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Quality Measure Attainment After Add-on Therapy of Both Saxagliptin and Dapagliflozin to Metformin Versus Single Add-On of Saxagliptin or Dapagliflozin
Author(s)
Lawrence Blonde, MD
John J. Sheehan, PhD
Yu Chen Barrett, PhD
Ricardo Garcia-Sanchez, MD

From the Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA (Dr. Blonde), and AstraZeneca, Gaithersburg, MD (Drs. Sheehan, Barrett, and Garcia-Sanchez).

 

Abstract

  • Objective: To evaluate diabetes care quality measure attainment, specifically, blood glucose and blood pressure (BP) control, with saxagliptin, a dipeptidyl peptidase-4 inhibitor, and dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added singly or as dual add-on therapy in patients with type 2 diabetes inadequately controlled with metformin alone.
  • Methods: Analysis of a phase 3, randomized, double-blind, active-controlled, parallel-group trial was conducted. Patients were randomized 1:1:1 to receive saxagliptin 5 mg/d plus dapagliflozin 10 mg/d, saxagliptin 5 mg/d, or dapagliflozin 10 mg/d as add-on to metformin 1500 to 2000 mg/d. Assessments included attainment of individual and composite glycated hemoglobin (A1C) and BP measures at 24 weeks of treatment.
  • Results: Compared with single add-on saxagliptin or dapagliflozin, dual add-on saxagliptin plus dapagliflozin to metformin was associated with significantly more patients attaining the individual quality measures of A1C < 7% and A1C < 8%. Similarly, dual add-on saxagliptin plus dapagliflozin was associated with significantly more patients attaining the composite quality measures A1C < 7% and BP < 140/90 mm Hg and A1C < 8% and BP < 140/90 mmHg (vs saxagliptin plus metformin).
  • Conclusion: Dual add-on saxagliptin plus dapagliflozin to metformin was associated with a higher proportion of patients achieving glycemic and BP quality measures compared with single add-on saxagliptin or dapagliflozin.

Assessment of performance is a focus of many health care organizations as a means to evaluate and improve the quality of health care. Standardized performance measures have been developed to improve quality of care as well as to allow for comparative assessment of health plans and to support pay for performance models [1]. A widely used set of performance measures is the Healthcare Effectiveness Data and Information Set or HEDIS [2,3], measures that are maintained by the National Committee for Quality Assurance [4,5] and used by most US health plans [6].

Type 2 diabetes (T2D) is a focus of quality measure assessment and performance improvement because of its high prevalence, substantial personal and economic impact on society, high morbidity and mortality, and because it is a condition that requires coordinated care. Important outcome measures for diabetes include blood glucose control and blood pressure (BP) control. HEDIS measures for T2D include a glycated hemoglobin (A1C) > 9%, indicating poor glucose control, < 8%, indicating good control, and < 7%, a more stringent measure of good glycemic control. The HEDIS measure for BP in T2D is < 140/90 mm Hg, which is considered good BP control. All of these HEDIS measures are currently or were previously (A1C < 7%) endorsed by the National Quality Forum [1,7–10]. Endorsement of a quality measure by the NQF indicates that the measure has been thoroughly evaluated, meets specific criteria, and is based on recognized standards of care grounded in evidence-based medicine [1].

A number of oral agents are utilized in the treatment of diabetes. Saxagliptin, an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, and dapagliflozin, an oral sodium-glucose cotransporter-2 (SGLT-2) inhibitor, are indicated as adjuncts to diet and exercise in adults with T2D [11,12]. Saxagliptin inhibits DPP-4, and thereby reduces fasting and postprandial glucose concentrations by preventing degradation of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide [13]. Dapagliflozin reduces blood glucose concentrations by inhibiting glucose reabsorption in the proximal tubule of the kidney, which results in enhanced urinary glucose excretion [14]. Because their mechanisms of action are glucose-dependent, both saxagliptin and dapagliflozin have a low intrinsic potential to cause hypoglycemia [13,14]. In a randomized, double-blind study of patients with T2D inadequately controlled with metformin, Rosenstock et al assessed the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone (ClinicalTrials.gov identifier, NCT01606007) [15]. The dual add-on therapy resulted in a greater adjusted mean reduction from baseline in A1C at week 24 (–1.47%) compared with either saxagliptin (–0.88%) or dapagliflozin (–1.20%) alone added to metformin; the difference for dual add-on saxagliptin plus dapagliflozin to metformin vs. single add-on saxagliptin and single add-on dapagliflozin was –0.59% (P < 0.001) and –0.27% (P = 0.0166), respectively. The incidence of adverse events was similar across the 3 treatment groups, and hypo-glycemia was infrequent (1%), with no reports of severe hypoglycemia events (symptomatic events with glucose ≤ 54 mg/dL requiring assistance).

In this paper, we assess the attainment of diabetes quality measures among patients in this study, specifically, measures of glycemic and BP control.

Methods

Study Design and Patients

This was a post hoc analysis of a phase 3, multicenter, randomized, double-blind, active-controlled, parallel-group, 24-week study. Details of the study design, inclusion/exclusion criteria, and primary results have been previously reported [15]. In brief, men and women aged ≥ 18 years with T2D poorly controlled (A1C 8.0%–12.0%) with metformin monotherapy were randomized 1:1:1 to receive saxagliptin 5 mg/d and dapagliflozin 10 mg/d, saxagliptin 5 mg/d and placebo, or dapagliflozin 10 mg/d and placebo on a background of metformin extended release 1500 to 2000 mg/d (Figure 1). Patients were required to be on stable metformin (≥ 1500 mg/d) for ≥ 8 weeks before screening and to have a C-peptide concentration ≥ 1.0 ng/mL and a body mass index ≤ 45.0 kg/m2. The trial was designed and monitored in accordance with the ethical principles of Good Clinical Practice as defined by the International Conference on Harmonisation and the Declaration of Helsinki. Institutional review boards or ethics committees at each study site approved the protocol, and all patients gave written informed consent.

Quality Measure Assessment

Individual measures assessed included the proportion of patients with A1C < 7%, A1C < 8%, A1C > 9%, and BP < 140/90 mm Hg. Composite measures assessed includedthe proportion of patients with A1C < 7% and BP < 140/90 mm Hg and the proportion of patients with A1C < 8% and BP < 140/90 mm Hg.

Antihypertensive or cholesterol-lowering medication use was not controlled for in this study. Patients were maintained on their prescribed dosing regimen for antihypertensive and cholesterol-lowering medications, with adjustments as needed per the standard of care for their diagnosis. Treatment outcomes for A1C < 7%, < 8%, or > 9% were prespecified. The BP treatment outcome was also prespecified per the statistical analysis plan; however, a change to the HEDIS quality measure treatment outcome for BP during the clinical study resulted in this analysis being no longer relevant. Therefore, analyses of the currently endorsed quality measures for BP were conducted post hoc. Quality measure assessments for A1C and BP treatment outcomes were conducted using data from the 24-week, double-blind treatment period.

Statistical Analysis

P values for the differences in proportion of patients with individual treatment outcomes and composite treatment outcomes with saxagliptin plus dapagliflozin plus metformin versus saxagliptin plus metformin or dapagliflozin plus metformin were calculated using Fisher’s exact test. The numerator and denominator for each percentage are the number of responders and the number of patients with non-missing values in the treatment group at the corresponding baseline category, respectively, and are not corrected for baseline A1C. Because some patients experienced improvement in A1C during the lead-in period and could have already been at treatment goal at baseline, a sensitivity analysis excluding these patients was completed. Results are presented for the total number of patients with non-missing values in the treatment group, as well as patients with non-missing values in the treatment group who did not meet quality measure criteria at baseline. The number needed to treat (NNT) was calculated for all comparisons reaching statistical significance.

