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Real-world Clinical Outcomes Among Patients With Type 2 Diabetes Receiving Canagliflozin at a Specialty Diabetes Clinic: Subgroup Analysis by Baseline HbA1c and Age
Address correspondence to: June Felice Johnson, PharmD, Drake University College of Pharmacy and Health Sciences, 2507 University Avenue, Cline Atrium 009, Des Moines, IA 50311.
Canagliflozin, a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM), has demonstrated effectiveness in patients with T2DM receiving care at a specialty diabetes clinic. We report the outcomes in these patients in subgroups classified by baseline hemoglobin A1c (HbA1c) and age.
Methods
This subgroup analysis was based on a review of data from the electronic health records of adults with T2DM who were prescribed canagliflozin at a specialty diabetes clinic and who returned for ≥1 follow-up office visit. Mean changes from baseline to the first and second follow-up office visits in HbA1c, body weight, and systolic and diastolic blood pressure (BP) were calculated in each subgroup classified by baseline HbA1c (≥7.0%, ≥8.0%, and >9.0%) and age (<65 and ≥65 years).
Findings
Of the 462 patients included in the study, 430, 305, and 169 patients had baseline HbA1c ≥7.0%, ≥8.0%, and >9.0%, respectively; 396 and 66 patients were aged <65 and ≥65 years, respectively. With canagliflozin use, patients across subgroups classified by baseline HbA1c and age experienced clinically and statistically significant reductions from baseline in HbA1c, body weight, and systolic BP that were sustained over 2 office visits; diastolic BP was also reduced across baseline HbA1c and age subgroups. Greater reductions in HbA1c were seen among the canagliflozin-treated patients with higher baseline HbA1c and among younger versus older patients.
Implication
These findings from clinical practice demonstrate real-world effectiveness of canagliflozin in lowering HbA1c, body weight, and systolic BP among patients with T2DM, regardless of baseline HbA1c levels or age.
Canagliflozin is a sodium glucose co-transporter 2 inhibitor approved for the treatment of hyperglycemia in adults with type 2 diabetes mellitus (T2DM).
Canagliflozin lowers blood glucose by decreasing the renal threshold for glucose and increasing urinary glucose excretion, resulting in a mild osmotic diuresis and a net caloric loss, which contribute to reductions in body weight and blood pressure (BP).
Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus.
The insulin-independent mechanism of action of canagliflozin makes it complementary to other antihyperglycemic agents (AHAs), with a low inherent risk for hypoglycemia. Across clinical trials in patients with T2DM, canagliflozin has been shown to provide clinically meaningful reductions in hemoglobin A1c (HbA1c), body weight, and BP when administered as monotherapy and in combination with metformin with or without other AHAs.
Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study.
Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial.
Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.
Efficacy and safety of canagliflozin, an inhibitor of sodium glucose co-transporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.
Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial.
Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study.
Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week, randomized trial.
Patients’ characteristics, such as baseline HbA1c and age, have been shown to be related to the magnitude of changes associated with glucose-lowering treatments.
in clinical trials. Age-related differences in the glycemic efficacy of canagliflozin may reflect differences in renal function status, as the efficacy of canagliflozin is affected by glomerular filtration rate (GFR), which may be diminished in older patients.
The choice of therapy in older patients requires careful consideration of the benefit–risk profiles of AHA options; for instance, hypoglycemia is a particular concern, as the risk for hypoglycemia increases with age.
While randomized controlled trials report on clinical outcomes in controlled settings, such results may not be generalizable to patients seen in clinical practice. Previous real-world studies based on large-scale prescription claims databases and electronic health records (EHRs) have demonstrated improvements in glycemic control following the initiation of canagliflozin treatment in patients with T2DM.
Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors.
Real-world glycemic, blood pressure, and weight control in patients with type 2 diabetes mellitus treated with canagliflozin-an electronic health-record-based study.
Patients receiving care in specialty diabetes clinics tend to have a longer duration of disease and greater medication complexity than those seen in other treatment settings.
It is therefore important to consider how baseline HbA1c and age may affect outcomes in patients prescribed canagliflozin in such settings. In a study conducted at the Iowa Diabetes Endocrinology Center (IDEC), a specialty diabetes clinic, patients treated with canagliflozin experienced statistically and clinically significant reductions in HbA1c, body weight, and BP.
Using data from the previous IDEC study, the present analysis examined outcomes in subgroups of canagliflozin-treated patients with T2DM, classified by baseline HbA1c and age.
