Discussion Guide

Keeping Up With Guidelines for Treating Type 2 Diabetes Mellitus to Overcome Clinical Inertia

This discussion guide is part of the educational initiative, "Advancements in Individualizing Treatments for Type 2 Diabetes." This series of interprofessional activities focuses on individualizing treatment with an emphasis on overcoming clinical inertia to improve patient care. These learning opportunities provide live, on-demand, monograph, and spaced-education formats, and are designed to build upon each other to facilitate the application of these concepts to your clinical practice. CE/CME information and instructions for processing CE/CME are listed in the Assessment Section. To access other educational opportunities in the initiative, visit the activities section of this website.

Learning Objectives

After attending this knowledge-based educational activity, participants should be able to

  1. Describe the prevalence, clinical and economic impact, and pathogenesis of type 2 diabetes mellitus in the United States.
  2. Discuss similarities and differences among the A1C goals in current guidelines for the management of type 2 diabetes mellitus.
  3. Review the stepwise approach to drug therapy for type 2 diabetes mellitus.
  4. Explain the potential clinical and economic impact of and factors contributing to clinical inertia in treating patients with type 2 diabetes mellitus.
  5. List strategies for overcoming clinical inertia in the treatment of type 2 diabetes mellitus.

Target Audience

This continuing pharmacy education activity was planned to meet the needs of pharmacists, physicians, nurse practitioners, and physician assistants caring for patients with type 2 diabetes mellitus.

Reviewers and Disclosures

The assistance of the planners and reviewers of this educational activity is gratefully acknowledged.

In accordance with ACCME and ACPE Standards for Commercial Support, ASHP policy requires that all faculty, planners, reviewers, staff, and others in a position to control the content of this presentation disclose their financial relationships. In this activity, only the individuals below have disclosed a relevant financial relationship. No other persons associated with this presentation have disclosed any relevant financial relationships.

Curtis L. Triplitt, Pharm.D., CDE
Clinical Associate Professor
Medicine/Diabetes
University of Texas Health Science Center at San Antonio
Associate Director
Diabetes Research Unit
Texas Diabetes Institute, University Health System
San Antonio, Texas

Curtis L. Triplitt, Pharm.D., CDE, is Clinical Associate Professor of Medicine, Division of Diabetes and Clinical Assistant Professor of Pharmacy at the University of Texas Health Science Center at San Antonio. Dr. Triplitt practices at the Texas Diabetes Institute, where he manages patients with an endocrinologist and is involved with diabetes and metabolism research. 

Dr. Triplitt received his doctor of pharmacy from the University of Texas Health Science Center at San Antonio and the University of Texas at Austin. He completed an ASHP-accredited primary-care residency at the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin.

Dr. Triplitt is Vice-Chair of the Texas Diabetes Council, Texas Department of State Health Services. He is a current Associate Editor and future Editor-in-Chief of Diabetes Spectrum. Dr. Triplitt has served as an investigator on multiple clinical trials focusing on the effects of medications on insulin sensitivity in overweight and obese subjects with hypertension and type 2 diabetes, as well as many type 2 diabetes medication trials and has published over 50 peer-reviewed articles and 8 book chapters on diabetes. In 2008 he was honored as Pharmacy Preceptor of the Year for the University of Texas. He lectures at both the national and statewide levels concerning diabetes and has been involved with the development of multiple clinical treatment algorithms for the prevention and treatment of diabetes in the State of Texas.

  • AstraZeneca; BI; Eli Lilly; Janssen – Speakers Bureau
  • Merck – Consultant

Eric L. Johnson, M.D.
Associate Professor, Department of Family and Community Medicine
University of North Dakota School of Medicine and Health Sciences
Assistant Medical Director, Altru Diabetes Center
Altru Health System
Grand Forks, North Dakota

Eric L. Johnson, M.D., is Associate Professor in the Department of Family and Community Medicine and Director of Interprofessional Education at the University of North Dakota School of Medicine and Health Sciences in Grand Forks, N.D. He also serves as Assistant Medical Director at Altru Diabetes Center, also in Grand Forks.

A graduate of University of Nebraska Medical Center, Dr. Johnson completed his residency at the University of North Dakota Family Practice Program in Fargo and is Board Certified in Family Medicine. His clinical areas of expertise are outpatient management of diabetes, long-term care, and tobacco cessation/control. His research interests include tobacco cessation, fatty liver disease, and celiac disease in diabetes. He has served as the principal investigator for several clinical trials through Altru Health System. 

Dr. Johnson is a member of the American Diabetes Association (ADA) Primary Care Advisory Group. He also is President of the American Diabetes Association – North Dakota and President of Tobacco Free North Dakota.

  • Medtronic – Speakers Bureau
  • Novo Nordisk – Advisory Board, Speakers Bureau
  • Sanofi – Advisory Board

Susan R. Dombrowski, M.S., B.S.Pharm., Writer

  • Ms. Dombrowski declares that she has no relationships pertinent to this activity.

Tony R. Martin, Pharm.D., M.B.A., Staff

  • Dr. Martin declares that he has no relationships pertinent to this activity.

