Impact of Glycemic Control on Healthcare Resource Utilization and Costs of Type 2 Diabetes: Current and Future Pharmacologic Approaches to Improving Outcomes

The incidence and prevalence of type 2 diabetes continue to grow in the United States as the population ages and becomes more obese.^1,2 The prevalence of type 2 diabetes is projected to increase from current estimates of 14% to at least 21% of the US population by 2050, but the prevalence rate could reach 33% of the population.³

The impact of weight on the prevalence of type 2 diabetes is dramatic. In the 1999-2002 National Health and Nutrition Examination Survey (NHANES), among patients with type 2 diabetes, the proportion of participants who were overweight (ie, body mass index [BMI] ≥25 kg/m²) or obese (ie, BMI ≥30 kg/m²) was 85.2%, and the proportion of obese patients without diabetes was 54.8% (Figure 1).¹ Obese patients with type 2 diabetes were characterized by younger age, poorer glycemic control, higher blood pressure, worse lipid profile, and use of antihypertensive and lipid-lowering drugs compared with their nondiabetic counterparts.

Figure 1

Patients with diabetes are at greater risk for microvascular and macrovascular disease, including coronary artery disease, stroke, peripheral vascular disease, end-stage renal disease, retinopathy, and mortality, compared with persons without diabetes.⁴ Large-scale studies in patients with diabetes consistently report a direct association between lower hemoglobin (Hb) A_1c levels and lower complication rates.^5-7

The proportion of the national healthcare expenditure attributed to patients with type 2 diabetes is expected to increase from the reported 10% in 2011 to 15% by 2031.⁸ In addition, studies show that overall healthcare costs for type 2 diabetes are reduced with improved glycemic control in patients with diabetes.^9-11 Improvements in the management of type 2 diabetes and weight control, which are linked to increased medication adherence, are a critical component of any effort to reduce the healthcare costs of type 2 diabetes.

An unmet need in the treatment of type 2 diabetes is the availability of effective, safe, and well-tolerated treatments that will achieve and maintain glycemic control, reduce body weight, and decrease cardiovascular (CV) risk, while also ensuring patient adherence and persistence with therapy.

This article provides a comprehensive review of the impact of type 2 diabetes on patient morbidity and mortality, the implications of and increased prevalence of type 2 diabetes and its associated comorbidities on the costs of healthcare, and potential new pharmacologic approaches to control the prevalence of disease and their associated costs. For the purposes of this review, comprehensive searches were conducted for the years 2000 to 2013 using MEDLINE for individual and combinations of search terms, including “type 2 diabetes,” “adherence,” “compliance,” “nonadherence,” “drug therapy,” “resource use,” “cost,” and “cost-effectiveness.” Articles in the English language and representing healthcare practices in the United States were selected for inclusion.

Impact of Type 2 Diabetes on Morbidity and Mortality
Despite improvements in the management of CV risk factors in patients with type 2 diabetes in recent years, substantial proportions of patients remain with elevated HbA_1c (29%-45%), blood pressure (49%), and low-­density lipoprotein cholesterol (LDL-C; 47%) according to NHANES data.^12,13 As the prevalence of type 2 diabetes grows, a parallel increase in comorbidity and mortality can be expected.^2,14,15

The incidence of CV disease (CVD) is markedly exacerbated by poor glycemic control in patients with type 2 diabetes.^16,17 Increased rates of hypertension, dyslipidemia, heart failure, angina, and myocardial infarction are closely linked to poor glycemic control in type 2 diabetes.⁶ Microvascular complications also are affected by poor glycemic control.⁶ An analysis of the UKPDS study showed a significant association between HbA_1c levels and the risk for microvascular complications.⁷ Each 1% reduction in mean HbA1c was associated with a 21% reduction in the risk of any adverse outcome and a 37% reduction in the risk of microvascular complications.7 An HbA_1c reduction from 8% to <7%, and the associated reductions in risk, would result in savings for hospitalization from diabetes of $486 per patient per year, with even greater cost reductions when comparing higher HbA_1c levels with HbA1c levels <7%.¹⁸

