Serial Medication Nonadherence in Patients with Type 2 Diabetes
D
iabetes is one of the leading medical causes of mortality, and was responsible for an estimated 4.9 million deaths worldwide in 2014.1 Despite significant recent innovation in diabetes drug development, less than half of patients with diabetes achieve or maintain glycemic control in the United States, as reflected in healthcare quality measures.2 Better adherence to medication regimens is recognized as an important contributor to improved glycemic control.3 However, there is limited published research on the predictors of medication nonadherence. Curkendall and colleagues reported that the type of antidiabetes drug, its method of administration, the complexity of the treatment protocol, and patient demographics affected patients’ willingness to use the prescribed medications.3 Davies and colleagues described 4 categories that are associated with medication nonadherence, including (1) predictive factors, (2) patient-perceived barriers to adherence, (3) type of drug delivery device, and (4) the cost burden to the patient.4 In their systematic literature review, Davies and colleagues found that switching from a vial or a syringe to a pen device to administer insulin improved patient adherence to diabetes medications.4
Frois and colleagues showed that serial nonadherence is sizable and is a key predictor of subsequent nonadherence to therapy. Regardless of the cause, the impact of medication nonadherence on glycemic control can be challenging for physicians to evaluate.5 In particular, little is known about serial nonadherence––the repeated nonadherence to multiple medications (antidiabetes and nondiabetes medications)—in diabetes over time.6 Frois and colleagues showed that serial nonadherence is sizable and is a key predictor of subsequent nonadherence to therapy. Consistent with previous literature, serial nonadherence was associated with an increased risk for hypoglycemia and with higher medical care costs compared with adherence.6 The concept of serial nonadherence is particularly relevant to patients with type 2 diabetes, because pharmacotherapy tends to be additive rather than substitu-
S12
l
American Health & Drug Benefits
l
tive; therefore, patients may be nonadherent to several medications at the same time.6 Furthermore, because patients with type 2 diabetes frequently have multiple comorbidities, they are often prescribed antidiabetes and nondiabetes medications. Fortunately, serial nonadherence is observable and is therefore actionable.6 One recent study showed that the history of nonadherence is highly predictive of future nonadherence, and intervention strategies that can curb nonadherence early in patients’ treatment may be particularly effective in improving the care of patients with diabetes.6 If adherence is improved in earlier lines of treatment, the potential value to providers, payers, and especially patients could be considerable in terms of improved quality of care, reduced costs associated with diabetes-related complications, and improved outcomes and quality of life.6 Several potential strategies could be used to address serial nonadherence in type 2 diabetes. One such approach would minimize the need for patient decision-making related to the administration of a drug. This could be accomplished by an implantable drug delivery device that is capable of delivering a therapeutic agent for an extended duration of time. Of course, the therapeutic agent must be stable in a liquid formulation and must remain biologically active for the full treatment period after implantation. This agent should be capable of delivering hemoglobin (Hb) A1c reductions that are comparable to the currently approved drugs, with minimal impact on patient weight. In addition, the agent selected should have a low risk for hypoglycemia and other side effects. For an implantable device, safety and tolerability would be critical considerations. Table 1 shows the profiles of different drug classes that are frequently used in the treatment of patients with diabetes.7 After first-line treatment with metformin, sulfonylureas and insulins are associated with an elevated risk for hypoglycemia; sulfonylureas, thiazolidinediones, and insulins result in weight gain; and dipeptidyl peptidase-4 inhibitors and sodium-glucose linked transporter-2 inhibitors are oral agents with associated immune-mediated dermatologic effects and volume depletion, respectively.7 Of the different classes of antidiabetes agents, glucagon-like peptide-1 agonists have the most favorable profile of a therapeutic agent that is delivered via an implantable delivery device, with a con-
www.AHDBonline.com
April 2015
l
Supplement
Serial Medication Nonadherence in Patients with Type 2 Diabetes
Table 1 Comparison of Drug/Medication Classes in Diabetes After First-Line Metformin Therapy Drug/medication Weight Hypoglycemia class Cellular mechanism change risk Side effects Sulfonylureas
Closes KATP channels on beta-cell plasma membranes
Thiazolidinediones
Activates the nuclear transcription factor PPAR-gamma
Alpha-glucosidase inhibitors
Inhibits intestinal alpha-glucosidase
DPP-4 inhibitors
Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations
SGLT-2 inhibitors
Potentially blunts myocardial ischemic preconditioning None
Edema/heart failure; bone fractures
None
None
Gastrointestinal side effects (flatulence, diarrhea)
None
None
Angioedema/urticarial and other immune-mediated dermatologic effects; acute pancreatitis; increase in heart failure hospitalizations
Inhibits SGLT-2 in the proximal nephron
None
Genitourinary infections; polyuria; volume depletion/hypotension/ dizziness
GLP-1 receptor agonists
Activates GLP-1 receptors
None
Gastrointestinal side effects (nausea, vomiting, diarrhea); acute pancreatitis
Insulins
Activates insulin receptors
Potential mitogenic effects
DPP indicates dipeptidyl peptidase; GIP, gastric inhibitory polypeptide; GLP, glucagon-like peptide; PPAR, peroxisome proliferatoractivated receptor; SGLT, sodium-glucose linked transporter. Source: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140-149.