 

 

Results

Patients

Patient disposition, baseline demographics, and disease characteristics have been previously published [15]. A total of 534 patients were randomized to saxagliptin plus dapagliflozin plus metformin (n = 179), saxagliptinplus metformin (n = 176), or dapagliflozin plus metformin (n = 179) and received ≥ 1 dose of study medication. Patient demographics and baseline disease characteristics were generally balanced across all 3 treatment groups (Table). Mean age across the 3 treatment groups was 54 years, and there was a generally equal distribution of men and women. The mean known duration of T2D across the 3 treatment groups was 7.6 years, and mean baseline A1C was 8.94%. At baseline, 93% to 98% of patients had A1C > 7%, 74% to 82% had A1C > 8%, and 39% to 44% had A1C > 9%. At baseline, 18% to 28% of patients had BP > 140/90 mm Hg.

Individual Quality Measures

A significantly greater proportion of patients attained A1C < 7% (good glycemic control) with the dual add-on of saxagliptin plus dapagliflozin to metformin (41.8%) compared with saxagliptin plus metformin (16.6%, P < 0.001; NNT 4, 95% confidence interval [CI], 3–6) or dapagliflozin plus metformin (23.1%, P < 0.001; NNT 5, 95% CI, 4–11; Figure 2). The data were similar when the analysis excluded patients with baseline A1C < 7% (proportions of patients: 40.8% vs 15.6% vs 21.1%; P < 0.001 for both; NNTs 4 [95% CI 3–6] and 5 [95% CI 3–10]).

The dual addition of saxagliptin plus dapagliflozin to metformin resulted in a significantly greater proportion of patients achieving A1C < 8.0% compared with saxagliptin plus metformin (71.2% vs 49.1%; P < 0.001; NNT 5 [95% CI 3–8]) or dapagliflozin plus metformin (60.1%; P = 0.033; NNT 9 [95% CI 5–85]; Figure 2). Similar results (proportions of patients: 66.4% vs 40.0% vs 51.9%; P ≤ 0.02; NNTs 4 [95% CI 3–7]) and 7 [95% CI 4–34]) were attained when the analysis excluded patients with baseline A1C < 8.0%.

Significantly fewer patients had A1C > 9% (a measure of poor glycemic control) with saxagliptin plus dapagliflozin plus metformin (12.4%) compared with saxagliptin plus metformin (22.3%; P = 0.017; NNT –10 [95% CI –50 to –6]; Figure 2). The proportion of patients with A1C > 9% was similar for both regimens that included dapagliflozin (12.4% vs 10.4%; P = 0.616).

No significant difference was observed among treatment groups in the proportion of patients with BP < 140/90 mm Hg (Figure 2). However, most patients had BP < 140/90 mm Hg (72%–82%) at baseline, which was generally maintained at week 24.

Composite Quality Measures

A significantly greater proportion of patients attained the composite of A1C < 7% and BP < 140/90 mm Hg with saxagliptin plus dapagliflozin plus metformin (33.5%) compared with saxagliptin plus metformin (13.1%; P < 0.001; NNT 5 [95% CI 4–9]) or dapagliflozin plus metformin (18.6%; P = 0.002; NNT 7 [95% CI 4–17]; Figure 3). Results were similar when patients already at these goals at baseline were excluded from the analysis (32.4% vs 12.1% vs 16.3%; P < 0.001 for both; NNTs 5 [95% CI 4–9] and 6 [95% CI 4–14]).

A significantly greater proportion of patients achieved the composite of A1C < 8% and BP < 140/90 mm Hg with saxagliptin plus dapagliflozin plus metformin compared with saxagliptin plus metformin (56.8% vs 37.1%; P < 0.001; NNT 5 [95% CI 3–11]). Although not statistically significant, a numerically greater proportion of patients achieved A1C < 8% and BP < 140/90 mmHg with saxagliptin plus dapagliflozin plus metformin compared with dapagliflozin plus metformin (56.8% vs 50.0%; P = 0.237; Figure 4). Results were similar when patients already at these goals at baseline were excluded from the analysis (55.9% vs 30.2% [P < 0.001] vs 42.6% [P = 0.025]; NNTs 4 [95% CI 3–7] and 8 [95% CI 4–55]).

Discussion

This post hoc analysis evaluated attainment of glycemic and BP quality measures for diabetes. A significantly greater proportion of patients achieved the individual quality measures of A1C < 7% and A1C < 8% with dual add-on saxagliptin plus dapagliflozin to metformin compared with single add-on saxagliptin or dapagliflozin to metformin after 24 weeks. Similar results were seen when the analysis excluded patients with A1C < 7% and < 8% at baseline. All measures of good glycemic control had clinically relevant NNTs ≤ 10 after 24 weeks with saxagliptin plus dapagliflozin plus metformin compared with saxagliptin or dapagliflozin plus metformin, regardless of baseline status. Very few patients experienced lackof improvement in glycemic control, evidenced by small proportions of patients with A1C > 9%.

 

 

There was little difference in BP between dual add-on saxagliptin plus dapagliflozin or single add-on saxagliptin or dapagliflozin to metformin. The proportion of patients who attained the BP quality measure of BP < 140/90 mm Hg was similar across the 3 treatments, as might be expected because most patients already met this target at baseline. However, as might be expected based on the mild diuretic effect and weight loss associated with SGLT-2 inhibitors [16,17], trends in BP favored groups treated with dapagliflozin.

Attainment of multiple treatment targets is desirable in reducing complications of diabetes. A significantly greater proportion of patients achieved both A1C < 7% and BP < 140/90 mm Hg when both saxagliptin and dapagliflozin were added to metformin compared with single-agent addition of either saxagliptin or dapagliflozin plus metformin. Similarly, a significantly greater proportion of patients achieved both A1C < 8% and BP < 140/90 mm Hg with dual addition of saxagliptin and dapagliflozin plus metformin compared with saxagliptin plus metformin. There was also a numerically greater number of patients who achieved both of these goals with triple therapy compared with dapagliflozin plus metformin, but this finding did not reach statistical significance. Clinically relevant NNT values ≤ 10 were observed for both composite outcomes for saxagliptin plus dapagliflozin plus metformin compared with saxagliptin plus metformin or dapagliflozin plus metformin after 24 weeks.

Despite advances in the medical management of T2D, a report published in 2013 showed that between 2007 and 2010, only 53% of patients achieved an A1C < 7.0% and only 19% simultaneously achieved all 3 American Diabetes Association (ADA) goals recommended for most patients at that time: A1C < 7.0%, BP < 130/80 mm Hg, and low-density lipoprotein cholesterol LDL-C < 100 mg/dL [18]. These data highlight a need for new approaches to help patients attain glycemic, BP, and cholesterol goals. Our results demonstrated that a higher proportion of patients attained glycemic and BP quality measures with dual add-on saxagliptin plus dapagliflozin compared with single add-on saxagliptin or dapagliflozin to metformin. As a result of recent updates for cholesterol management from the American College of Cardiology and the American Heart Association [19], attainment of a cholesterol level was retired as a diabetes quality measure and replaced with a recommendation for statin therapy use [20,21]. Although the current analysis did not include assessment of LDL, DPP-4 inhibitors have demonstrated neutral effects on lipids [22,23], and SGLT-2 inhibitors have demonstrated generally modest increases in LDL-C (placebo-adjusted change from baseline: 4.5%–8.0% for canagliflozin 100 and 300 mg/d, 3.9% for dapagliflozin 10 mg, and 2.3%–4.2% for empagliflozin 10 and 25 mg/d) [12,24,25], as well as increases in high-density lipoprotein cholesterol and reductions in triglycerides [26].