Executive Summary & Introduction

Executive Summary

Diabetes mellitus is an increasingly common cause of morbidity and mortality with a substantial economic burden in the United States. The pathogenesis of type 2 disease is complex and involves insulin resistance, lipotoxicity, and multiple organ system defects that can be targeted with pharmacotherapeutic interventions. The optimal A1C goal has been the subject of recent debate because of the conflicting results of large clinical trials of intensive therapy. The goals and strategy for treating type 2 diabetes mellitus should be individualized, taking into consideration patient characteristics and the potential advantages and disadvantages of available drug therapies. A stepwise approach with intensification of drug therapy is needed for most patients with type 2 diabetes because of the progressive nature of the disease. Clinical inertia in the treatment of type 2 diabetes mellitus is a common multifactorial problem with substantial clinical and economic consequences. Team-based patient-centered care and various strategies can be used to overcome clinical inertia and optimize treatment outcomes.

Introduction

An estimated 30.3 million Americans (9.4% of the U.S. population) had diabetes mellitus in 2015, including 7.2 million persons in whom the disease was undiagnosed.[1] Approximately 84.1 million adults had prediabetes, a condition characterized by abnormal glucose metabolism that often leads to diabetes.[1] The prevalence of diagnosed diabetes in the United States increased by 382% between 1988 and 2014.[2] In 2015, diabetes was the seventh leading cause of death in the United States.[1] Diabetes increases the risk for macrovascular complications (ischemic heart disease, peripheral arterial disease, and stroke) and microvascular complications (retinopathy, nephropathy, and neuropathy).[3] In 2014, diabetes was among the hospital discharge diagnoses for 7.2 million adults, including 1.5 million patients with major cardiovascular diseases (e.g., ischemic heart disease, stroke).[1] In the same year, 14.2 million emergency department visits by adults were attributed at least in part to diabetes.[1]

The estimated total cost of diabetes in the United States in 2017 was $327 billion, including $237 billion in direct costs and $90 billion in indirect costs for lost productivity (e.g., increased absenteeism, inability to work, premature death).[4] The direct costs of diabetes in the United States increased by 26% between 2012 and 2017 after adjusting for inflation.[4] This change is attributed to increases in the prevalence of the disease and medical expenditures for each patient, primarily among elderly persons 65 years of age or older.[4] Medical expenditures are approximately 2.3 times higher for patients with diabetes than for persons without the disease.[4]

Which of the following trends in the prevalence of diagnosed diabetes mellitus in the United States has been observed over the past two decades?
A A 20% decrease
B A more than threefold increase
C A more than fivefold increase
D No substantial change

Rationale
An increase in the prevalence of diagnosed diabetes mellitus in the United States by 382% was observed between 1988 and 2014.

Pathogenesis

The vast majority (90% to 95%) of patients with diabetes have type 2 disease.[5] Risk factors for developing type 2 diabetes include advanced age, male gender, certain racial or ethnic groups (e.g., American Indians, African Americans, Hispanics/Latinos, Asians, Pacific Islanders), and low socioeconomic status.[3]

Type 2 diabetes is characterized by insulin resistance and progressive pancreatic β-cell dysfunction resulting in hyperglycemia and target organ damage (i.e., macrovascular and microvascular complications). These changes typically begin long before the disease is diagnosed.[5,6] Glucose homeostasis is maintained in healthy persons by pancreatic β-cell release of insulin in response to high blood glucose concentrations, which promotes hepatic and skeletal muscle uptake of glucose and inhibits hepatic glucose production and lipolysis by fat cells. When blood glucose concentrations fall too low, pancreatic α-cells release glucagon, which opposes the actions of insulin. Glucagon reduces glucose uptake in hepatic and muscle tissues and increases hepatic glucose production and lipolysis by fat cells. In prediabetes and the early stages of type 2 diabetes, insulin resistance in liver, muscle, and other tissues is largely overcome by compensatory increases in β-cell insulin secretion, resulting in mild hyperglycemia.[3] More overt hyperglycemia manifests in later stages of the disease when β-cell function deteriorates and insulin secretion is inadequate to compensate for insulin resistance. Persistent hyperglucagonemia contributes to hyperglycemia.[7]

Multiple organ systems and tissues appear to be involved in the pathogenesis of type 2 diabetes. Dysfunction of gastrointestinal (GI) hormones (i.e., incretins, such as glucagon-like peptide [GLP]-1) that stimulate meal-related insulin release, suppress glucagon secretion, and promote satiety has been implicated.[6] Increased glucose reabsorption in the kidneys also may contribute. Disruption of brain satiety signals resulting in overeating and reduced dopamine levels also could play a role in type 2 diabetes.[6]

The increased risk for type 2 diabetes and cardiovascular complications associated with obesity is mediated in part through lipotoxicity (i.e., accumulation of toxic lipid metabolites) in hepatic, muscle, and arterial tissues and fat and β-cells, which causes insulin resistance and inflammation and contributes to β-cell dysfunction.[3,8] Accumulation of toxic lipid metabolites also accelerates atherosclerosis in arteries.[8] The immune system, inflammation, and oxidative stress also are thought to contribute to the pathogenesis of type 2 diabetes, although the exact mechanisms remain to be elucidated.[9-11]