Patients and Methods
Study Design and Population
This subgroup analysis was based on a retrospective, noninterventional review of data from the EHRs (Centricity) of patients who were prescribed canagliflozin at a specialty diabetes clinic (IDEC) from June 2013 to June 2015. Details of the overall study design, patient population, and data collection were described previously.
Briefly, eligible patients were aged ≥18 years, had T2DM, were of active status in the clinic, had received initial and regular follow-up care in the clinic, had received the initial prescription for canagliflozin from the clinic, and had returned to the clinic for ≥1 follow-up office visit after canagliflozin was prescribed. Patients were excluded if they failed to return to the clinic for ≥1 follow-up office visit, were prescribed canagliflozin by a provider outside of the clinic, were diagnosed with T1DM or any other type of diabetes other than T2DM, were aged <18 years, had gestational diabetes, or were pregnant.
Ethics Approval
The study protocol was approved by the independent institutional review board affiliated with Mercy Medical Center (Des Moines, Iowa) and adhered to all human-subject protections regulations. Patients’ data included in the study were de-identified, using assignment to a unique patient number, to ensure confidentiality and compliance with the Health Insurance Portability and Accountability Act.
Data Collection and Statistical Analysis
Baseline characteristics were obtained from EHRs from the initial date of canagliflozin prescription (index date). HbA1c, body weight, and systolic and diastolic BP were assessed at all visits. First and second follow-up office visits were defined as the first and second time that the patient returned to the clinic after the index date. Mean changes from baseline to the first and second follow-up office visits in HbA1c, body weight, and systolic and diastolic BP were calculated in each subgroup classified by baseline HbA1c (≥7.0%, ≥8.0%, and >9.0%, per Healthcare Effectiveness Data and Information Set [HEDIS] criteria
) and age (<65 and ≥65 years). Each patient served as his or her own control. Paired t tests were used for determining the significance of changes from baseline to each office visit, with statistical significance defined as P < 0.05.
Results
Baseline Clinical Characteristics
A total of 462 patients met the study inclusion criteria over the 2-year period.
In the overall sample, the mean (SD) duration of canagliflozin prescribing was 10.7 (6.13) months; the mean (SD) times to first and second follow-up office visits were 106 (60.72) days and 215 (76.1) days, respectively (medians, 98 and 202 days, respectively).
At baseline, 430 patients had HbA1c ≥7.0%, 305 patients had HbA1c ≥8.0%, and 169 patients had HbA1c >9.0%; mean (SD) baseline HbA1c was 9.00% (1.53), 9.58% (1.45), and 10.49% (1.37) in each respective subgroup (Table I). Demographic and disease characteristics were similar across the baseline-HbA1c subgroups; the majority of patients were men, and the mean duration of T2DM was >12 years in all 3 HbA1c subgroups. The mean numbers of diabetes, antihypertensive, and lipid-lowering medications being used per patient at baseline were similar across the 3 HbA1c subgroups.
Table IPatients׳ characteristics at baseline, by HbA1c and age (N = 462). Data are given as mean (SD) unless otherwise noted.
In the overall sample, 396 patients were aged <65 years (mean, 52.9 years) and 66 patients were aged ≥65 years (mean, 69.8 years) (Table I). Patients aged ≥65 years had a longer mean duration of T2DM and lower mean baseline HbA1c, body weight, and body mass index values compared with those aged <65 years. The mean baseline systolic BP was higher and diastolic BP was lower in the subgroup aged ≥65 years compared with those in the subgroup aged <65 years. The mean numbers of diabetes medications and lipid-lowering medications per patient were similar across the 2 age subgroups; however, the subgroup aged ≥65 years was taking more antihypertensive medications than the subgroup aged <65 years.
Clinical Outcomes
Changes from baseline in clinical parameters measured at the first and second follow-up office visits in the subgroups classified by baseline HbA1c and age are shown in Table II. With canagliflozin treatment, patients across the 3 baseline HbA1c subgroups had significant reductions in HbA1c over the 2 follow-up office visits. Larger HbA1c reductions were seen among patients with higher baseline HbA1c (Figure 1A). Across subgroups by baseline HbA1c, body weight was significantly reduced from baseline to the first follow-up office visit. Weight loss was generally sustained at the second follow-up office visit (Figure 1B). Across all 3 baseline HbA1c subgroups, significant reductions in systolic BP at both follow-up office visits were seen (Figure 1C). Across all 3 HbA1c subgroups, diastolic BP was reduced from baseline to the first follow-up office visit, with reductions from baseline also seen at the second follow-up office visit in all 3 baseline HbA1c subgroups (Figure 1D). Across all 3 baseline HbA1c subgroups, the mean numbers of diabetes medications per patient were similar between the first and second follow-up office visits and baseline (≥7.0%: 3.6, 3.5, and 3.6, respectively; ≥8.0%: 3.6, 3.5, and 3.6; and >9.0%: 3.5, 3.4, and 3.6).