siderable body of evidence showing good efficacy and tolerability, very low risk for hypoglycemia, and weightloss capability.7
A Retrospective Study of Serial Nonadherence In a novel research initiative whose results were recently presented at the European Association for the Study of Diabetes, Frois and colleagues described the prevalence of nonadherence and of serial nonadherence, in particular, in a large cohort of US patients with diabetes; identified key predictors of nonadherence to antidiabetes therapy; and characterized the burden of illness that is associated with nonadherence to antidiabetes therapy. In this study, serial nonadherence was defined as repeated nonadherence to antidiabetes and nondiabetes medications.6 This retrospective cohort study was conducted using patient-level data from a large commercial claims and encounter database.6 The analyses focused on patients who received second-line antidiabetes therapy, defined as patients who took another diabetes therapy after first starting metformin or a metformin-containing antidiabe-
Supplement
l
April 2015
tes medication. This cohort represents a large population that is receiving sequential pharmacotherapy, which is a prerequisite for studying this patient population.6 In the study, the researchers measured medication adherence by using the proportion of days covered, calculated as the total number of nonoverlapping days of medication supply 1 year after starting therapy, divided by 365 days.6 Nonadherence was defined as less than 80% of the proportion of days covered. Adherence was measured for selected nondiabetes medications at baseline, first-line antidiabetes therapy during the first year after the index date, and second-line antidiabetes medications during the study period. The economic burden associated with nonadherence was measured during the 12 months after starting second-line antidiabetes therapy and included medical costs that were attributable to inpatient, outpatient, and emergency department utilization, including treatment for hypoglycemia.6 The researchers used logistic regression models to identify predictors of nonadherence to second-line antidiabetes therapy.6 The potential predictors of medication
www.AHDBonline.com
l
American Health & Drug Benefits
l
S13
Nonadherent to Table 2 History of Adherence Among Patients Second-Line Antidiabetes Therapya Patients, Adherence history N (%) Not adherent to first7448 (27) Not adherent to line diabetes therapy nondiabetes therapy (80%, N = 21,632) (serial nonadherenceb)
Adherent to first-line diabetes therapy (20%, N = 5529)
Adherent to nondiabetes therapy
7448 (27)
Otherc
7689 (28)
Not adherent to nondiabetes therapy
1035 (4)
Adherent to nondiabetes therapy
3088 (11)
Otherc
1406 (5)
a
Adherence was defined as the proportion of days covered ≥80%, and was measured as the total of nonoverlapping days of supply of any antidiabetes drug 1 year after initiating second-line therapy divided by 365 days. b Serial nonadherence is defined as nonadherence to second-line diabetes therapy, nonadherence to first-line diabetes therapy, and nonadherence to baseline nondiabetes therapy. c Other groups included patients with no prescription fill for nondiabetes medications observed during the baseline period. Adapted with permission from Frois C, Dea K, Ling D, et al. The burden of “serial non-adherence” in patients with type 2 diabetes. Poster presented at: European Association for the Study of Diabetes Conference; September 15-19, 2014; Vienna, Austria.