Treatment Goals

Achieving and maintaining glycemic control is essential for preventing long-term macrovascular and microvascular complications in patients with type 2 diabetes.[12,13] The evidence of benefit from controlling blood glucose concentrations is well established for preventing microvascular complications and less robust for cardiovascular complications. Elevated fasting glucose concentrations, abdominal obesity, dyslipidemia, and hypertension comprise the metabolic syndrome, a cluster of conditions associated with an increased risk for cardiovascular disease.[14] Therefore, correcting obesity, dyslipidemia, and hypertension as well as controlling blood glucose concentrations are therapeutic goals for patients with type 2 diabetes.

Laboratory values for A1C reflect glycemic control over the preceding 2-3 months. The recommended A1C goals in current evidence-based guidelines for the treatment of type 2 diabetes (Table 1) have been the subject of recent controversy because of the conflicting results of large randomized controlled clinical trials comparing the use of intensive glycemic control (i.e., therapy to achieve very low A1C goals) with less intensive (i.e., standard) glycemic control in this patient population.[17-23] These studies include the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, Veterans Affairs Diabetes Trial (VADT), United Kingdom Prospective Diabetes Study (UKPDS), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The A1C goals recommended by the American College of Physicians (ACP) are more conservative (i.e., higher) than those recommended by the American Diabetes Association (ADA) and in the American Association of Clinical Endocrinologists/American College of Endocrinology comprehensive type 2 diabetes management algorithm. According to ACP, data from the large randomized controlled clinical trials do not conclusively demonstrate a reduction in clinically relevant microvascular or macrovascular events (e.g., loss of vision, end-stage renal disease) or death from the use of intensive therapy instead of standard therapy.[17] An increased risk for severe hypoglycemia and other adverse effects was associated with intensive therapy in all of the studies. In UKPDS 34, reduced mortality was associated with the use of intensive metformin therapy instead of standard therapy in overweight adults, and a 10-year follow-up study demonstrated that this benefit was maintained on a long-term basis.[21,22] However, the ACCORD trial was terminated early because of increases in the risk for all-cause and cardiovascular death.[18] The incidence of severe hypoglycemic events was significantly higher with the use of intensive therapy than standard therapy.[18] The ACP recommendations for target A1C have been criticized for failing to adequately reflect recently introduced antihyperglycemic drug therapies that provide weight loss and cardiovascular benefits with a lower risk for hypoglycemia than older therapies.[24] The lack of consensus among current treatment guidelines about the preferred A1C goal for patients with type 2 diabetes underscores the need to individualize therapeutic goals.

Table 1. Guideline-Recommended A1C Goals for Patients with Type 2 Diabetes Mellitus [15-17]
AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ACP = American College of Physicians; ADA = American Diabetes Association
[ a ] More stringent (e.g., <6.5%) for selected patients not at risk for significant hypoglycemia or other adverse effects (e.g., with short duration of diabetes, long life expectancy, no significant cardiovascular disease)
[ b ] Less stringent (e.g., <8%) for selected patients with a history of severe hypoglycemia, short life expectancy, advanced diabetes complications, comorbid conditions, or long duration of diabetes
Organization Recommendation
ADA <7% for many nonpregnant adults [a,b]
AACE/ACE ≤6.5% for patients without serious concurrent illness and at low risk for hypoglycemia
>6.5% for patients with serious concurrent illness and at risk for hypoglycemia
ACP 7% - 8% for most patients
Which of the following A1C values is currently recommended by the American Diabetes Association (ADA) as a reasonable goal for many nonpregnant patients with type 2 diabetes mellitus?
A Less than or equal to 6.5%
B 6%-7%
C Less than 7%
D 7%-8%

Rationale
According to the ADA, a goal A1C <7% is reasonable for many nonpregnant patients with type 2 diabetes mellitus based on the results of clinical trials comparing the benefits and risks associated with the use of intensive and less stringent goals.

Table 2 lists factors to consider in establishing A1C goals for patients with type 2 diabetes mellitus. Less stringent goals might be chosen for older patients with a high risk of hypoglycemia or other adverse effects from drug therapy, long-standing disease, a short life expectancy, severe vascular complications or other comorbidities, low motivation, and limited self-care capabilities, resources, and support. Conversely, more stringent goals might be chosen for younger, recently-diagnosed patients with a long life expectancy, no vascular complications or comorbidities, high motivation, good self-care capabilities, and ample resources and support.[15]

Table 2. Considerations in Setting A1C Goals for Patients with Type 2 Diabetes Mellitus [13,15-17]
  • Age and life expectancy
  • Disease duration
  • Comorbid conditions (especially vascular complications)
  • Risk for hypoglycemia, weight gain, and other adverse effects from treatment
  • Medication complexity and cost burdens
  • Patient preferences and attitude
  • Functional and cognitive impairments
  • Ability to manage a complex regimen and adhere to treatment
  • Availability of resources and support system

Treatment Approach

Lifestyle management is the foundation of treatment for type 2 diabetes mellitus.[16] It involves medical nutrition therapy, regular physical activity, weight loss (if the patient is overweight or obese), smoking cessation, adequate sleep, and diabetes self-management education and support.[15,16] A plant-based diet with limited intake of saturated fatty acids and avoidance of trans fats is recommended.[16] There is no ideal percentage of dietary caloric intake for protein, carbohydrates, and fats for all patients with type 2 diabetes.[15] The eating plan should be individualized based on current eating patterns, preferences, and metabolic goals.