Table IIClinical parameters, by baseline HbA1c and age.
In patients with data at baseline and at the first or second follow-up office visit, not all patients had values recorded at each time point. P values were determined using paired t tests; statistical significance was defined as P < 0.05.
In patients with data at baseline and at the first or second follow-up office visit, not all patients had values recorded at each time point. P values were determined using paired t tests; statistical significance was defined as P < 0.05.
† To convert from pounds to kilograms, multiply by 0.45.
Figure 1Mean hemoglobin A1c (HbA1c) (A), body weight (B), systolic blood pressure (BP) (C), and diastolic BP (D) over time, by baseline HbA1c, in patients with data from baseline and any follow-up office visit (OV). Paired t tests were performed for determining the significance of changes from baseline to each OV; statistical significance was defined as P < 0.05. To convert pounds to kilograms, multiply by 0.45.
With canagliflozin treatment, the subgroups aged <65 and ≥65 years had significant reductions in HbA1c from baseline to the first follow-up office visit; this change was sustained at the second follow-up office visit. Smaller changes from baseline were seen among patients aged ≥65 years compared with those in the subgroup aged <65 years (Figure 2A). Body weight was significantly reduced at the first follow-up office visit in patients aged <65 and ≥65 years; this change was generally sustained across age subgroups at the second follow-up office visit (Figure 2B). Significant reductions from baseline in systolic BP were seen over 2 office visits, regardless of age (Figure 2C), with larger reductions seen among older versus younger patients. At the first follow-up office visit, diastolic BP was decreased from baseline in both subgroups regardless of age (Figure 2D). Reductions from baseline were sustained at the second follow-up office visit in the subgroup aged <65 years, while smaller changes from baseline were seen in the subgroup aged ≥65 years.
Figure 2Mean hemoglobin A1c (HbA1c) (A), body weight (B), systolic blood pressure (BP) (C), and diastolic BP (D) over time, by age, in patients with data from baseline and any follow-up office visit (OV). Paired t tests were performed for determining the significance of changes from baseline to each OV; statistical significance was defined as P < 0.05. To convert pounds to kilograms, multiply by 0.45.
In the previous study of EHR data, glycemic control, body weight, and systolic BP were improved among patients with T2DM treated with canagliflozin at a specialty diabetes clinic.
In the present subgroup analysis, which was based on data from the previous study, patients treated with canagliflozin at the clinic experienced clinically and statistically significant reductions from baseline in HbA1c, body weight, and systolic BP, regardless of baseline HbA1c or age; these reductions were generally sustained over 2 office visits (mean, 215 days). With canagliflozin treatment, patients also had reductions in diastolic BP across baseline HbA1c and age subgroups.
Greater reductions in HbA1c were seen among canagliflozin-treated patients with higher baseline HbA1c values; this finding is consistent with observations from a separate analysis of claims data from clinical practice
Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.
Efficacy and safety of canagliflozin, an inhibitor of sodium glucose co-transporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.
Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week, randomized trial.
These findings suggest that there may be an opportunity for reducing medication burden when canagliflozin is given as add-on therapy in patients with higher baseline HbA1c, as additional agents may not be needed for lowering HbA1c. It is noteworthy that the mean number of diabetes medications was the same at each follow-up office visit regardless of baseline HbA1c. Reductions in body weight and BP with canagliflozin were generally similar across the 3 baseline-HbA1c subgroups.
With canagliflozin, significant reductions from baseline in HbA1c were seen over 2 follow-up office visits in the subgroups aged <65 and ≥65 years. As expected, older patients had smaller reductions in HbA1c at each office visit, which may reflect potentially reduced renal functioning in this population; although most patients had an estimated GFR of >60 mL/min/1.73 m2 at baseline, renal-function measures (eg, eGFR, creatinine clearance) were not consistently recorded throughout the study. These findings are consistent with the effects of canagliflozin in older patients reported in real-world studies of claims data
In addition, the older subgroup had a lower mean baseline HbA1c, which may have also contributed to the smaller changes compared with those in the younger subgroup. There were no notable differences in body weight changes between the subgroups aged <65 and ≥65 years in this analysis, and changes were consistent with observations from younger versus older patients in clinical trials of canagliflozin.