Current ADA guidelines recommend an individualized, stepwise approach to treatment with sequential addition of single oral antihyperglycemic agents for patients who do not achieve their glycemic goal in 3 months [27]. Although T2D may progress at different rates in different patients, T2D does generally progress over time [28], and the ADA and American Association of Clinical Endocrinologists treatment guidelines recommend initial dual add-on therapy for individuals with higher A1C, which is suggestive of more advanced disease [27,29]. For individuals requiring initial combination therapy, guidelines note that antihyperglycemic agents that have a low risk of hypoglycemia and low potential for weight gain should be preferentially selected [29]. Attainment of A1C ≤ 7%, the guideline recommendation considered appropriate for many patients, is associated with reductions in microvascular disease and, if attained soon after diagnosis of diabetes, studies have shown reductions in macrovascular disease with long-term follow-up [27,30,31]. However, it may be challenging to achieve A1C < 7% with the addition of single oral antihyperglycemic agents, especially in patients with higher A1C [32]. Less stringent A1C goals (eg, A1C < 8%) may be appropriate in individuals with a long duration of diabetes that is difficult to control, history of severe hypoglycemia, limited life expectancy, numerous comorbidities, and extensive complications or comorbidities, especially cardiovascular disease [27]. Given the shift toward individualized treatment plans with patient-specific treatment goals, it is valuable to understand how different treatment strategies effect attainment of guideline-recommended less stringent and more stringent glycemic targets that may be appropriate for certain patients.

 

 

In addition to quality measures that assess glucose lowering with pharmacotherapy, it is important to consider measures that assess other aspects of diabetes care. For example, quality measures related to hypoglycemia and hyperglycemia may help avoid potentially adverse glucose levels, and quality measures related to weight may provide insight on treatment and lifestyle efforts directed at weight loss and management. NQF-endorsed measures of hypoglycemia and hyperglycemia are currently moving through annual review and are paired measures, intended to be interpreted with respect to one another to ensure balanced outcomes [33,34]. This underscores the value of efficacious antihyperglycemic agents with low intrinsic potential for hypoglycemia. Although this analysis did not include quality measures related to hypoglycemia or weight, future studies evaluating these aspects of diabetes care will likely further contribute to a more comprehensive and holistic treatment approach.

In addition to assessing a broad range of quality measures, an important aspect of care to consider is patient affordability. Affordability for an individual patient will depend on access in the patient’s individual plan, the financial resources of the patient, and the potential for medical cost offsets from improved control of the patient’s disease. For example, fixed-dose combination products are associated with increased patient adherence and may increase pharmacy costs but decrease medical costs [35].

Limitations of this study include the post hoc design and that quality measure attainment was assessed over a shorter duration of time (24 weeks) than is commonly assessed in the real-world/community setting (~12 months).

Dual add-on therapy with oral antihyperglycemic agents that have complementary mechanisms of action should lead to enhanced reductions in A1C. The results reported here and from the primary study, in which saxagliptin and dapagliflozin added to metformin significantly reduced mean A1C from baseline to week 24 compared with single add-on saxagliptin or dapagliflozin [15], showed that greater reductions in A1C were attained with the coadministration of saxagliptin and dapagliflozin. The glucuretic effect of SGLT-2 inhibitors has been associated with increased plasma glucagon concentrations and increased endogenous glucose production, which may impair the full glucose-lowering potential of SGLT-2 inhibitors [36,37]. Administering saxagliptin with dapagliflozin as dual therapy was shown to blunt the rise in plasma glucagon caused by dapagliflozin [38], and this may have contributed to the greater glucose control achieved with dual add-on of these 2 antihyperglycemic drugs [15].

By targeting multiple aspects of the underlying pathophysiology in T2D, greater improvements in A1C can be achieved. Dual add-on saxagliptin plus dapagliflozin to metformin resulted in a greater proportion of patients achieving NQF-endorsed HEDIS quality measures, as well as A1C < 7% (no longer an NQF-endorsed measure). As health care shifts to a more value-based payment structure, measuring quality outcomes will assume a greater role in guiding decision making and influence the care that patients receive. Understanding how antihyperglycemic medication regimens affect quality measures can help clinicians make informed decisions.

 

Corresponding author: Lawrence Blonde, MD, Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA.

Funding/support: This study was supported by AstraZeneca. Medical writing support for the preparation of this manuscript was provided by Lauren D’Angelo, PhD, and Janet Matsuura, PhD, from Complete Healthcare Communications, LLC (Chadds Ford, PA), with funding from AstraZeneca.

Financial disclosures: Dr. Blonde has received grant and research support from AstraZeneca, Jansen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis and has received honoraria for participating as a speaker from AstraZeneca, Janssen Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis as well as honoraria for consultant work from AstraZeneca, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis. R. Garcia-Sanchez is an employee of AstraZeneca. J. Sheehan and Y. C. Barrett were employees of AstraZeneca at the time of this research.

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Issue
Journal of Clinical Outcomes Management - SEPTEMBER 2016, VOL. 23, NO. 9
Publications
Journal of Clinical Outcomes Management
Type 2 Diabetes ICYMI
Topics
Diabetes
Sections
Original Research
Author(s)
Lawrence Blonde, MD
John J. Sheehan, PhD
Yu Chen Barrett, PhD
Ricardo Garcia-Sanchez, MD
Author(s)
Lawrence Blonde, MD
John J. Sheehan, PhD
Yu Chen Barrett, PhD
Ricardo Garcia-Sanchez, MD

From the Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA (Dr. Blonde), and AstraZeneca, Gaithersburg, MD (Drs. Sheehan, Barrett, and Garcia-Sanchez).

 

Abstract

  • Objective: To evaluate diabetes care quality measure attainment, specifically, blood glucose and blood pressure (BP) control, with saxagliptin, a dipeptidyl peptidase-4 inhibitor, and dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added singly or as dual add-on therapy in patients with type 2 diabetes inadequately controlled with metformin alone.
  • Methods: Analysis of a phase 3, randomized, double-blind, active-controlled, parallel-group trial was conducted. Patients were randomized 1:1:1 to receive saxagliptin 5 mg/d plus dapagliflozin 10 mg/d, saxagliptin 5 mg/d, or dapagliflozin 10 mg/d as add-on to metformin 1500 to 2000 mg/d. Assessments included attainment of individual and composite glycated hemoglobin (A1C) and BP measures at 24 weeks of treatment.
  • Results: Compared with single add-on saxagliptin or dapagliflozin, dual add-on saxagliptin plus dapagliflozin to metformin was associated with significantly more patients attaining the individual quality measures of A1C < 7% and A1C < 8%. Similarly, dual add-on saxagliptin plus dapagliflozin was associated with significantly more patients attaining the composite quality measures A1C < 7% and BP < 140/90 mm Hg and A1C < 8% and BP < 140/90 mmHg (vs saxagliptin plus metformin).
  • Conclusion: Dual add-on saxagliptin plus dapagliflozin to metformin was associated with a higher proportion of patients achieving glycemic and BP quality measures compared with single add-on saxagliptin or dapagliflozin.