nonadherence included baseline demographic and clinical characteristics, baseline healthcare costs, time to second-line therapy, metformin regimen, and previous medication adherence. The incremental costs associated with nonadherence to second-line antidiabetes therapies were estimated using a generalized linear model that included controls for age, sex, region, type of insurance plan, comorbidities, Charlson Comorbidity Index, pharmacy costs, and medical costs.6 A total of 46,789 patients started second-line antidiabetes therapy with a minimum follow-up time of 12 months, thereby meeting the inclusion criteria for this study.6 Patients who were nonadherent to second-line therapy were more likely to have been nonadherent to first-line antidiabetes therapy and to baseline nondiabetes medications compared with patients who were adherent to second-line antidiabetes therapy. Demographically, patients who were adherent to second-line antidiabetes therapy were younger, more likely to be female, and more likely to reside in the southern United States than patients who were nonadherent to second-line antidiabetes therapy.6
S14
l
American Health & Drug Benefits
l
Overall, 58% of patients became nonadherent to antidiabetes therapy during the first year after starting second-line antidiabetes therapy (N = 27,161).6 Among the patients who were nonadherent to second-line therapy, 80% (N = 21,632) were nonadherent to first-line metformin. Furthermore, 27% (N = 7448) of patients who were nonadherent to first-line metformin were also nonadherent to nondiabetes therapy, and were therefore characterized as serially nonadherent (Table 2).6 When researchers limited their analysis to antidiabetes therapy, they found that 69% of patients who were nonadherent to first-line metformin therapy were also nonadherent to second-line antidiabetes therapy. Conversely, 66% of patients who were adherent to first-line therapy were also adherent to second-line therapy.6 Analysis of the logistic regression modeling, which was used to identify the predictors of nonadherence to second-line antidiabetes therapy, revealed that serial nonadherence was most closely associated with second-line nonadherence (odds ratio [OR], 4.67; 95% confidence interval [CI], 4.37-5.00; P
D
iabetes is one of the leading medical causes of mortality, and was responsible for an estimated 4.9 million deaths worldwide in 2014.1 Despite significant recent innovation in diabetes drug development, less than half of patients with diabetes achieve or maintain glycemic control in the United States, as reflected in healthcare quality measures.2 Better adherence to medication regimens is recognized as an important contributor to improved glycemic control.3 However, there is limited published research on the predictors of medication nonadherence. Curkendall and colleagues reported that the type of antidiabetes drug, its method of administration, the complexity of the treatment protocol, and patient demographics affected patients’ willingness to use the prescribed medications.3 Davies and colleagues described 4 categories that are associated with medication nonadherence, including (1) predictive factors, (2) patient-perceived barriers to adherence, (3) type of drug delivery device, and (4) the cost burden to the patient.4 In their systematic literature review, Davies and colleagues found that switching from a vial or a syringe to a pen device to administer insulin improved patient adherence to diabetes medications.4
Frois and colleagues showed that serial nonadherence is sizable and is a key predictor of subsequent nonadherence to therapy. Regardless of the cause, the impact of medication nonadherence on glycemic control can be challenging for physicians to evaluate.5 In particular, little is known about serial nonadherence––the repeated nonadherence to multiple medications (antidiabetes and nondiabetes medications)—in diabetes over time.6 Frois and colleagues showed that serial nonadherence is sizable and is a key predictor of subsequent nonadherence to therapy. Consistent with previous literature, serial nonadherence was associated with an increased risk for hypoglycemia and with higher medical care costs compared with adherence.6 The concept of serial nonadherence is particularly relevant to patients with type 2 diabetes, because pharmacotherapy tends to be additive rather than substitu-