Currently available hypoglycemic drugs demonstrate limited effects on CV risk factors beyond glycemic control.¹⁹ Development of CVD is a major complication of type 2 diabetes. Chronic hyperglycemia is often accompanied by dyslipidemia, hypertension, systemic inflammation, and oxidative stress, which increase the risk for microvascular and macrovascular complications of type 2 diabetes.¹⁹ Although metformin exhibits favorable effects on body weight, sulfonylureas, thiazolidinediones, and insulin have a negative impact on weight in patients with type 2 diabetes.²⁰

Glucagon-like peptide (GLP)-1 receptor agonists enhance insulin secretion but may also exert effects beyond glycemic control. Ongoing studies are examining the effects of administering GLP-1 agonists to patients at risk for CVD, patients postangioplasty, patients post–coronary artery bypass, and patients with heart failure.²¹ Additional studies are evaluating the potential benefits on arrhythmias, heart failure, myocardial infarction, and death.^22,23

Implications of Growing Prevalence of Type 2 Diabetes and Comorbidities on Healthcare Costs
Despite current availability of a wide range of drugs for the management of patients with type 2 diabetes, a number of limitations associated with their use persist, such as suboptimal efficacy, poor weight control, tolerability concerns, and high rates of medication nonadherence. In addition, suboptimal control of comorbid conditions, including hypertension and dyslipidemia, are common.²⁴

Data from NHANES were examined to assess the achievement of therapeutic targets for glycemic control, blood pressure, and LDL-C among patients with diabetes in the United States.²⁵ The proportion of patients with diabetes achieving HbA_1c levels <7%, blood pressure <130/80 mm Hg, and LDL-C <100 mg/dL had risen from 7% during 1999-2002 to 12.2% during 2003-2006, but this increased rate represents a striking indication of the need for greater efforts to manage diabetes and its comorbidities.²⁵

The costs associated with the management of patients with type 2 diabetes are increasing dramatically as the prevalence of the disease increases.26 Estimates of the economic burden of diabetes in the United States in 2007 reached $153 billion in excess medical costs and $65 billion in lost productivity.²⁶ Healthcare expenditures associated with type 2 diabetes are expected to increase approximately 3-fold during the next 20 years,2 and additional costs are projected to arise from poor adherence to drug therapy.^27,28

Obstacles to Effective Management of Type 2 Diabetes
Despite the availability of therapies to improve glycemic control and reduce the associated comorbidities, medication adherence and long-term persistence with long-term drug therapy remains inadequate. This level of poor adherence is estimated to account for 33% to 69% of hospital admissions in the United States.²⁹ Causes of poor adherence include complex drug regimens, chronic disease, adverse effects, cost, poor communication between patients and providers, lack of symptomatology, and psychosocial issues such as lack of education and support for behavioral modification.²⁹

From a payer perspective, this gap between investing in programs and therapies needs to be addressed to avoid consequences that may not be seen for decades for a patient who is not a member of the specific health plan. Furthermore, the conundrum of covering weight-loss medications needs to be evaluated. Many health plans do not cover weight-loss medications, despite the association between obesity, diabetes, and CVD, because of concerns of cost, adverse plan selection, and poor sustained efficacy and tolerability of weight-loss agents.

Medication adherence to different classes of antidiabetic drugs was evaluated from pharmacy claims for 75,589 patients enrolled in 3 health plans over a 12-month period in 2003, and average medication nonadherence was approximately 31% (range, 25%-55%).³⁰ A systematic review of adherence to the prescribed dose of antidiabetic drugs showed adherence rates from 67% to 85% for oral drugs and from 62% to 64% for insulin.³¹ In contrast, diabetic patients using subcutaneous injection of insulin were found adherent in only 36.1% of cases before conversion to an insulin pen device (which led to 54.6% adherence).³² An analysis of therapy with GLP-1 agonists between 2005 and 2010 showed adherence rates of 31% to 34%, suggesting that the need for injection even at a weekly frequency is a barrier to adherence.³³

A 2005 analysis of persistence with drug therapy for 6 chronic diseases showed 6-month persistence rates of 28% to 66%.³⁴ For diabetes, hypertension, and dyslipidemia, the medication possession ratio (MPR) averaged 72%, but only 59% of patients were adherent to their medication for >80% of the days, annually.³⁵ Medication adherence refers to the intensity of drug use during therapy, whereas persistence refers to the overall duration of drug therapy; therefore, a patient can have poor adherence (eg, does not take medication as prescribed) but a high persistence rate (or MPR), because the patient continues to take the medication long-term.³⁶