Assessment of performance is a focus of many health care organizations as a means to evaluate and improve the quality of health care. Standardized performance measures have been developed to improve quality of care as well as to allow for comparative assessment of health plans and to support pay for performance models [1]. A widely used set of performance measures is the Healthcare Effectiveness Data and Information Set or HEDIS [2,3], measures that are maintained by the National Committee for Quality Assurance [4,5] and used by most US health plans [6].

Type 2 diabetes (T2D) is a focus of quality measure assessment and performance improvement because of its high prevalence, substantial personal and economic impact on society, high morbidity and mortality, and because it is a condition that requires coordinated care. Important outcome measures for diabetes include blood glucose control and blood pressure (BP) control. HEDIS measures for T2D include a glycated hemoglobin (A1C) > 9%, indicating poor glucose control, < 8%, indicating good control, and < 7%, a more stringent measure of good glycemic control. The HEDIS measure for BP in T2D is < 140/90 mm Hg, which is considered good BP control. All of these HEDIS measures are currently or were previously (A1C < 7%) endorsed by the National Quality Forum [1,7–10]. Endorsement of a quality measure by the NQF indicates that the measure has been thoroughly evaluated, meets specific criteria, and is based on recognized standards of care grounded in evidence-based medicine [1].

A number of oral agents are utilized in the treatment of diabetes. Saxagliptin, an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, and dapagliflozin, an oral sodium-glucose cotransporter-2 (SGLT-2) inhibitor, are indicated as adjuncts to diet and exercise in adults with T2D [11,12]. Saxagliptin inhibits DPP-4, and thereby reduces fasting and postprandial glucose concentrations by preventing degradation of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide [13]. Dapagliflozin reduces blood glucose concentrations by inhibiting glucose reabsorption in the proximal tubule of the kidney, which results in enhanced urinary glucose excretion [14]. Because their mechanisms of action are glucose-dependent, both saxagliptin and dapagliflozin have a low intrinsic potential to cause hypoglycemia [13,14]. In a randomized, double-blind study of patients with T2D inadequately controlled with metformin, Rosenstock et al assessed the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone (ClinicalTrials.gov identifier, NCT01606007) [15]. The dual add-on therapy resulted in a greater adjusted mean reduction from baseline in A1C at week 24 (–1.47%) compared with either saxagliptin (–0.88%) or dapagliflozin (–1.20%) alone added to metformin; the difference for dual add-on saxagliptin plus dapagliflozin to metformin vs. single add-on saxagliptin and single add-on dapagliflozin was –0.59% (P < 0.001) and –0.27% (P = 0.0166), respectively. The incidence of adverse events was similar across the 3 treatment groups, and hypo-glycemia was infrequent (1%), with no reports of severe hypoglycemia events (symptomatic events with glucose ≤ 54 mg/dL requiring assistance).

In this paper, we assess the attainment of diabetes quality measures among patients in this study, specifically, measures of glycemic and BP control.

Methods

Study Design and Patients

This was a post hoc analysis of a phase 3, multicenter, randomized, double-blind, active-controlled, parallel-group, 24-week study. Details of the study design, inclusion/exclusion criteria, and primary results have been previously reported [15]. In brief, men and women aged ≥ 18 years with T2D poorly controlled (A1C 8.0%–12.0%) with metformin monotherapy were randomized 1:1:1 to receive saxagliptin 5 mg/d and dapagliflozin 10 mg/d, saxagliptin 5 mg/d and placebo, or dapagliflozin 10 mg/d and placebo on a background of metformin extended release 1500 to 2000 mg/d (Figure 1). Patients were required to be on stable metformin (≥ 1500 mg/d) for ≥ 8 weeks before screening and to have a C-peptide concentration ≥ 1.0 ng/mL and a body mass index ≤ 45.0 kg/m2. The trial was designed and monitored in accordance with the ethical principles of Good Clinical Practice as defined by the International Conference on Harmonisation and the Declaration of Helsinki. Institutional review boards or ethics committees at each study site approved the protocol, and all patients gave written informed consent.

Quality Measure Assessment

Individual measures assessed included the proportion of patients with A1C < 7%, A1C < 8%, A1C > 9%, and BP < 140/90 mm Hg. Composite measures assessed includedthe proportion of patients with A1C < 7% and BP < 140/90 mm Hg and the proportion of patients with A1C < 8% and BP < 140/90 mm Hg.

Antihypertensive or cholesterol-lowering medication use was not controlled for in this study. Patients were maintained on their prescribed dosing regimen for antihypertensive and cholesterol-lowering medications, with adjustments as needed per the standard of care for their diagnosis. Treatment outcomes for A1C < 7%, < 8%, or > 9% were prespecified. The BP treatment outcome was also prespecified per the statistical analysis plan; however, a change to the HEDIS quality measure treatment outcome for BP during the clinical study resulted in this analysis being no longer relevant. Therefore, analyses of the currently endorsed quality measures for BP were conducted post hoc. Quality measure assessments for A1C and BP treatment outcomes were conducted using data from the 24-week, double-blind treatment period.

Statistical Analysis

P values for the differences in proportion of patients with individual treatment outcomes and composite treatment outcomes with saxagliptin plus dapagliflozin plus metformin versus saxagliptin plus metformin or dapagliflozin plus metformin were calculated using Fisher’s exact test. The numerator and denominator for each percentage are the number of responders and the number of patients with non-missing values in the treatment group at the corresponding baseline category, respectively, and are not corrected for baseline A1C. Because some patients experienced improvement in A1C during the lead-in period and could have already been at treatment goal at baseline, a sensitivity analysis excluding these patients was completed. Results are presented for the total number of patients with non-missing values in the treatment group, as well as patients with non-missing values in the treatment group who did not meet quality measure criteria at baseline. The number needed to treat (NNT) was calculated for all comparisons reaching statistical significance.

 

 

Results

Patients

Patient disposition, baseline demographics, and disease characteristics have been previously published [15]. A total of 534 patients were randomized to saxagliptin plus dapagliflozin plus metformin (n = 179), saxagliptinplus metformin (n = 176), or dapagliflozin plus metformin (n = 179) and received ≥ 1 dose of study medication. Patient demographics and baseline disease characteristics were generally balanced across all 3 treatment groups (Table). Mean age across the 3 treatment groups was 54 years, and there was a generally equal distribution of men and women. The mean known duration of T2D across the 3 treatment groups was 7.6 years, and mean baseline A1C was 8.94%. At baseline, 93% to 98% of patients had A1C > 7%, 74% to 82% had A1C > 8%, and 39% to 44% had A1C > 9%. At baseline, 18% to 28% of patients had BP > 140/90 mm Hg.

Individual Quality Measures

A significantly greater proportion of patients attained A1C < 7% (good glycemic control) with the dual add-on of saxagliptin plus dapagliflozin to metformin (41.8%) compared with saxagliptin plus metformin (16.6%, P < 0.001; NNT 4, 95% confidence interval [CI], 3–6) or dapagliflozin plus metformin (23.1%, P < 0.001; NNT 5, 95% CI, 4–11; Figure 2). The data were similar when the analysis excluded patients with baseline A1C < 7% (proportions of patients: 40.8% vs 15.6% vs 21.1%; P < 0.001 for both; NNTs 4 [95% CI 3–6] and 5 [95% CI 3–10]).