S12
l
American Health & Drug Benefits
l
tive; therefore, patients may be nonadherent to several medications at the same time.6 Furthermore, because patients with type 2 diabetes frequently have multiple comorbidities, they are often prescribed antidiabetes and nondiabetes medications. Fortunately, serial nonadherence is observable and is therefore actionable.6 One recent study showed that the history of nonadherence is highly predictive of future nonadherence, and intervention strategies that can curb nonadherence early in patients’ treatment may be particularly effective in improving the care of patients with diabetes.6 If adherence is improved in earlier lines of treatment, the potential value to providers, payers, and especially patients could be considerable in terms of improved quality of care, reduced costs associated with diabetes-related complications, and improved outcomes and quality of life.6 Several potential strategies could be used to address serial nonadherence in type 2 diabetes. One such approach would minimize the need for patient decision-making related to the administration of a drug. This could be accomplished by an implantable drug delivery device that is capable of delivering a therapeutic agent for an extended duration of time. Of course, the therapeutic agent must be stable in a liquid formulation and must remain biologically active for the full treatment period after implantation. This agent should be capable of delivering hemoglobin (Hb) A1c reductions that are comparable to the currently approved drugs, with minimal impact on patient weight. In addition, the agent selected should have a low risk for hypoglycemia and other side effects. For an implantable device, safety and tolerability would be critical considerations. Table 1 shows the profiles of different drug classes that are frequently used in the treatment of patients with diabetes.7 After first-line treatment with metformin, sulfonylureas and insulins are associated with an elevated risk for hypoglycemia; sulfonylureas, thiazolidinediones, and insulins result in weight gain; and dipeptidyl peptidase-4 inhibitors and sodium-glucose linked transporter-2 inhibitors are oral agents with associated immune-mediated dermatologic effects and volume depletion, respectively.7 Of the different classes of antidiabetes agents, glucagon-like peptide-1 agonists have the most favorable profile of a therapeutic agent that is delivered via an implantable delivery device, with a con-
www.AHDBonline.com
April 2015
l
Supplement
Serial Medication Nonadherence in Patients with Type 2 Diabetes
Table 1 Comparison of Drug/Medication Classes in Diabetes After First-Line Metformin Therapy Drug/medication Weight Hypoglycemia class Cellular mechanism change risk Side effects Sulfonylureas
Closes KATP channels on beta-cell plasma membranes
Thiazolidinediones
Activates the nuclear transcription factor PPAR-gamma
Alpha-glucosidase inhibitors
Inhibits intestinal alpha-glucosidase
DPP-4 inhibitors
Inhibits DPP-4 activity, increasing postprandial active incretin (GLP-1, GIP) concentrations
SGLT-2 inhibitors
Potentially blunts myocardial ischemic preconditioning None
Edema/heart failure; bone fractures
None
None
Gastrointestinal side effects (flatulence, diarrhea)
None
None
Angioedema/urticarial and other immune-mediated dermatologic effects; acute pancreatitis; increase in heart failure hospitalizations
Inhibits SGLT-2 in the proximal nephron
None
Genitourinary infections; polyuria; volume depletion/hypotension/ dizziness
GLP-1 receptor agonists
Activates GLP-1 receptors
None
Gastrointestinal side effects (nausea, vomiting, diarrhea); acute pancreatitis
Insulins
Activates insulin receptors
Potential mitogenic effects
DPP indicates dipeptidyl peptidase; GIP, gastric inhibitory polypeptide; GLP, glucagon-like peptide; PPAR, peroxisome proliferatoractivated receptor; SGLT, sodium-glucose linked transporter. Source: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140-149.