At least 150 minutes per week of moderate intensity aerobic physical activity spread over at least 3 nonconsecutive days are recommended for most adults with type 2 diabetes.[15,16] Resistance exercise and for older adults flexibility and balance training also are recommended two or three times weekly.

A weight loss of at least 5% to 10% of the body weight is recommended for overweight and obese patients with type 2 diabetes.[15,16] This loss should be achieved through diet, physical activity, and behavioral strategies designed to produce a 500- to 750-kcal/day energy deficit.[15]

The organs and tissues targeted by various antidiabetes drug therapies and the advantages and disadvantages of these therapies are listed in Tables 3 and 4. None of the currently available drug therapies address all of the organ defects associated with type 2 diabetes. The antihyperglycemic mechanism of action of metformin primarily involves a reduction in hepatic glucose production.[13] The GLP-1 agonists increase meal-related insulin secretion, decrease meal-related glucagon secretion, delay gastric emptying, and increase satiety.[6] Inhibition of dipeptidyl peptidase (DPP)-4, an enzyme that rapidly inactivates GLP-1, increases GLP-1 levels, although smaller reductions in A1C levels are associated with DPP-4 inhibitors than GLP-1 agonists.[6] Inhibition of sodium glucose cotransporter (SGLT)-2, a protein expressed in the proximal renal tubules, reduces reabsorption of most of the glucose filtered by the kidneys and promotes glycosuria. Thiazolidinediones increase insulin sensitivity in peripheral tissues. The α-glucosidase inhibitors delay intestinal carbohydrate digestion and absorption. Sulfonylureas and glinides increase insulin secretion. Insulin therapy increases hepatic and skeletal muscle glucose uptake and decreases hepatic glucose production. The antihyperglycemic mechanism of action of the bile acid sequestrant colesevelam may involve decreased hepatic glucose production and increased incretin levels. The dopamine agonist bromocriptine appears to increase insulin sensitivity and modulate metabolism through effects on the hypothalamus.[13]

The drug-related factors in Table 4 and patient characteristics (e.g., age, comorbidities) should be taken into consideration in choosing drug therapy. For example, the biguanide metformin, GLP-1 agonists, and SGLT-2 inhibitors can cause weight loss and are preferred for overweight and obese patients instead of other therapies that promote weight gain. Certain adverse effects might be used to therapeutic advantage (e.g., α-glucosidase inhibitors, which may cause loose stools, could be helpful for patients with chronic constipation).[25]

Table 3. Antidiabetes Drug Therapy Targets [3,6]
DPP = dipeptidyl peptidase; GLP = glucagon-like peptide; SGLT = sodium glucose cotransporter; TZD = thiazolidinedione
Organ or Tissue Drug Therapies
Brain GLP-1 agonists
DPP-4 inhibitors
Dopamine agonist bromocriptine
Pancreas GLP-1 agonists
DPP-4 inhibitors
Sulfonylureas
Glinides
Liver Biguanide metformin
GLP-1 agonists
DPP-4 inhibitors
Insulins
Bile acid sequestrant colesevelam
GI tract GLP-1 agonists
α-glucosidase inhibitors
Bile acid sequestrant colesevelam
Kidneys SGLT-2 inhibitors
Peripheral tissues TZDs
Insulins
Table 4. Advantages and Disadvantages of Commonly Used Drug Therapies for Type 2 Diabetes [6,13,15,16,25]
CV = cardiovascular; DPP = dipeptidyl peptidase; GI = gastrointestinal; GLP = glucagon-like peptide; LDL= low-density lipoprotein; QR = quick release; SGLT = sodium glucose cotransporter
Drug Class (Drugs) Potential Benefits, Risks, and Other Considerations
Biguanide (metformin) Potential Benefits
Weight loss
Low risk of hypoglycemia
Oral route of administration
Possible CV benefit
Inexpensive

Risks and Other Considerations
GI side effects (diarrhea, abdominal cramps, nausea)
Use with caution in renal impairment
GLP-1 agonists (dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) Potential Benefits
Weight loss
Low risk of hypoglycemia

Possible CV benefit and reduction in diabetic kidney disease progression from liraglutide

Risks and Other Considerations
Injectable route of administration
GI side effects (nausea, vomiting, diarrhea)
Caution in renal insufficiency
Expensive
SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) Potential Benefits
Weight loss
Low risk of hypoglycemia
Oral route of administration