The dual addition of saxagliptin plus dapagliflozin to metformin resulted in a significantly greater proportion of patients achieving A1C < 8.0% compared with saxagliptin plus metformin (71.2% vs 49.1%; P < 0.001; NNT 5 [95% CI 3–8]) or dapagliflozin plus metformin (60.1%; P = 0.033; NNT 9 [95% CI 5–85]; Figure 2). Similar results (proportions of patients: 66.4% vs 40.0% vs 51.9%; P ≤ 0.02; NNTs 4 [95% CI 3–7]) and 7 [95% CI 4–34]) were attained when the analysis excluded patients with baseline A1C < 8.0%.

Significantly fewer patients had A1C > 9% (a measure of poor glycemic control) with saxagliptin plus dapagliflozin plus metformin (12.4%) compared with saxagliptin plus metformin (22.3%; P = 0.017; NNT –10 [95% CI –50 to –6]; Figure 2). The proportion of patients with A1C > 9% was similar for both regimens that included dapagliflozin (12.4% vs 10.4%; P = 0.616).

No significant difference was observed among treatment groups in the proportion of patients with BP < 140/90 mm Hg (Figure 2). However, most patients had BP < 140/90 mm Hg (72%–82%) at baseline, which was generally maintained at week 24.

Composite Quality Measures

A significantly greater proportion of patients attained the composite of A1C < 7% and BP < 140/90 mm Hg with saxagliptin plus dapagliflozin plus metformin (33.5%) compared with saxagliptin plus metformin (13.1%; P < 0.001; NNT 5 [95% CI 4–9]) or dapagliflozin plus metformin (18.6%; P = 0.002; NNT 7 [95% CI 4–17]; Figure 3). Results were similar when patients already at these goals at baseline were excluded from the analysis (32.4% vs 12.1% vs 16.3%; P < 0.001 for both; NNTs 5 [95% CI 4–9] and 6 [95% CI 4–14]).

A significantly greater proportion of patients achieved the composite of A1C < 8% and BP < 140/90 mm Hg with saxagliptin plus dapagliflozin plus metformin compared with saxagliptin plus metformin (56.8% vs 37.1%; P < 0.001; NNT 5 [95% CI 3–11]). Although not statistically significant, a numerically greater proportion of patients achieved A1C < 8% and BP < 140/90 mmHg with saxagliptin plus dapagliflozin plus metformin compared with dapagliflozin plus metformin (56.8% vs 50.0%; P = 0.237; Figure 4). Results were similar when patients already at these goals at baseline were excluded from the analysis (55.9% vs 30.2% [P < 0.001] vs 42.6% [P = 0.025]; NNTs 4 [95% CI 3–7] and 8 [95% CI 4–55]).

Discussion

This post hoc analysis evaluated attainment of glycemic and BP quality measures for diabetes. A significantly greater proportion of patients achieved the individual quality measures of A1C < 7% and A1C < 8% with dual add-on saxagliptin plus dapagliflozin to metformin compared with single add-on saxagliptin or dapagliflozin to metformin after 24 weeks. Similar results were seen when the analysis excluded patients with A1C < 7% and < 8% at baseline. All measures of good glycemic control had clinically relevant NNTs ≤ 10 after 24 weeks with saxagliptin plus dapagliflozin plus metformin compared with saxagliptin or dapagliflozin plus metformin, regardless of baseline status. Very few patients experienced lackof improvement in glycemic control, evidenced by small proportions of patients with A1C > 9%.

 

 

There was little difference in BP between dual add-on saxagliptin plus dapagliflozin or single add-on saxagliptin or dapagliflozin to metformin. The proportion of patients who attained the BP quality measure of BP < 140/90 mm Hg was similar across the 3 treatments, as might be expected because most patients already met this target at baseline. However, as might be expected based on the mild diuretic effect and weight loss associated with SGLT-2 inhibitors [16,17], trends in BP favored groups treated with dapagliflozin.

Attainment of multiple treatment targets is desirable in reducing complications of diabetes. A significantly greater proportion of patients achieved both A1C < 7% and BP < 140/90 mm Hg when both saxagliptin and dapagliflozin were added to metformin compared with single-agent addition of either saxagliptin or dapagliflozin plus metformin. Similarly, a significantly greater proportion of patients achieved both A1C < 8% and BP < 140/90 mm Hg with dual addition of saxagliptin and dapagliflozin plus metformin compared with saxagliptin plus metformin. There was also a numerically greater number of patients who achieved both of these goals with triple therapy compared with dapagliflozin plus metformin, but this finding did not reach statistical significance. Clinically relevant NNT values ≤ 10 were observed for both composite outcomes for saxagliptin plus dapagliflozin plus metformin compared with saxagliptin plus metformin or dapagliflozin plus metformin after 24 weeks.

Despite advances in the medical management of T2D, a report published in 2013 showed that between 2007 and 2010, only 53% of patients achieved an A1C < 7.0% and only 19% simultaneously achieved all 3 American Diabetes Association (ADA) goals recommended for most patients at that time: A1C < 7.0%, BP < 130/80 mm Hg, and low-density lipoprotein cholesterol LDL-C < 100 mg/dL [18]. These data highlight a need for new approaches to help patients attain glycemic, BP, and cholesterol goals. Our results demonstrated that a higher proportion of patients attained glycemic and BP quality measures with dual add-on saxagliptin plus dapagliflozin compared with single add-on saxagliptin or dapagliflozin to metformin. As a result of recent updates for cholesterol management from the American College of Cardiology and the American Heart Association [19], attainment of a cholesterol level was retired as a diabetes quality measure and replaced with a recommendation for statin therapy use [20,21]. Although the current analysis did not include assessment of LDL, DPP-4 inhibitors have demonstrated neutral effects on lipids [22,23], and SGLT-2 inhibitors have demonstrated generally modest increases in LDL-C (placebo-adjusted change from baseline: 4.5%–8.0% for canagliflozin 100 and 300 mg/d, 3.9% for dapagliflozin 10 mg, and 2.3%–4.2% for empagliflozin 10 and 25 mg/d) [12,24,25], as well as increases in high-density lipoprotein cholesterol and reductions in triglycerides [26].

Current ADA guidelines recommend an individualized, stepwise approach to treatment with sequential addition of single oral antihyperglycemic agents for patients who do not achieve their glycemic goal in 3 months [27]. Although T2D may progress at different rates in different patients, T2D does generally progress over time [28], and the ADA and American Association of Clinical Endocrinologists treatment guidelines recommend initial dual add-on therapy for individuals with higher A1C, which is suggestive of more advanced disease [27,29]. For individuals requiring initial combination therapy, guidelines note that antihyperglycemic agents that have a low risk of hypoglycemia and low potential for weight gain should be preferentially selected [29]. Attainment of A1C ≤ 7%, the guideline recommendation considered appropriate for many patients, is associated with reductions in microvascular disease and, if attained soon after diagnosis of diabetes, studies have shown reductions in macrovascular disease with long-term follow-up [27,30,31]. However, it may be challenging to achieve A1C < 7% with the addition of single oral antihyperglycemic agents, especially in patients with higher A1C [32]. Less stringent A1C goals (eg, A1C < 8%) may be appropriate in individuals with a long duration of diabetes that is difficult to control, history of severe hypoglycemia, limited life expectancy, numerous comorbidities, and extensive complications or comorbidities, especially cardiovascular disease [27]. Given the shift toward individualized treatment plans with patient-specific treatment goals, it is valuable to understand how different treatment strategies effect attainment of guideline-recommended less stringent and more stringent glycemic targets that may be appropriate for certain patients.