Improving medication adherence offers the possibility of reducing costs and improving care for patients with a chronic illness. A 2010 analysis of nonadherence (ie, MPR <80%) to medications used to treat diabetes, dyslipidemia, or hypertension estimated that the direct cost of nonadherence was $105.8 billion in that year.²⁷ In addition, the CVS Caremark pharmacy and administrative claims database was used to determine the effect of medication adherence from 2005 to 2008 on healthcare costs, including hospital days, emergency department visits, and outpatient visits.³⁷ Based on this analysis, greater medication adherence was projected to reduce the average annual medical spending per patient with diabetes by $4413 for all adults and by $5170 for patients aged ≥65 years.³⁷

Adherence and Healthcare Resource Use
Poor medication adherence in patients with diabetes is associated with poor glycemic control, which ultimately increases morbidity and mortality and further impacts healthcare costs.^38-43 Extensive data exist that link poor medication adherence to increased medical resource use and higher healthcare costs in type 2 diabetes. Improved medication adherence may lead to reductions of the total healthcare costs in type 2 diabetes.

A systematic literature review investigated the economic impact of adherence and/or persistence with treatment on the overall cost of type 2 diabetes care.³⁸ The average total annual costs per patient ranged from $4570 to $17,338. Medication adherence was inversely associated with total healthcare costs or hospitalization costs.³⁸

In a population of patients with diabetes examined from 2005 to 2008, improved adherence to diabetes medications was associated with a 13% reduction in the risk of hospitalization or emergency department visits, whereas poor adherence was associated with a 15% increase in risk.⁴¹ Based on these findings, adherence to diabetes medication was projected to save $4.7 billion annually, and eliminating poor adherence would save the US healthcare system $3.6 billion annually.⁴¹ Thus, improved medication adherence among diabetic patients has the potential for a significant impact on costs.

A retrospective analysis using an administrative claims database of 137,277 patients enrolled in a healthcare system from June 1997 to May 1999 was performed to determine the impact of adherence (percentage of days that a patient had a supply of medication) on hospitalization rates and costs related to diabetes, hypertension, congestive heart failure, and hypercholesterolemia.⁴² For patients with diabetes, a significant increase in adherence rates was associated with reductions in hospitalization risk from 30% to 13% (P <.05) and total costs (ie, medical and drug costs) increased from $8867 to $4570 (P <.05) over a 12-month period (Figure 2).⁴²

Figure 2

A model that was created to estimate the impact of medication adherence in 56,744 patients with type 2 diabetes who were enrolled in private insurance plans from 2001 to 2002 showed that increasing medication adherence (using MPR) from 50% to 100% would reduce the hospitalization rate from 15% to 11.5% and emergency department visits from 17.3% to 9.3%.⁴⁴ The cost to achieve this level of adherence was projected to be an increase of $776 annually per patient, but this added cost was projected to be offset by cost-savings from lower rates of hospitalization and emergency department visits, which were estimated at $886 per patient annually.⁴⁴

A longitudinal study from 2002 to 2006 evaluated medication adherence in patients with type 2 diabetes and the cost benefits of improving adherence.³⁹ The mean MPR over 5 years was 0.93 for the adherent group and 0.58 for the nonadherent group. The costs increased approximately 3% annually (P = .001) during the 5-year study period. Nonadherence was associated with a 37% lower pharmacy cost and a 7% lower outpatient cost, but a 41% higher inpatient cost. Improving adherence in the nonadherent group was projected to result in annual cost-savings in the range of $661 million to $1.16 billion.³⁹

A retrospective, cross-sectional study evaluated the effect of adherence to antidiabetic medications on adherence rates, healthcare utilization, and work productivity.⁴⁰ Patients with type 2 diabetes using oral antidiabetic medications with or without insulin (N = 96,734) and patients using oral medication only (N = 55,356) were evaluated. Adherence (ie, MPR >80%) was associated with fewer complications of diabetes and fewer emergency department visits and short-term disability days. Among patients taking oral antidiabetic medications only, adherence was associated with significantly lower rates of acute myocardial infarction, amputation, neuropathy, renal events, and retinopathy (P <.05).⁴⁰

The impact of increased persistency with medication use on hospitalization rates and healthcare costs was evaluated in 7441 Medicare patients with type 2 diabetes between 1997 and 2004 using prescription data to estimate costs.⁴³ Persistency with prescriptions for oral antidiabetic medications, antihypertensives, and statins was associated with a significantly lower risk of hospitalization, fewer hospital days, and lower healthcare costs (P <.05).