Possible CV benefit and reduction in diabetic kidney disease progression (canagliflozin, empagliflozin)

Risks and Other Considerations
Caution in renal insufficiency
Expensive
Genitourinary infections
Fractures (canagliflozin)
Volume depletion/hypotension
Increased LDL cholesterol
Diabetic ketoacidosis
Amputations (canagliflozin)
DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin) Potential Benefits
Weight neutral
Low risk for hypoglycemia
Oral route of administration

Risks and Other Considerations
Caution in renal insufficiency (need for dosage reduction, except for linagliptin)
Expensive

Possible increased hospitalization for heart failure (alogliptin, saxagliptin)

Thiazolidinedione (pioglitazone) Potential Benefits
Low risk for hypoglycemia
Reduces triglycerides
May reduce stroke risk
Oral route of administration
Inexpensive

Risks and Other Considerations
Weight gain
Edema and heart failure
Fractures (postmenopausal women and elderly men)
Bladder cancer
α-glucosidase inhibitors (acarbose, miglitol) Potential Benefits
Weight neutral
Low risk for hypoglycemia
Oral route of administration

Risks and Other Considerations
GI side effects (flatulence, diarrhea)
Second-generation sulfonylureas (glipizide, glimepiride) and glinides (nateglinide, repaglinide) Potential Benefits
Oral route of administration
Inexpensive

Risks and Other Considerations
Weight gain
Hypoglycemia
Possible CV risk (sulfonylureas)
Glyburide use not recommended
Insulins Potential Benefits
Useful for patients who are pregnant, symptomatic, or have high A1C or long duration of disease

Risks and Other Considerations
Weight gain
Hypoglycemia
Injectable route of administration
Expensive (analogs)
Colesevelam (bile acid sequestrant) Potential Benefits
Low risk for hypoglycemia
Oral route of administration
Useful for patients unable to meet LDL cholesterol goal with statins

Risks and Other Considerations
GI side effects (constipation)
May reduce absorption of other medications
May increase triglycerides (use not recommended if >500 mg/dL)
Expensive
Bromocriptine QR (dopamine agonist) Potential Benefits
Weight loss or neutral
Low risk for hypoglycemia
Oral route of administration
Expensive

Risks and Other Considerations
GI side effects (nausea)
Dizziness/syncope
Use with caution in patients receiving antipsychotic drugs
Which of the following antidiabetes drug therapies is preferred based on GI tolerability for a patient who is unable to take metformin because of persistent GI side effects?
A The dopamine agonist bromocriptine
B An α-glucosidase inhibitor
C A glucagon-like peptide (GLP)-1 agonist
D A dipeptidyl peptidase (DPP)-4 inhibitor

Rationale
The use of metformin may be limited by diarrhea and abdominal cramps. The potential for GI side effects should be considered in choosing alternative antidiabetes drug therapy for a patient unable to tolerate metformin because of persistent GI side effects. A risk for GI side effects is associated with GLP-1 agonists (nausea, vomiting, diarrhea), α-glucosidase inhibitors (flatulence, diarrhea), and the dopamine agonist bromocriptine (nausea). A DPP-4 inhibitor is the best choice based on GI tolerability for patients unable to take metformin because GI side effects are not associated with DPP-4 inhibitors.

Evidence-based treatment guidelines for type 2 diabetes mellitus (Table 5) recommend a stepwise approach for most patients based on the A1C at the time of presentation, with initial monotherapy recommended for patients with an A1C less than 7.5% and initial dual therapy for patients with higher A1C levels. Symptomatic patients with A1C values exceeding 9.0% at the time of presentation and pregnant women are exceptions for whom initial insulin therapy with or without other agents is recommended. Initial dual or triple drug therapy may be warranted for asymptomatic patients with an elevated A1C (i.e., >9.0%) at the time of presentation. Drug therapy should be intensified (e.g., switching from monotherapy to dual therapy, dual therapy to triple therapy, or adding or intensifying insulin therapy) after 3 months if the goal A1C has not been achieved.

Table 5. AACE/ACE Drug Therapy Algorithm for Glycemic Control in Patients with Type 2 Diabetes Mellitus Based on A1C at Time of Presentation [16]
AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; DPP = dipeptidyl peptidase; GLP = glucagon-like peptide; QR = quick release; SGLT = sodium glucose cotransporter; TZD = thiazolidinedione
[a] The order of drug therapies represents the suggested hierarchy of use. Lifestyle therapy should be used in conjunction with all drug therapies.
[b] Thiazolidinediones, sulfonylureas, glinides, and basal insulin should be used with caution.
A1C Recommended Drug Therapy [a]
<7.5% Monotherapy with a first-line agent:
  • Metformin
  • GLP-1 agonist
  • SGLT-2 inhibitor
  • DPP-4 inhibitor
  • TZD [b]
  • α-glucosidase inhibitor
  • Sulfonylurea [b]
  • Glinide [b]
≥7.5% Dual therapy with metformin or another first-line agent + a second-line agent:
  • GLP-1 agonist
  • SGLT-2 inhibitor
  • DPP-4 inhibitor
  • TZD [b]
  • Basal insulin [b]
  • Colesevelam
  • Bromocriptine QR
  • α-glucosidase inhibitor
  • Sulfonylurea [b]
  • Glinide [b]
≥7.5% Triple therapy with metformin or another first-line agent + a second-line agent + a third-line agent:
  • GLP-1 agonist
  • SGLT-2 inhibitor
  • TZD [b]
  • Basal insulin [b]
  • DPP-4 inhibitor
  • Colesevelam
  • Bromocriptine QR
  • α-glucosidase inhibitor
  • Sulfonylurea [b]
  • Glinide [b]
>9.0% without symptoms Dual or triple therapy
>9.0% with symptoms Insulin with or without other agents