 

 

In addition to quality measures that assess glucose lowering with pharmacotherapy, it is important to consider measures that assess other aspects of diabetes care. For example, quality measures related to hypoglycemia and hyperglycemia may help avoid potentially adverse glucose levels, and quality measures related to weight may provide insight on treatment and lifestyle efforts directed at weight loss and management. NQF-endorsed measures of hypoglycemia and hyperglycemia are currently moving through annual review and are paired measures, intended to be interpreted with respect to one another to ensure balanced outcomes [33,34]. This underscores the value of efficacious antihyperglycemic agents with low intrinsic potential for hypoglycemia. Although this analysis did not include quality measures related to hypoglycemia or weight, future studies evaluating these aspects of diabetes care will likely further contribute to a more comprehensive and holistic treatment approach.

In addition to assessing a broad range of quality measures, an important aspect of care to consider is patient affordability. Affordability for an individual patient will depend on access in the patient’s individual plan, the financial resources of the patient, and the potential for medical cost offsets from improved control of the patient’s disease. For example, fixed-dose combination products are associated with increased patient adherence and may increase pharmacy costs but decrease medical costs [35].

Limitations of this study include the post hoc design and that quality measure attainment was assessed over a shorter duration of time (24 weeks) than is commonly assessed in the real-world/community setting (~12 months).

Dual add-on therapy with oral antihyperglycemic agents that have complementary mechanisms of action should lead to enhanced reductions in A1C. The results reported here and from the primary study, in which saxagliptin and dapagliflozin added to metformin significantly reduced mean A1C from baseline to week 24 compared with single add-on saxagliptin or dapagliflozin [15], showed that greater reductions in A1C were attained with the coadministration of saxagliptin and dapagliflozin. The glucuretic effect of SGLT-2 inhibitors has been associated with increased plasma glucagon concentrations and increased endogenous glucose production, which may impair the full glucose-lowering potential of SGLT-2 inhibitors [36,37]. Administering saxagliptin with dapagliflozin as dual therapy was shown to blunt the rise in plasma glucagon caused by dapagliflozin [38], and this may have contributed to the greater glucose control achieved with dual add-on of these 2 antihyperglycemic drugs [15].

By targeting multiple aspects of the underlying pathophysiology in T2D, greater improvements in A1C can be achieved. Dual add-on saxagliptin plus dapagliflozin to metformin resulted in a greater proportion of patients achieving NQF-endorsed HEDIS quality measures, as well as A1C < 7% (no longer an NQF-endorsed measure). As health care shifts to a more value-based payment structure, measuring quality outcomes will assume a greater role in guiding decision making and influence the care that patients receive. Understanding how antihyperglycemic medication regimens affect quality measures can help clinicians make informed decisions.

 

Corresponding author: Lawrence Blonde, MD, Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA.

Funding/support: This study was supported by AstraZeneca. Medical writing support for the preparation of this manuscript was provided by Lauren D’Angelo, PhD, and Janet Matsuura, PhD, from Complete Healthcare Communications, LLC (Chadds Ford, PA), with funding from AstraZeneca.

Financial disclosures: Dr. Blonde has received grant and research support from AstraZeneca, Jansen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis and has received honoraria for participating as a speaker from AstraZeneca, Janssen Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis as well as honoraria for consultant work from AstraZeneca, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis. R. Garcia-Sanchez is an employee of AstraZeneca. J. Sheehan and Y. C. Barrett were employees of AstraZeneca at the time of this research.

From the Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA (Dr. Blonde), and AstraZeneca, Gaithersburg, MD (Drs. Sheehan, Barrett, and Garcia-Sanchez).

 

Abstract

  • Objective: To evaluate diabetes care quality measure attainment, specifically, blood glucose and blood pressure (BP) control, with saxagliptin, a dipeptidyl peptidase-4 inhibitor, and dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, added singly or as dual add-on therapy in patients with type 2 diabetes inadequately controlled with metformin alone.
  • Methods: Analysis of a phase 3, randomized, double-blind, active-controlled, parallel-group trial was conducted. Patients were randomized 1:1:1 to receive saxagliptin 5 mg/d plus dapagliflozin 10 mg/d, saxagliptin 5 mg/d, or dapagliflozin 10 mg/d as add-on to metformin 1500 to 2000 mg/d. Assessments included attainment of individual and composite glycated hemoglobin (A1C) and BP measures at 24 weeks of treatment.
  • Results: Compared with single add-on saxagliptin or dapagliflozin, dual add-on saxagliptin plus dapagliflozin to metformin was associated with significantly more patients attaining the individual quality measures of A1C < 7% and A1C < 8%. Similarly, dual add-on saxagliptin plus dapagliflozin was associated with significantly more patients attaining the composite quality measures A1C < 7% and BP < 140/90 mm Hg and A1C < 8% and BP < 140/90 mmHg (vs saxagliptin plus metformin).
  • Conclusion: Dual add-on saxagliptin plus dapagliflozin to metformin was associated with a higher proportion of patients achieving glycemic and BP quality measures compared with single add-on saxagliptin or dapagliflozin.

Assessment of performance is a focus of many health care organizations as a means to evaluate and improve the quality of health care. Standardized performance measures have been developed to improve quality of care as well as to allow for comparative assessment of health plans and to support pay for performance models [1]. A widely used set of performance measures is the Healthcare Effectiveness Data and Information Set or HEDIS [2,3], measures that are maintained by the National Committee for Quality Assurance [4,5] and used by most US health plans [6].

Type 2 diabetes (T2D) is a focus of quality measure assessment and performance improvement because of its high prevalence, substantial personal and economic impact on society, high morbidity and mortality, and because it is a condition that requires coordinated care. Important outcome measures for diabetes include blood glucose control and blood pressure (BP) control. HEDIS measures for T2D include a glycated hemoglobin (A1C) > 9%, indicating poor glucose control, < 8%, indicating good control, and < 7%, a more stringent measure of good glycemic control. The HEDIS measure for BP in T2D is < 140/90 mm Hg, which is considered good BP control. All of these HEDIS measures are currently or were previously (A1C < 7%) endorsed by the National Quality Forum [1,7–10]. Endorsement of a quality measure by the NQF indicates that the measure has been thoroughly evaluated, meets specific criteria, and is based on recognized standards of care grounded in evidence-based medicine [1].

A number of oral agents are utilized in the treatment of diabetes. Saxagliptin, an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, and dapagliflozin, an oral sodium-glucose cotransporter-2 (SGLT-2) inhibitor, are indicated as adjuncts to diet and exercise in adults with T2D [11,12]. Saxagliptin inhibits DPP-4, and thereby reduces fasting and postprandial glucose concentrations by preventing degradation of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide [13]. Dapagliflozin reduces blood glucose concentrations by inhibiting glucose reabsorption in the proximal tubule of the kidney, which results in enhanced urinary glucose excretion [14]. Because their mechanisms of action are glucose-dependent, both saxagliptin and dapagliflozin have a low intrinsic potential to cause hypoglycemia [13,14]. In a randomized, double-blind study of patients with T2D inadequately controlled with metformin, Rosenstock et al assessed the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone (ClinicalTrials.gov identifier, NCT01606007) [15]. The dual add-on therapy resulted in a greater adjusted mean reduction from baseline in A1C at week 24 (–1.47%) compared with either saxagliptin (–0.88%) or dapagliflozin (–1.20%) alone added to metformin; the difference for dual add-on saxagliptin plus dapagliflozin to metformin vs. single add-on saxagliptin and single add-on dapagliflozin was –0.59% (P < 0.001) and –0.27% (P = 0.0166), respectively. The incidence of adverse events was similar across the 3 treatment groups, and hypo-glycemia was infrequent (1%), with no reports of severe hypoglycemia events (symptomatic events with glucose ≤ 54 mg/dL requiring assistance).