siderable body of evidence showing good efficacy and tolerability, very low risk for hypoglycemia, and weightloss capability.7
A Retrospective Study of Serial Nonadherence In a novel research initiative whose results were recently presented at the European Association for the Study of Diabetes, Frois and colleagues described the prevalence of nonadherence and of serial nonadherence, in particular, in a large cohort of US patients with diabetes; identified key predictors of nonadherence to antidiabetes therapy; and characterized the burden of illness that is associated with nonadherence to antidiabetes therapy. In this study, serial nonadherence was defined as repeated nonadherence to antidiabetes and nondiabetes medications.6 This retrospective cohort study was conducted using patient-level data from a large commercial claims and encounter database.6 The analyses focused on patients who received second-line antidiabetes therapy, defined as patients who took another diabetes therapy after first starting metformin or a metformin-containing antidiabe-
Supplement
l
April 2015
tes medication. This cohort represents a large population that is receiving sequential pharmacotherapy, which is a prerequisite for studying this patient population.6 In the study, the researchers measured medication adherence by using the proportion of days covered, calculated as the total number of nonoverlapping days of medication supply 1 year after starting therapy, divided by 365 days.6 Nonadherence was defined as less than 80% of the proportion of days covered. Adherence was measured for selected nondiabetes medications at baseline, first-line antidiabetes therapy during the first year after the index date, and second-line antidiabetes medications during the study period. The economic burden associated with nonadherence was measured during the 12 months after starting second-line antidiabetes therapy and included medical costs that were attributable to inpatient, outpatient, and emergency department utilization, including treatment for hypoglycemia.6 The researchers used logistic regression models to identify predictors of nonadherence to second-line antidiabetes therapy.6 The potential predictors of medication
www.AHDBonline.com
l
American Health & Drug Benefits
l
S13
Nonadherent to Table 2 History of Adherence Among Patients Second-Line Antidiabetes Therapya Patients, Adherence history N (%) Not adherent to first7448 (27) Not adherent to line diabetes therapy nondiabetes therapy (80%, N = 21,632) (serial nonadherenceb)
Adherent to first-line diabetes therapy (20%, N = 5529)
Adherent to nondiabetes therapy
7448 (27)
Otherc
7689 (28)
Not adherent to nondiabetes therapy
1035 (4)
Adherent to nondiabetes therapy
3088 (11)
Otherc
1406 (5)
a
Adherence was defined as the proportion of days covered ≥80%, and was measured as the total of nonoverlapping days of supply of any antidiabetes drug 1 year after initiating second-line therapy divided by 365 days. b Serial nonadherence is defined as nonadherence to second-line diabetes therapy, nonadherence to first-line diabetes therapy, and nonadherence to baseline nondiabetes therapy. c Other groups included patients with no prescription fill for nondiabetes medications observed during the baseline period. Adapted with permission from Frois C, Dea K, Ling D, et al. The burden of “serial non-adherence” in patients with type 2 diabetes. Poster presented at: European Association for the Study of Diabetes Conference; September 15-19, 2014; Vienna, Austria.
nonadherence included baseline demographic and clinical characteristics, baseline healthcare costs, time to second-line therapy, metformin regimen, and previous medication adherence. The incremental costs associated with nonadherence to second-line antidiabetes therapies were estimated using a generalized linear model that included controls for age, sex, region, type of insurance plan, comorbidities, Charlson Comorbidity Index, pharmacy costs, and medical costs.6 A total of 46,789 patients started second-line antidiabetes therapy with a minimum follow-up time of 12 months, thereby meeting the inclusion criteria for this study.6 Patients who were nonadherent to second-line therapy were more likely to have been nonadherent to first-line antidiabetes therapy and to baseline nondiabetes medications compared with patients who were adherent to second-line antidiabetes therapy. Demographically, patients who were adherent to second-line antidiabetes therapy were younger, more likely to be female, and more likely to reside in the southern United States than patients who were nonadherent to second-line antidiabetes therapy.6
S14
l
American Health & Drug Benefits
l
Overall, 58% of patients became nonadherent to antidiabetes therapy during the first year after starting second-line antidiabetes therapy (N = 27,161).6 Among the patients who were nonadherent to second-line therapy, 80% (N = 21,632) were nonadherent to first-line metformin. Furthermore, 27% (N = 7448) of patients who were nonadherent to first-line metformin were also nonadherent to nondiabetes therapy, and were therefore characterized as serially nonadherent (Table 2).6 When researchers limited their analysis to antidiabetes therapy, they found that 69% of patients who were nonadherent to first-line metformin therapy were also nonadherent to second-line antidiabetes therapy. Conversely, 66% of patients who were adherent to first-line therapy were also adherent to second-line therapy.6 Analysis of the logistic regression modeling, which was used to identify the predictors of nonadherence to second-line antidiabetes therapy, revealed that serial nonadherence was most closely associated with second-line nonadherence (odds ratio [OR], 4.67; 95% confidence interval [CI], 4.37-5.00; P