Combination drug therapy may be more effective than monotherapy, especially when two or more drug therapies with different targets are used because of the defects in multiple organ systems and tissues (brain, pancreas, liver, GI tract, kidneys, muscle, fat) involved in the pathogenesis of type 2 diabetes (Table 3). The potential for additive adverse effects should be taken into consideration when choosing combination therapies (Table 4).

Clinical Inertia

Clinical inertia (also known as therapeutic inertia) has been defined as the failure to initiate or intensify treatment when appropriate based on evidence-based treatment guidelines.[25,26] Although delays in treatment initiation often are the focus of initiatives to address clinical inertia, the problem can arise at any stage of the disease (i.e., when treatment intensification is warranted).[27] Intensification of treatment eventually is needed for most patients because of the progressive nature of type 2 diabetes. The possibility of “apparent” clinical inertia should be considered when not initiating or intensifying treatment in accordance with treatment guidelines is appropriate based on patient characteristics or the clinical situation (e.g., because of advanced age, frail health, presence of comorbidities).[27]

Clinical inertia results in inadequate glycemic control in 40% to 60% of patients with type 2 diabetes.[28,29] A recent systematic review revealed that the median time to intensification of treatment for type 2 diabetes was more than 1 year in patients with an A1C value above their goal.[26] Another analysis revealed a median time to intensification of therapy of 3.7 years in patients with type 2 diabetes who had not achieved their A1C goal despite the use of basal insulin therapy.[30]

In patients receiving metformin monotherapy for type 2 diabetes, early initiation (within 6 months after detection of diabetes) resulted in significantly lower A1C and body mass index values and a significantly lower likelihood of needing treatment intensification compared with delayed treatment initiation.[31] In patients with newly diagnosed type 2 diabetes and an inadequate response to metformin monotherapy, early treatment intensification (within 6 months after treatment failure) has been shown to increase the likelihood and shorten the time to achievement of A1C goals compared with later intensification.[32] A systematic review and meta-analysis of randomized controlled trials of patients with previously untreated type 2 diabetes revealed that initial combination therapy that included metformin was associated with a significantly greater reduction in A1C (0.43%) and a 1.4-fold higher likelihood of achieving a target A1C less than 7% compared with metformin alone.[33]

Delayed treatment intensification in conjunction with poor glycemic control in newly diagnosed patients increases the risk of cardiovascular events and stroke.[27] Poor glycemic control often is accompanied by inadequate blood pressure and lipid management, which increase the risk for cardiovascular events and death.[28] Poor quality of life and increased morbidity, mortality, and healthcare costs are among the potential consequences of clinical inertia.[27]

Table 6 lists clinician-, patient-, and health system-related factors that can contribute to clinical inertia. Clinician-related factors are thought to make the largest contribution to clinical inertia, although patient nonadherence also is an important factor.[25,27] Clinical inertia usually can be attributed to a combination of clinician-, patient-, and health system-related factors. Some factors, especially clinician- and patient-related ones, are interrelated. For example, treatment intensification is more likely for patients with elevated A1C values who are adherent than those who are nonadherent.[35]

Table 6. Factors That Can Contribute to Clinical Inertia in the Treatment of Type 2 Diabetes Mellitus [25,27,28,34]
Clinician-related
  • Insufficient time
  • Lack of clear therapeutic goals or awareness of current treatment guidelines
  • Low expectations of patients
  • Misperception of hyperglycemia as mild and treatable with lifestyle management alone
  • Failure to identify and manage comorbid conditions
  • Tendency to prioritize other patient complaints
  • Type of practice (specialty vs. primary care)
  • Insufficient education and training
  • Concerns about adverse effects from medications
Patient-related
  • Denial about disease and its severity
  • Lack of symptoms and motivation
  • Reluctance to adopt lifestyle measures and injection therapies
  • Medication complexity and high cost burden
  • Adverse effects from medications
  • Lack of trust in and open communication with clinician
  • Low health literacy and lack of knowledge about diabetes
  • Misperception of therapeutic adjustments as a sign of treatment failure
  • Poor self-management skills
Health system-related
  • Lack of institutional treatment guidelines and computerized clinical decision support
  • Poor coordination of care and communication among staff
  • Lack of effective patient self-management education
  • Reimbursement issues
  • Lack of access to or understanding of electronic health record or other health system resources