In this paper, we assess the attainment of diabetes quality measures among patients in this study, specifically, measures of glycemic and BP control.

Methods

Study Design and Patients

This was a post hoc analysis of a phase 3, multicenter, randomized, double-blind, active-controlled, parallel-group, 24-week study. Details of the study design, inclusion/exclusion criteria, and primary results have been previously reported [15]. In brief, men and women aged ≥ 18 years with T2D poorly controlled (A1C 8.0%–12.0%) with metformin monotherapy were randomized 1:1:1 to receive saxagliptin 5 mg/d and dapagliflozin 10 mg/d, saxagliptin 5 mg/d and placebo, or dapagliflozin 10 mg/d and placebo on a background of metformin extended release 1500 to 2000 mg/d (Figure 1). Patients were required to be on stable metformin (≥ 1500 mg/d) for ≥ 8 weeks before screening and to have a C-peptide concentration ≥ 1.0 ng/mL and a body mass index ≤ 45.0 kg/m2. The trial was designed and monitored in accordance with the ethical principles of Good Clinical Practice as defined by the International Conference on Harmonisation and the Declaration of Helsinki. Institutional review boards or ethics committees at each study site approved the protocol, and all patients gave written informed consent.

Quality Measure Assessment

Individual measures assessed included the proportion of patients with A1C < 7%, A1C < 8%, A1C > 9%, and BP < 140/90 mm Hg. Composite measures assessed includedthe proportion of patients with A1C < 7% and BP < 140/90 mm Hg and the proportion of patients with A1C < 8% and BP < 140/90 mm Hg.

Antihypertensive or cholesterol-lowering medication use was not controlled for in this study. Patients were maintained on their prescribed dosing regimen for antihypertensive and cholesterol-lowering medications, with adjustments as needed per the standard of care for their diagnosis. Treatment outcomes for A1C < 7%, < 8%, or > 9% were prespecified. The BP treatment outcome was also prespecified per the statistical analysis plan; however, a change to the HEDIS quality measure treatment outcome for BP during the clinical study resulted in this analysis being no longer relevant. Therefore, analyses of the currently endorsed quality measures for BP were conducted post hoc. Quality measure assessments for A1C and BP treatment outcomes were conducted using data from the 24-week, double-blind treatment period.

Statistical Analysis

P values for the differences in proportion of patients with individual treatment outcomes and composite treatment outcomes with saxagliptin plus dapagliflozin plus metformin versus saxagliptin plus metformin or dapagliflozin plus metformin were calculated using Fisher’s exact test. The numerator and denominator for each percentage are the number of responders and the number of patients with non-missing values in the treatment group at the corresponding baseline category, respectively, and are not corrected for baseline A1C. Because some patients experienced improvement in A1C during the lead-in period and could have already been at treatment goal at baseline, a sensitivity analysis excluding these patients was completed. Results are presented for the total number of patients with non-missing values in the treatment group, as well as patients with non-missing values in the treatment group who did not meet quality measure criteria at baseline. The number needed to treat (NNT) was calculated for all comparisons reaching statistical significance.

 

 

Results

Patients

Patient disposition, baseline demographics, and disease characteristics have been previously published [15]. A total of 534 patients were randomized to saxagliptin plus dapagliflozin plus metformin (n = 179), saxagliptinplus metformin (n = 176), or dapagliflozin plus metformin (n = 179) and received ≥ 1 dose of study medication. Patient demographics and baseline disease characteristics were generally balanced across all 3 treatment groups (Table). Mean age across the 3 treatment groups was 54 years, and there was a generally equal distribution of men and women. The mean known duration of T2D across the 3 treatment groups was 7.6 years, and mean baseline A1C was 8.94%. At baseline, 93% to 98% of patients had A1C > 7%, 74% to 82% had A1C > 8%, and 39% to 44% had A1C > 9%. At baseline, 18% to 28% of patients had BP > 140/90 mm Hg.

Individual Quality Measures

A significantly greater proportion of patients attained A1C < 7% (good glycemic control) with the dual add-on of saxagliptin plus dapagliflozin to metformin (41.8%) compared with saxagliptin plus metformin (16.6%, P < 0.001; NNT 4, 95% confidence interval [CI], 3–6) or dapagliflozin plus metformin (23.1%, P < 0.001; NNT 5, 95% CI, 4–11; Figure 2). The data were similar when the analysis excluded patients with baseline A1C < 7% (proportions of patients: 40.8% vs 15.6% vs 21.1%; P < 0.001 for both; NNTs 4 [95% CI 3–6] and 5 [95% CI 3–10]).

The dual addition of saxagliptin plus dapagliflozin to metformin resulted in a significantly greater proportion of patients achieving A1C < 8.0% compared with saxagliptin plus metformin (71.2% vs 49.1%; P < 0.001; NNT 5 [95% CI 3–8]) or dapagliflozin plus metformin (60.1%; P = 0.033; NNT 9 [95% CI 5–85]; Figure 2). Similar results (proportions of patients: 66.4% vs 40.0% vs 51.9%; P ≤ 0.02; NNTs 4 [95% CI 3–7]) and 7 [95% CI 4–34]) were attained when the analysis excluded patients with baseline A1C < 8.0%.

Significantly fewer patients had A1C > 9% (a measure of poor glycemic control) with saxagliptin plus dapagliflozin plus metformin (12.4%) compared with saxagliptin plus metformin (22.3%; P = 0.017; NNT –10 [95% CI –50 to –6]; Figure 2). The proportion of patients with A1C > 9% was similar for both regimens that included dapagliflozin (12.4% vs 10.4%; P = 0.616).

No significant difference was observed among treatment groups in the proportion of patients with BP < 140/90 mm Hg (Figure 2). However, most patients had BP < 140/90 mm Hg (72%–82%) at baseline, which was generally maintained at week 24.

Composite Quality Measures

A significantly greater proportion of patients attained the composite of A1C < 7% and BP < 140/90 mm Hg with saxagliptin plus dapagliflozin plus metformin (33.5%) compared with saxagliptin plus metformin (13.1%; P < 0.001; NNT 5 [95% CI 4–9]) or dapagliflozin plus metformin (18.6%; P = 0.002; NNT 7 [95% CI 4–17]; Figure 3). Results were similar when patients already at these goals at baseline were excluded from the analysis (32.4% vs 12.1% vs 16.3%; P < 0.001 for both; NNTs 5 [95% CI 4–9] and 6 [95% CI 4–14]).

A significantly greater proportion of patients achieved the composite of A1C < 8% and BP < 140/90 mm Hg with saxagliptin plus dapagliflozin plus metformin compared with saxagliptin plus metformin (56.8% vs 37.1%; P < 0.001; NNT 5 [95% CI 3–11]). Although not statistically significant, a numerically greater proportion of patients achieved A1C < 8% and BP < 140/90 mmHg with saxagliptin plus dapagliflozin plus metformin compared with dapagliflozin plus metformin (56.8% vs 50.0%; P = 0.237; Figure 4). Results were similar when patients already at these goals at baseline were excluded from the analysis (55.9% vs 30.2% [P < 0.001] vs 42.6% [P = 0.025]; NNTs 4 [95% CI 3–7] and 8 [95% CI 4–55]).