Larger reductions in systolic BP were seen with canagliflozin treatment in older versus younger patients, which was expected based on clinical trial results that also demonstrated an increased prevalence of volume depletion adverse events in older patients receiving canagliflozin.
The greater reduction in systolic BP from baseline to the first office visit in the subgroup aged >65 years compared with the subgroup aged ≤65 years (10.5 vs 2.9 mmHg, respectively) suggests that closer and earlier monitoring of BP changes may be prudent. The subgroup aged >65 years also had greater use of antihypertensive medications at baseline, which may have contributed to the observed BP reductions in this study; however, it should be noted that a previous analysis of clinical trial data found similar BP reductions in patients treated with canagliflozin regardless of antihypertensive medication usage.
Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus.
Overall, results suggest that the BP-lowering effects of canagliflozin seen early during therapy may be especially important in older patients receiving a combination of antihypertensive and diuretic medications. Enhanced education may be needed for ensuring that patients are aware of the potential for canagliflozin to reduce BP, particularly among older patients who are already taking hypertensive medications; increased awareness may help in the development of individualized T2DM treatment plans for these patients.
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.
Limitations of this study included the retrospective study design, which did not allow for control of sample bias, and the small number of patients included in the subgroup aged ≥65 years. In addition, information on some variables was not recorded at each office visit, which resulted in missing data in some analyses. The lack of a control group in this study represents a further limitation. Additionally, this descriptive analysis did not control for other factors, such as the initiation of treatment with other medications, that might have contributed to the changes in body weight and BP observed over the course of the study. It is also important to acknowledge that the results from this study may not be generalizable to broader populations, as the sample in this study generally had more advanced T2DM based on disease duration and number of diabetes medications. In this analysis, adverse events with canagliflozin use were not recorded, as this information may be more appropriately captured using medical claims data rather than EHRs. Despite these limitations, findings from the present study supplement the growing body of evidence on real-world outcomes with canagliflozin.
Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors.
Real-world glycemic, blood pressure, and weight control in patients with type 2 diabetes mellitus treated with canagliflozin-an electronic health-record-based study.
The results from this subgroup analysis of data from a patient population at a specialty diabetes clinic suggest that canagliflozin may be a suitable therapeutic option for patients with T2DM, regardless of baseline HbA1c level or age.
Conflicts Of Interest
This research and medical writing and editing support were funded by Janssen Scientific Affairs, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation. The sponsor was involved in the study design, data collection, data analysis, manuscript preparation, and publication decisions.
Drs. Johnson and Parsa received financial support for this project from Janssen Pharmaceuticals and are not employees of Janssen. Dr. Bailey is a full-time employee of Janssen Scientific Affairs, LLC, and holds stock options in Johnson & Johnson. The authors have indicated that they have no other conflicts of interest with regard to the content of this article.
Acknowledgments
Medical writing support was provided by Alaina Mitsch, PhD, of MedErgy. Drs. Johnson and Parsa contributed to the design and conduct of the study; the acquisition, analysis, and interpretation of the data; and the drafting, review, and approval of the manuscript. Dr. Bailey contributed to the analysis and interpretation of the data and the drafting, review, and approval of the manuscript. All of the authors had full access to study data; were involved in the integrity of the data and the accuracy of the data analysis; and reviewed, edited, and approved the report for publication.
References
INVOKANA® (canagliflozin) tablets, for oral use [package insert].
Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus.
Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study.
Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial.
Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.
Efficacy and safety of canagliflozin, an inhibitor of sodium glucose co-transporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes.
Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial.
Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study.
Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week, randomized trial.
Real-world evaluation of glycemic control among patients with type 2 diabetes mellitus treated with canagliflozin versus dipeptidyl peptidase-4 inhibitors.
Real-world glycemic, blood pressure, and weight control in patients with type 2 diabetes mellitus treated with canagliflozin-an electronic health-record-based study.
Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus.
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.
HbA1c ≥7.0%, ≥8.0%, and >9.0%, n = 428, 305, and 169, respectively; age <65 and ≥65 years, n = 395 and 65, respectively.
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