In a survey of 252 primary care providers, a lack of provider time and patient nonadherence were common causes of clinical inertia and barriers to achieving glycemic control.[34] The cost of drug therapy was a relatively uncommon factor.[34]

Many endocrinologists, diabetologists, and other specialists are more comfortable initiating insulin therapy than are primary care providers, although the latter are no less likely to initiate or intensify oral antidiabetes therapies.[27,28] A lack of staff support can present a barrier to initiation or intensification of therapy by specialists as well as primary care providers.[27]

Competing demands during primary care visits, the tendency to prioritize patient complaints when an illness is asymptomatic, and hijacking of the visit by the patient can contribute to clinical inertia.[25,27] Failure to establish and monitor progress in achieving therapeutic goals, underestimation of the need for initiation or intensification of therapy, and misperception of hyperglycemia as mild and treatable with lifestyle management alone are other clinician-related factors.[27,28]

Lack of institutional treatment guidelines and computerized clinical decision support are among the health system-related factors that can cause clinical inertia. Issues related to inconsistencies between reimbursement policies and evidence-based treatment guidelines also may contribute to clinical inertia.[27]

Deciding not to initiate or intensify treatment in accordance with treatment guidelines because of patient characteristics or the clinical situation is known as:
A Apparent clinical inertia
B Clinical inertia
C Therapeutic inertia

Rationale
Failure to initiate or intensify treatment sometimes is appropriate based on patient characteristics or the clinical situation, and this phenomenon has been referred to as apparent clinical inertia.

Using an interprofessional team-based patient-centered approach and shared decision making are recommended to avoid or overcome clinical inertia by improving coordination of care and communication among staff and with the patient.[27] In patient-centered medical home models, team changes are among the most effective strategies for achieving glycemic goals in patients with type 2 diabetes.[36] Electronic technology (e.g., computerized clinical decision support, patient telemonitoring) can facilitate patient-centered care. Various methods (e.g., face-to-face meetings, electronic interactions) may be used to optimize the effectiveness of communication among team members and with patients. Communication with patients also may be facilitated by establishing liaisons (e.g., medical home nurses).

Incorporating current treatment guidelines into computerized clinical decision support systems can help overcome clinical inertia associated with a lack of guideline awareness or application and promote the use of early treatment intensification.[28,32] Providing education and performance feedback for clinicians is recommended.[27] The considerations in using (i.e., potential advantages and disadvantages of) early (i.e., initial) combination therapy instead of monotherapy for an individual should be addressed in educational programs for clinicians. Whether initial combination therapy is rational based on complementary mechanisms of action and likely to hasten achievement of glycemic control, address unmet needs (e.g., promote weight loss, reduce hypoglycemia and other adverse effects), improve adherence, delay disease progression, and reduce complications at a reasonable cost is part of this risk-benefit analysis for an individual.[37] Educating clinicians can increase their knowledge, skills, confidence, and engagement in efforts to reduce clinical inertia.[27]

Because patient nonadherence plays a large role in clinical inertia, efforts to reduce clinical inertia should address nonadherence. Patient education is an important strategy. The progressive nature of type 2 diabetes should be explained to patients, and misperceptions about the implications of treatment modifications should be dispelled.[27] Clinicians should avoid using antidiabetes drug therapies with known adverse effects that could pose problems for an individual based on his or her characteristics or situation (e.g., hypoglycemia from sulfonylurea use in a patient whose A1C is close to his or her goal and has erratic meal consumption).[25] Drug therapy should be individualized based on tolerability. Efforts also should be made to simplify and optimize the convenience and ease of use of drug therapy. Minimizing the frequency of administration (e.g., using once-weekly instead of once-daily or twice-daily GLP-1 agonists) and the number of medications by using fixed-dose combination products once glycemic control has been achieved are potential strategies to achieve these goals.[27] Patient preferences should be accommodated to promote adherence. The use of pen devices instead of conventional vials and syringes for injection of insulin and other parenteral medications may help overcome needle phobias.[27]

Which of the following types of factors contributing to clinical inertia in the treatment of type 2 diabetes mellitus is addressed by the use of computerized clinical decision support?
A Patient-related
B Health system-related
C Cost-related

Rationale
The lack of computerized clinical decision support has been identified as a health system-related factor that contributes to clinical inertia in the treatment of type 2 diabetes mellitus.

Conclusion

Type 2 diabetes mellitus is a progressive disease caused by multiple organ defects for which individualization of A1C goals and stepwise drug therapy usually are required. Clinical inertia in the treatment of diabetes is a common multifactorial problem with a substantial clinical impact. Strategies to overcome clinical inertia have the potential to improve patient care and treatment outcomes.