Adherence and Glycemic Control
The impact of medication adherence on glycemic control in type 2 diabetes has been evaluated in a number of prospective and retrospective studies.

The effect of adherence on glycemic control was evaluated in 249 patients in a managed care plan who had recently initiated therapy with oral antidiabetic drugs between 2001 and 2004.⁴⁵ Overall, mean adherence (MPR >80%) was 81%, and older age and comorbidity were associated with better adherence. Each 10% increase in adherence was associated with a 0.1% reduction in HbA1c (P = .004), and adherent patients were more likely to achieve glycemic control.

A retrospective study was conducted between 1991 and 2001 among 1560 patients with type 2 diabetes to determine the effect of medication adherence with oral drugs on glycemic control measured by HbA1c during a 1-year follow-up.46 After adjusting for age, sex, BMI, and other factors, glycemic control rates improved progressively in accordance with higher rates of medication adherence. HbA1c levels were 0.34% lower with improvements in medication adherence (P = .009).

The effect of medication adherence on glycemic control was also evaluated in a retrospective analysis of patients with type 2 diabetes enrolled in an independent practice association model HMO between 2001 and 2002.⁴⁷ The HbA_1c target of ≤7% was achieved by 42% to 46% of patients using oral antidiabetic drugs. The mean MPR for patients who reached HbA1c goal versus patients who did not reach that goal was 0.82 and 0.72 for sulfonylureas and 0.77 and 0.62 for metformin (P <.001). An inverse relationship was observed between mean HbA_1c level and MPR.⁴⁷

Adherence and Mortality
Poor medication adherence also is associated with an increase in mortality in type 2 diabetes. A retrospective cohort study was conducted between 2002 and 2005 to investigate the effects of poor adherence on hospitalization and mortality in 11,532 patients with type 2 diabetes in a managed care organization.36 Medication adherence was defined as the proportion of days covered for filled prescriptions of oral hypoglycemic, antihypertensive, and statin medications. Patients who were nonadherent had higher levels of HbA1c, blood pressure, and LDL-C. Medication nonadherence was significantly (P <.001) associated with an increased risk for all-cause hospitalization and for all-cause mortality (Figure 3).³⁶

Figure 3

An analysis of the association between medication adherence and mortality in patients with type 2 diabetes found that medication nonadherence and clinic non­attendance were independent risk factors for all-cause mortality.⁴⁸ Data were obtained from general practices in the United Kingdom for 15,984 patients with type 2 diabetes who were treated with an oral antidiabetic drug and insulin. Medication nonadherence was significantly more common in women, smokers, and those with a higher HbA_1c.⁴⁸

Glycemic Control and Healthcare Resource Use
A strong association has been reported between poor glycemic control in type 2 diabetes and healthcare resource use and costs. A retrospective analysis from a managed care organization evaluated the relationship between glycemic control and hospitalization rate and hospital costs among patients with type 1 or type 2 diabetes.18 The hospitalization rate was significantly higher among patients with an HbA_1c ≥10% compared with patients with HbA_1c <7% (P <.05). Average costs per pa­tient increased markedly from $2792 to $6759 over a 40-­month period that coincided with increasing HbA1c values (Figure 4).¹⁸

Figure 4

An administrative database from a healthcare plan was used to assess the effects of glycemic control on healthcare costs between 1998 and 2003 among 10,780 patients with type 2 diabetes.49 Total annual diabetes-­related costs increased significantly (P <.05) from $1505 among patients with good glycemic control (HbA_1c ≤7%) to $1871 among patients with poor control (HbA_1c >9%).49 Among members of a managed care plan with type 2 diabetes who maintained HbA_1c levels ≤7% during a 1-year follow-up in 2002, diabetes-related costs were significantly reduced.¹⁰ This retrospective analysis compared medical and pharmacy claims data for 3121 patients at target HbA_1c levels and for 3659 patients above target. At a 1-year follow-up, average diabetes-related costs per patient were $1540 for the cohort with high HbA1c levels versus $1171 for the group at target HbA_1c (P <.001). These results demonstrate that higher medical costs associated with type 2 diabetes management are linked to poor glycemic control.¹⁰

