLog Mix 70/30)

Appearance: clear; 

covers insulin needs at 

the time of the 

injection Insulin lispro Subcutaneous: 0.25 to 

0.5 hr 

Subcutaneous: 0.5 to 

2.5 hrs

Subcutaneous: ≤5 hrs Subcutaneous: ≈ 1 hr, 

IV: 51 to 55 mins

Insulin glulisine 5 to 15 mins 1.6 to 2.8 hr <5 hrs IV: 13 mins, 

Subcutaneous: 42 mins

Short-Acting

Regular insulin Subcutaneous: ≈ 0.5 hr,

IV: 10 to 15 mins 

Subcutaneous: 3 hrs U 100: 4 to 12 hrs; 

U 500: up to 24 hrs

IV: 17 mins, 

Subcutaneous: 86 to 

141 mins 

Appearance: clear; 

covers insulin needs 

for meals eaten within 

30-60 mins

Basal Insulin

Intermediate-Acting

Insulin isophane 

(NPH)

1 to 1.5 hrs 4 to 12 hrs 14.5 hrs ≈ 4.4 hrs Appearance: cloudy; 

covers insulin needs 

for about half the day 

or overnight. Often 

combined with rapidor short-acting insulin

Long-Acting (Not be mixed with other insulins)

Insulin detemir 3 to 4 hrs None Up to 24 hrs 5 to 7 hrs Appearance: clear; 

covers insulin needs 

for about 1 full day. 

Often used as needed, 

or with rapid- or shortacting insulin

Insulin glargine Lantus: 3 to 4 hrs None Lantus: Up to 24 hrs

Toujeo: ≥24 hrs Toujeo: 6 hrs

Insulin degludec 1 hr 9 hrs At least 42 hrs 25 hrs
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Insulin Onset Peak Duration Half-life Comments

Pre-Mixed Products

70 NPH/30 Regular Not to be mixed with other insulins. Cloudy/generally taken twice a day before meals.

50 NPH/50 Regular

75 NPH/25 lispro

50 NPH/50 lispro

70 aspart/30 aspart

50 aspart/50 aspart

Abbreviations: hr: hour; IV: intravenous; min: minute; NPH: neutral protamine Hagedorn
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Table 14: FDA Approved/ Studied Combination Therapy1,2 [28] 

AGIs

DPP-4

inhibitors

GLP-1 

agonists Insulin Meglitinides Metformin

SGLT2 

inhibitors SUs TZDs 

AGIs N/A

DPP-4 

inhibitors N/A

GLP-1 

agonists* N/A

Insulin X X X† N/A

Meglitinides N/A

Metformin X X X X X N/A

SGLT2 

inhibitors X X X N/A

SUs X X X X X X N/A

TZDs X X X± X X X X N/A

Abbreviations: AGI: α-glucosidase; DPP4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide-1; SGLT2: sodium glucose cotransporter 2; SU: sulfonylurea; TZD: thiazolidinedione

1 Agents listed in alphabetical order

2This table reflects FDA approved indications and/or well-studied combinations. All combinations have not been studied at this 

time and evidence is rapidly evolving. 

*The data for GLP-1 agonists in combination with both basal and prandial insulin are very limited at this time.

†Exenatide once weekly + insulin is not recommended per product labeling.

±Rosiglitazone + insulin is not recommended per product labeling.

X. Methods

A. Strength of Recommendations

This CPG uses the GRADE methodology to assess the quality of the evidence base and assign a grade for 

the strength for each recommendation. The GRADE system uses the following four domains to assess 

the strength of each recommendation: [29] 

• Balance of desirable and undesirable outcomes

• Confidence in the quality of the evidence

• Values and preferences

• Other implications, as appropriate, e.g.,:

 Resource use

 Equity

 Acceptability

 Feasibility

 Subgroup considerations
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The framework below (Table 15) was used by the Work Group to guide discussions on each domain.

Table 15. Evidence to Recommendation Framework

Decision Domain Judgment

Balance of desirable and undesirable outcomes

 Given the best estimate of typical values and preferences, are you

confident that the benefits outweigh the harms and burden or vice

versa?

 Are the desirable anticipated effects large?

 Are the undesirable anticipated effects small?

 Are the desirable effects large relative to undesirable effects?

 Benefits outweigh harms/

burden

 Benefits slightly outweigh

harms/burden

 Benefits and harms/burden are

balanced

 Harms/burden slightly outweigh

benefits

 Harms/burden outweigh benefits

Confidence in the quality of the evidence

 Is there high or moderate quality evidence that answers this

question?