Assessment

Continuing Pharmacy Education

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Continuing Medical Education

The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Society of Health-System Pharmacists designates this live activity for a maximum of 1 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Activity Title: Keeping Up With Guidelines for Treating Type 2 Diabetes Mellitus to Overcome Clinical Inertia
ACPE Activity Number: 0204-0000-18-424-H01-P
Release Date: September 5, 2018
Expiration Date: May 31, 2020
Activity Type: Knowledge-based
CE Credits: 1.0 hours (0.1 CEUs), no partial credit
Activity Fee: Free of charge

Once you have read the discussion guide, click on the link below to take the online assessment (study aid below, minimum score 70%), complete the evaluation, and claim credit. Continuing pharmacy education (CPE) credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of a live activity or completion of a home-study activity.


Study Aid

  1. Which of the following statements about changes in the direct costs of diabetes mellitus in the United States between 2012 and 2017 after adjusting for inflation is correct?
    1. Costs have increased by 26% because of increases in both disease prevalence and medical expenditures per patient, especially elderly patients
    2. Costs have increased by 26% because of an increase in medical expenditures per patient in adults of all ages with little change in disease prevalence
    3. Costs have increased twofold primarily because of an increase in disease prevalence in adults of all ages with little change in medical expenditures per patient
    4. Costs have increased more than threefold because of increases in both disease prevalence and medical expenditures per patient, especially elderly patients

  2. Which of the following are among the changes associated with the pathogenesis of type 2 diabetes?
    1. Decreased lipolysis by fat cells, accumulation of toxic lipid metabolites in fat cells and hepatic tissues, and increased hepatic glucose production
    2. Decreased lipolysis by fat cells, accumulation of toxic lipid metabolites in fat cells and hepatic tissues, and decreased hepatic glucose production
    3. Increased lipolysis by fat cells, accumulation of toxic lipid metabolites in fat cells and hepatic tissues, and increased hepatic glucose production
    4. Increased lipolysis by fat cells, accumulation of toxic lipid metabolites in fat cells and hepatic tissues, and decreased hepatic glucose production

  3. Which of the following statements about the American College of Physicians (ACP) recommendations for target A1C is correct?
    1. They are more conservative than other guideline recommendations and have been criticized because they do not adequately reflect recently introduced antihyperglycemic drug therapies
    2. They are more conservative than other guideline recommendations and have been criticized because they are based on studies with an inadequate duration of follow up
    3. They are less conservative than other guideline recommendations and have been criticized because they are based on studies with inadequate numbers of patients
    4. They are less conservative than other guideline recommendations and have been criticized because they do not adequately reflect clinical inertia in real world practice

  4. In patients with which of the following characteristics is the use of a less stringent A1C goal most appropriate?
    1. Long life expectancy
    2. Short duration of diabetes
    3. Presence of severe cardiovascular complications from diabetes
    4. High motivation

  5. Which of the following antidiabetes drug classes is least preferred for an obese patient with type 2 diabetes mellitus who is trying to lose weight?
    1. Biguanides (i.e., metformin)
    2. Dipeptidyl peptidase (DPP)-4 inhibitors
    3. Glucagon-like peptide (GLP)-1 agonists
    4. Sodium glucose cotransporter (SGLT)-2 inhibitors

  6. The use of insulin as part of initial antidiabetes therapy is warranted in patients with type 2 diabetes mellitus and which of the following characteristics?
    1. History of severe hypoglycemia regardless of A1C value
    2. Advanced microvascular complications regardless of A1C value
    3. High A1C value and long-standing diabetes
    4. High A1C value with overt diabetes symptoms

  7. Which of the following types of factors is thought to make the largest contribution to clinical inertia in the treatment of type 2 diabetes mellitus?
    1. Clinician-related
    2. Cost-related
    3. Health system-related
    4. Patient-related

  8. In a recent systematic review, the median time to intensification of treatment for type 2 diabetes in patients with an A1C value above goal was:
    1. <3 months
    2. 6 months
    3. 9 months
    4. >12 months

  9. Compared with delayed treatment intensification, early treatment intensification (i.e., at the recommended time) in patients newly diagnosed with type 2 diabetes who have poor glycemic control despite the use of metformin monotherapy has been shown to increase:
    1. The time to achievement of glycemic goals
    2. The risk of cardiovascular events and stroke
    3. The probability of achieving glycemic goals
    4. Total healthcare costs

  10. Which of the following factors is least likely to contribute to clinical inertia in treating type 2 diabetes mellitus?
    1. Lack of provider time
    2. Patient nonadherence
    3. Lack of institutional treatment guidelines
    4. High cost of drug therapy

  11. Which of the following is the most appropriate solution to address patient nonadherence to complex drug therapy for type 2 diabetes mellitus?
    1. Computerized clinical decision support
    2. Fixed-dose combination drug therapy
    3. Clinician education
    4. Performance feedback for clinicians

  12. Which of the following are the most appropriate solutions to address clinical inertia in the treatment of type 2 diabetes mellitus associated with poor coordination of care and communication among staff and with the patient?
    1. Using a team-based patient-centered approach and shared decision making
    2. Developing institutional treatment guidelines and computerized clinical decision support
    3. Reducing medication complexity and improving convenience of drug therapy
    4. Implementing a standardized approach to establishing therapeutic goals and providing clinician performance feedback

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