Effect of Comorbidity on Healthcare Resource Use
In addition to the effects of type 2 diabetes on costs and resource utilization, the presence of underlying CVD magnifies the costs of care. The effect of comorbid CVD on healthcare costs was evaluated in patients with type 2 diabetes enrolled in an HMO in 2003.⁵⁰ Costs were compared in 9059 patients with type 2 diabetes and age-matched controls. Total healthcare costs were 3-fold higher in patients with comorbid CVD versus patients without comorbidities, which was similar to the control group of persons without type 2 diabetes (Figure 5). However, the total costs were approximately 2-fold higher in patients with type 2 diabetes, regardless of the presence of comorbid CVD.⁵⁰

Figure 5

An economic benefit from weight loss was demonstrated among patients with type 2 diabetes, especially among obese patients. The impact of weight change over 1 year was evaluated using a claims database among adults in an HMO between 1997 and 2005.²⁰ Of the 458 patients included, 224 (48.9%) experienced weight gain of ≤1 lb. The average 1-year healthcare cost was $6382 per person, and the diabetes-related cost was $2002. For patients who gained weight (mean, 3.9%) during the 1-year follow-up, the average healthcare cost was $7260 per person, and the diabetes-related cost was $2141. For those with no change in weight (mean, 3.3% decrease), the average healthcare cost was $5541 per person and the average diabetes-related cost was $1869.²⁰ Therefore, a 1% weight loss was associated with a significant 3.6% ($256) decrease in total healthcare cost and a 5.8% ($131) decrease in diabetes-related cost (P <.05).²⁰

Unmet Needs and Future Directions in Drug Therapy for Type 2 Diabetes
There remain unmet needs for better pharmacologic treatment of type 2 diabetes. The ideal therapy should halt disease progression, reduce CV complications, and have a benign safety and tolerability profile. Optimal therapy requires continuous control of glucose levels and a more intensive therapeutic effect to prevent or reduce glucose excursions.⁵¹ Progress toward developing new therapies for type 2 diabetes that satisfy the ideal profile is limited by the complex nature of diabetes and its effects on multiple organ systems, as well as the length of time required for symptoms to develop.

The goal is for effective, safe, and well-tolerated treatments that will achieve glycemic control and ensure adherence and persistence with therapy. Ideal treatments should provide additional benefits beyond glycemic control, such as significant effects on weight loss and CV risk factors (including blood pressure and lipids), with an expectation of reduced morbidity and mortality. In addition, ideal therapies will lack the inconvenience and barriers associated with frequent injections, offer patient convenience, and optimize medication adherence. An impor­tant treatment approach to type 2 diabetes that has the potential to improve adherence and disease outcomes is the use of dual- or triple-drug combination therapy.

Treatment guidelines for type 2 diabetes include recommendations for using combination therapy, and a growing body of literature supports the early use of triple-­drug therapy for patients who are not adequately controlled with monotherapy.^52-54

A number of fixed-dose combinations of antidiabetic drugs are already marketed or are undergoing clinical evaluation. Finally, healthcare payers expect that ideal therapies will provide cost-effective solutions to the long-term management of type 2 diabetes to address the high morbidity and costs associated with CVD.

Novel approaches for improving pharmacotherapy for type 2 diabetes include new delivery systems for existing drugs and new chemical entities, as outlined in the Table, based on ongoing clinical trials (clinicaltrials.gov; accessed July 16, 2013). Many of the new classes of drugs target comorbid CVD in patients with type 2 diabetes.

Table

Although a once-weekly formulation of exenatide (Bydureon; Amylin) is available and other once-weekly formulations of GLP-1 receptor agonists are in development and a once-monthly formulation is undergoing evaluation, the impact of these agents on long-term adherence remains uncertain.

New formulations of older drugs are focused on improved delivery of the active ingredient to provide increased ease of use and patient convenience. ITCA 650 (Intarcia Therapeutics) is a novel drug delivery system that is designed to provide continuous subcutaneous release of exenatide for up to 1 year. Phase 3 trials are under way in patients with type 2 diabetes to demonstrate its efficacy and tolerability.