 What is the overall certainty of this evidence?

 High

 Moderate

 Low

 Very low

Values and preferences

 Are you confident about the typical values and preferences and are

they similar across the target population?

 What are the patient’s values and preferences?

 Are the assumed or identified relative values similar across the target

population?

 Similar values

 Some variation

 Large variation

Other implications (e.g., resource use, equity, acceptability, feasibility, subgroup considerations)

 Are the resources worth the expected net benefit from the

recommendation?

 What are the costs per resource unit?

 Is this intervention generally available?

 Is this intervention and its effects worth withdrawing or not allocating

resources from other interventions?

 Is there lots of variability in resource requirements across settings?

 Various considerations

The strength of a recommendation is defined as the extent to which one can be confident that the 

desirable effects of an intervention outweigh its undesirable effects and is based on the framework above, 

which combines the four domains.[29] GRADE methodology does not allow for recommendations to be 

made based on expert opinion alone. While strong recommendations are usually based on high or 

moderate confidence in the estimates of effect (quality of the evidence) there may be instances where 

strong recommendations are warranted even when the quality of evidence is low.[30] In these types of 

instances where the balance of desirable and undesirable outcomes and values and preferences played 

large roles in determining the strength of a recommendation, this is explained in the discussion section for 

the recommendation in the full-text CPG. 
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The GRADE of a recommendation is based on the following elements:

• Four decision domains used to determine the strength and direction (described above)

• Relative strength (Strong or Weak)

• Direction (For or Against)

The relative strength of the recommendation is based on a binary scale, “Strong” or “Weak.” A strong 

recommendation indicates that the Work Group is highly confident that desirable outcomes outweigh 

undesirable outcomes. If the Work Group is less confident of the balance between desirable and 

undesirable outcomes, they present a weak recommendation.

Similarly, a recommendation for a therapy or preventive measure indicates that the desirable 

consequences outweigh the undesirable consequences. A recommendation against a therapy or 

preventive measure indicates that the undesirable consequences outweigh the desirable consequences.

Using these elements, the grade of each recommendation is presented as part of a continuum:

• Strong For (or “We recommend offering this option ...”)

• Weak For (or “We suggest offering this option ...”)

• Weak Against (or “We suggest not offering this option ...”)

• Strong Against (or “We recommend against offering this option ...”)

Note that weak (For or Against) recommendations may also be termed “Conditional,” “Discretionary,” or 

“Qualified.” Recommendations may be conditional based upon patient values and preferences, the 

resources available, or the setting in which the intervention will be implemented. Recommendations may 

be at the discretion of the patient and clinician or they may be qualified with an explanation about the 

issues that would lead decisions to vary.

B. Recommendation Categorization

For use in the 2017 DM CPG, a set of recommendation categories was adapted from those used by the 

United Kingdom National Institute for Health and Clinical Excellence.[31,32] These categories, along with 

their corresponding definitions, were used to account for the various ways in which recommendations 

could have been updated from the 2010 DM CPG. The categories and definitions can be found in Table 16. 
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Table 16. Recommendation Categories and Definitions 

Evidence

Reviewed*

Recommendation

Category* Definition*

Reviewed

New-added New recommendation following review of the evidence

New-replaced

Recommendation from previous CPG that has been carried over to 

the updated CPG that has been changed following review of the 

evidence

Not changed

Recommendation from previous CPG that has been carried 

forward to the updated CPG where the evidence has been 

reviewed but the recommendation is not changed

Amended

Recommendation from the previous CPG that has been carried 

forward to the updated CPG where the evidence has been 

reviewed and a minor amendment has been made

Deleted Recommendation from the previous CPG that has been removed 

based on review of the evidence

Not 

reviewed

Not changed

Recommendation from previous CPG that has been carried 

forward to the updated CPG, but for which the evidence has not 

been reviewed

Amended

Recommendation from the previous CPG that has been carried 

forward to the updated CPG where the evidence has not been 

reviewed and a minor amendment has been made

Deleted Recommendation from the previous CPG that has been removed 

because it was deemed out of scope for the updated CPG

*Adapted from the NICE guideline manual (2012) [31] and Garcia et al. (2014) [32]

Abbreviation: CPG: clinical practice guideline
VA/DoD Clinical Practice Guideline for the Management of Type 2 Diabetes Mellitus in Primary Care

April 2017 Page 33 of 34

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