A once-monthly suspension of exenatide (Bristol-Myers Squibb) has completed a phase 2 trial and is poised to enter phase 3 studies. Oral formulations of GLP-1 receptor agonists are in early clinical testing.

Inhaled insulin (Afrezza; MannKind Corporation) is an ultra–rapid-acting inhaled formulation that is intended as an alternative to rapid-acting injectable insulin and offers the major advantage of avoiding frequent daily injections. Additional phase 3 studies are being conducted for submission to the US Food and Drug Administration (Exubera was withdrawn from the market by its manufacturer in 2008).

Another approach to addressing unmet needs in type 2 diabetes is drug combinations that provide 2 mechanisms of action. The dipeptidyl peptidase-4 agonist alogliptin combined with pioglitazone (Oseni; Takeda Pharmaceuticals) and alogliptin combined with metformin (Kazano; Takeda Pharmaceuticals) were both approved and launched early in 2013, and insulin degludec combined with liraglutide is in late-stage development (Novo Nordisk).

Furthermore, the cost-effectiveness of fixed-dose combinations must be demonstrated in diabetes, especially when ≥1 of the components are available as generic drugs, and when patients are likely taking multiple medications. There is a need to establish a direct link between improved medication adherence and better outcomes.

A number of new chemical entities for type 2 diabetes are in clinical development or have recently been added to the market. The first sodium-glucose cotransporter (SGLT)2, canagliflozin (Invokana; Janssen), was approved and launched in early 2013. Other SGLT2 compounds are in late-stage development, and these agents increase secretion of urinary glucose and promote weight loss, with a low risk for hypoglycemia or blood pressure reduction. A dual SGLT1 and SGLT2 agonist that inhibits glucose absorption in the stomach and renal glucose reabsorption is in phase 3 development (Lexicon Pharmaceuticals).

G protein–coupled receptor agonists act as incretin mimetics (CymaBay), and acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) inhibitors are being developed by various manufacturers (Novartis; Pfizer) to reduce insulin resistance and lower triglycerides. These drug classes are in early-stage development.

Alternative approaches to treatment are in early clinical development and include drugs that reduce glycemia while providing beta-cell protection (GMC-252; Genmedica Therapeutics), selective inhibition of proinflammatory pathways, and activation of endogenous anti-­inflammatory pathways (CAT-1004; Catabasis). More effective weight-loss agents are needed, and healthcare plans need better tools to validate the return-on-investment to employers for treating obesity.

Conclusions
The information presented in this article should serve as a call to action for health insurance plans, pharmacy benefit managers, and employers to investigate the impact of medication adherence on costs and outcomes associated with type 2 diabetes. Greater effort is needed from these groups to assess the level of medication adherence, as well as adherence to evidence-based guidelines and connect potential improvements to quality measures in type 2 diabetes. With continuing growth in the prevalence of type 2 diabetes, its associated comorbidities, and a corresponding increase in healthcare costs, it is critical that better approaches are identified for achieving long-term glycemic control and managing comorbid conditions.

A major emphasis should be placed on achieving effective control of diabetes, but without imposing increased risks on the patient from excess weight, hypoglycemia, and other safety and tolerability concerns. Of equal importance is to find drug therapies that increase patient adherence and persistence levels beyond levels reported with currently available drugs. This combination of enhanced efficacy, better tolerability, and improved adherence has the potential to impart substantial positive benefits on healthcare costs and resource utilization and ensure a healthier population. New Centers for Medicare & Medicaid Services’ Clinical Quality Measures55 that are linking reimbursement to the attainment of quality measures may provide additional incentive to improving overall management of type 2 diabetes and its comorbidities.

Author Disclosure Statement
Dr Banerji has received research/grant support from Merck, is on the Speaker’s Bureau of and has received honoraria from Merck and from Sanofi-Aventis, and is a Consultant to Novartis. Dr Dunn is a Consultant to Takeda, Sanofi-­Aventis, and Janssen.

1. Centers for Disease Control and Prevention. Prevalence of overweight and obesity among adults with diagnosed diabetes—United States, 1988-1994 and 1999-2002. MMWR Morb Mortal Wkly Rep. 2004;53:1066-1068.
2. Huang ES, Basu A, O’Grady M, Capretta JC. Projecting the future diabetes population size and related costs for the U.S. Diabetes Care. 2009;32:2225-2229.
3. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.
4. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed August 20, 2013.
5. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004;141:421-431.
6. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.
7. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. Erratum in: Lancet. 1999;354:602.
8. Fitch K, Iwasaki K, Pyenson B. The cost and quality gap in diabetes care: an actuarial analysis. 2012. http://publications.milliman.com/publications/health-published/pdfs/cost-quality-gap-diabetes.pdf. Accessed August 20, 2013.
9. Gilmer TP, O’Connor PJ, Manning WG, Rush WA. The cost to health plans of poor glycemic control. Diabetes Care. 1997;20:1847-1853.
10. Shetty S, Secnik K, Oglesby AK. Relationship of glycemic control to total diabetes-related costs for managed care health plan members with type 2 diabetes. J Manag Care Pharm. 2005;11:559-564.
11. Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial. JAMA. 1998;280:1490-1496.
12. Ford ES. Trends in the control of risk factors for cardiovascular disease among adults with diagnosed diabetes: findings from the National Health and Nutrition Examination Survey 1999-2008. J Diabetes. 2011;3:337-347.
13. Ali MK, McKeever Bullard K, Imperatore G, et al; for the Centers for Disease Control and Prevention. Characteristics associated with poor glycemic control among adults with self-reported diagnosed diabetes—National Health and Nutrition Examination Survey, United States, 2007-2010. i. 2012;61(suppl):32-37.
14. Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 2007;116:151-157.
15. Zhang Y, Hu G, Yuan Z, Chen L. Glycosylated hemoglobin in relationship to cardiovascular outcomes and death in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2012;7:e42551.
16. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287:2570-2581.
17. Buse JB, Ginsberg HN, Bakris GL, et al; for the American Heart Association and the American Diabetes Association. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;115:114-126.
18. Menzin J, Korn JR, Cohen J, et al. Relationship between glycemic control and diabetes-related hospital costs in patients with type 1 or type 2 diabetes mellitus. J Manag Care Pharm. 2010;16:264-275.
19. van Genugten RE, Möller-Goede DL, van Raalte DH, Diamant M. Extra-pancreatic effects of incretin-based therapies: potential benefit for cardiovascular-risk management in type 2 diabetes. Diabetes Obes Metab. 2013;15:593-606.
20. Yu AP, Wu EQ, Birnbaum HG, et al. Short-term economic impact of body weight change among patients with type 2 diabetes treated with antidiabetic agents: analysis using claims, laboratory, and medical record data. Curr Med Res Opin. 2007; 23:2157-2169.
21. Anagnostis P, Athyros VG, Adamidou F, et al. Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control. Diabetes Obes Metab. 2011;13:302-312.
22. Okerson T, Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc Ther. 2012;30:e146-e155.
23. Mundil D, Cameron-Vendrig A, Husain M. GLP-1 receptor agonists: a clinical perspective on cardiovascular effects. Diab Vasc Dis Res. 2012;9:95-108.
24. Stark Casagrande S, Fradkin JE, Saydah SH, et al. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988-2010. Diabetes Care. 2013;36:2271-2279.
25. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122:443-453.v
26. Dall TM, Zhang Y, Chen YJ, et al. The economic burden of diabetes. Health Aff (Millwood). 2010;29:297-303.
27. Nasseh K, Frazee SG, Visaria J, et al. Cost of medication nonadherence associated with diabetes, hypertension, and dyslipidemia. Am J Pharm Benefits. 2012;4:e41-e47.
28. Wild H. The economic rationale for adherence in the treatment of type 2 diabetes mellitus. Am J Manag Care. 2012;18(3 suppl):S43-S48.
29. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.
30. Fischer MA, Stedman MR, Lii J, et al. Primary medication non-adherence: analysis of 195,930 electronic prescriptions. J Gen Intern Med. 2010;25:284-290.
31. Cramer JA. A systematic review of adherence with medications for diabetes. Diabetes Care. 2004;27:1218-1224.
32. Lee WC, Balu S, Cobden D, et al. Medication adherence and the associated health-economic impact among patients with type 2 diabetes mellitus converting to insulin pen therapy: an analysis of third-party managed care claims data. Clin Ther. 2006;28:1712-1725. Erratum in: Clin Ther. 2006;28:1968-1969.
33. Chou E, Wang H, Miao W, et al. Adherence to GLP-1 agonist therapy in US managed care. Poster presented at the American Diabetes Association annual scientific sessions; June 8-12, 2012, Philadelphia, PA.
34. Yeaw J, Benner JS, Walt JG, et al. Comparing adherence and persistence across 6 chronic medication classes. J Manag Care Pharm. 2009;15:728-740.
35. Cramer JA, Benedict A, Muszbek N, et al. The significance of compliance and persistence in the treatment of diabetes, hypertension and dyslipidaemia: a review. Int J Clin Pract. 2008;62:76-87.
36. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006;166:1836-1841.
37. Roebuck MC, Liberman JN, Gemmill-Toyama M, Brennan TA. Medication adherence leads to lower health care use and costs despite increased drug spending. i. 2011;30:91-99.
38. Breitscheidel L, Stamenitis S, Dippel FW, Schöffski O. Economic impact of compliance to treatment with antidiabetes medication in type 2 diabetes mellitus: a review paper. J Med Econ. 2010;13:8-15.
39. Egede LE, Gebregziabher M, Dismuke CE, et al. Medication nonadherence in diabetes: longitudinal effects on costs and potential cost savings from improvement. Diabetes Care. 2012;35:2533-2539.
40. Gibson TB, Song X, Alemayehu B, et al. Cost sharing, adherence, and health outcomes in patients with diabetes. Am J Manag Care. 2010;16:589-600.
41. Jha AK, Aubert RE, Yao J, et al. Greater adherence to diabetes drugs is linked to less hospital use and could save nearly $5 billion annually. Health Aff (Millwood). 2012;31:1836-1846.
42. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care. 2005;43:521-530.
43. Stuart BC, Simoni-Wastila L, Zhao L, et al. Increased persistency in medication use by U.S. Medicare beneficiaries with diabetes is associated with lower hospitalization rates and cost savings. Diabetes Care. 2009;32:647-649.
44. Encinosa WE, Bernard D, Dor A. Does prescription drug adherence reduce hospitalizations and costs? The case of diabetes. Adv Health Econ Health Serv Res. 2010; 22:151-173.
45. Rozenfeld Y, Hunt JS, Plauschinat C, Wong KS. Oral antidiabetic medication adherence and glycemic control in managed care. Am J Manag Care. 2008;14:71-75.
46. Rhee MK, Slocum W, Ziemer DC, et al. Patient adherence improves glycemic control. Diabetes Educ. 2005;31:240-250.
47. Lawrence DB, Ragucci KR, Long LB, et al. Relationship of oral antihyperglycemic (sulfonylurea or metformin) medication adherence and hemoglobin A1c goal attainment for HMO patients enrolled in a diabetes disease management program. J Manag Care Pharm. 2006;12:466-471.
48. Currie CJ, Peyrot M, Morgan CL, et al. The impact of treatment noncompliance on mortality in people with type 2 diabetes. Diabetes Care. 2012;35:1279-1284.
49. Oglesby AK, Secnik K, Barron J, et al. The association between diabetes related medical costs and glycemic control: a retrospective analysis. Cost Eff Resour Alloc. 2006;4:1.
50. Gandra SR, Lawrence LW, Parasuraman BM, et al. Total and component health care costs in a non-Medicare HMO population of patients with and without type 2 diabetes and with and without macrovascular disease. J Manag Care Pharm. 2006;12: 546-554.
51. Drucker DJ, Buse JB, Taylor K, et al; for the DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240-1250.
52. Defronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(suppl 2): S127-S138.
53. Harrison LB, Adams-Huet B, Raskin P, Lingvay I. β-cell function preservation after 3.5 years of intensive diabetes therapy. Diabetes Care. 2012;35:1406-1412.
54. Raz I. Guideline approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(suppl 2):S139-S144.
55. Centers for Medicare & Medicaid Services. Clinical Quality Measures. www.cms.gov/Regulations-and-Guidance/Legislation/EHRIncentivePrograms/ClinicalQualityMeasures.html. Accessed August 2, 2013.