Discussion

This post hoc analysis evaluated attainment of glycemic and BP quality measures for diabetes. A significantly greater proportion of patients achieved the individual quality measures of A1C < 7% and A1C < 8% with dual add-on saxagliptin plus dapagliflozin to metformin compared with single add-on saxagliptin or dapagliflozin to metformin after 24 weeks. Similar results were seen when the analysis excluded patients with A1C < 7% and < 8% at baseline. All measures of good glycemic control had clinically relevant NNTs ≤ 10 after 24 weeks with saxagliptin plus dapagliflozin plus metformin compared with saxagliptin or dapagliflozin plus metformin, regardless of baseline status. Very few patients experienced lackof improvement in glycemic control, evidenced by small proportions of patients with A1C > 9%.

 

 

There was little difference in BP between dual add-on saxagliptin plus dapagliflozin or single add-on saxagliptin or dapagliflozin to metformin. The proportion of patients who attained the BP quality measure of BP < 140/90 mm Hg was similar across the 3 treatments, as might be expected because most patients already met this target at baseline. However, as might be expected based on the mild diuretic effect and weight loss associated with SGLT-2 inhibitors [16,17], trends in BP favored groups treated with dapagliflozin.

Attainment of multiple treatment targets is desirable in reducing complications of diabetes. A significantly greater proportion of patients achieved both A1C < 7% and BP < 140/90 mm Hg when both saxagliptin and dapagliflozin were added to metformin compared with single-agent addition of either saxagliptin or dapagliflozin plus metformin. Similarly, a significantly greater proportion of patients achieved both A1C < 8% and BP < 140/90 mm Hg with dual addition of saxagliptin and dapagliflozin plus metformin compared with saxagliptin plus metformin. There was also a numerically greater number of patients who achieved both of these goals with triple therapy compared with dapagliflozin plus metformin, but this finding did not reach statistical significance. Clinically relevant NNT values ≤ 10 were observed for both composite outcomes for saxagliptin plus dapagliflozin plus metformin compared with saxagliptin plus metformin or dapagliflozin plus metformin after 24 weeks.

Despite advances in the medical management of T2D, a report published in 2013 showed that between 2007 and 2010, only 53% of patients achieved an A1C < 7.0% and only 19% simultaneously achieved all 3 American Diabetes Association (ADA) goals recommended for most patients at that time: A1C < 7.0%, BP < 130/80 mm Hg, and low-density lipoprotein cholesterol LDL-C < 100 mg/dL [18]. These data highlight a need for new approaches to help patients attain glycemic, BP, and cholesterol goals. Our results demonstrated that a higher proportion of patients attained glycemic and BP quality measures with dual add-on saxagliptin plus dapagliflozin compared with single add-on saxagliptin or dapagliflozin to metformin. As a result of recent updates for cholesterol management from the American College of Cardiology and the American Heart Association [19], attainment of a cholesterol level was retired as a diabetes quality measure and replaced with a recommendation for statin therapy use [20,21]. Although the current analysis did not include assessment of LDL, DPP-4 inhibitors have demonstrated neutral effects on lipids [22,23], and SGLT-2 inhibitors have demonstrated generally modest increases in LDL-C (placebo-adjusted change from baseline: 4.5%–8.0% for canagliflozin 100 and 300 mg/d, 3.9% for dapagliflozin 10 mg, and 2.3%–4.2% for empagliflozin 10 and 25 mg/d) [12,24,25], as well as increases in high-density lipoprotein cholesterol and reductions in triglycerides [26].

Current ADA guidelines recommend an individualized, stepwise approach to treatment with sequential addition of single oral antihyperglycemic agents for patients who do not achieve their glycemic goal in 3 months [27]. Although T2D may progress at different rates in different patients, T2D does generally progress over time [28], and the ADA and American Association of Clinical Endocrinologists treatment guidelines recommend initial dual add-on therapy for individuals with higher A1C, which is suggestive of more advanced disease [27,29]. For individuals requiring initial combination therapy, guidelines note that antihyperglycemic agents that have a low risk of hypoglycemia and low potential for weight gain should be preferentially selected [29]. Attainment of A1C ≤ 7%, the guideline recommendation considered appropriate for many patients, is associated with reductions in microvascular disease and, if attained soon after diagnosis of diabetes, studies have shown reductions in macrovascular disease with long-term follow-up [27,30,31]. However, it may be challenging to achieve A1C < 7% with the addition of single oral antihyperglycemic agents, especially in patients with higher A1C [32]. Less stringent A1C goals (eg, A1C < 8%) may be appropriate in individuals with a long duration of diabetes that is difficult to control, history of severe hypoglycemia, limited life expectancy, numerous comorbidities, and extensive complications or comorbidities, especially cardiovascular disease [27]. Given the shift toward individualized treatment plans with patient-specific treatment goals, it is valuable to understand how different treatment strategies effect attainment of guideline-recommended less stringent and more stringent glycemic targets that may be appropriate for certain patients.

 

 

In addition to quality measures that assess glucose lowering with pharmacotherapy, it is important to consider measures that assess other aspects of diabetes care. For example, quality measures related to hypoglycemia and hyperglycemia may help avoid potentially adverse glucose levels, and quality measures related to weight may provide insight on treatment and lifestyle efforts directed at weight loss and management. NQF-endorsed measures of hypoglycemia and hyperglycemia are currently moving through annual review and are paired measures, intended to be interpreted with respect to one another to ensure balanced outcomes [33,34]. This underscores the value of efficacious antihyperglycemic agents with low intrinsic potential for hypoglycemia. Although this analysis did not include quality measures related to hypoglycemia or weight, future studies evaluating these aspects of diabetes care will likely further contribute to a more comprehensive and holistic treatment approach.

In addition to assessing a broad range of quality measures, an important aspect of care to consider is patient affordability. Affordability for an individual patient will depend on access in the patient’s individual plan, the financial resources of the patient, and the potential for medical cost offsets from improved control of the patient’s disease. For example, fixed-dose combination products are associated with increased patient adherence and may increase pharmacy costs but decrease medical costs [35].

Limitations of this study include the post hoc design and that quality measure attainment was assessed over a shorter duration of time (24 weeks) than is commonly assessed in the real-world/community setting (~12 months).

Dual add-on therapy with oral antihyperglycemic agents that have complementary mechanisms of action should lead to enhanced reductions in A1C. The results reported here and from the primary study, in which saxagliptin and dapagliflozin added to metformin significantly reduced mean A1C from baseline to week 24 compared with single add-on saxagliptin or dapagliflozin [15], showed that greater reductions in A1C were attained with the coadministration of saxagliptin and dapagliflozin. The glucuretic effect of SGLT-2 inhibitors has been associated with increased plasma glucagon concentrations and increased endogenous glucose production, which may impair the full glucose-lowering potential of SGLT-2 inhibitors [36,37]. Administering saxagliptin with dapagliflozin as dual therapy was shown to blunt the rise in plasma glucagon caused by dapagliflozin [38], and this may have contributed to the greater glucose control achieved with dual add-on of these 2 antihyperglycemic drugs [15].

By targeting multiple aspects of the underlying pathophysiology in T2D, greater improvements in A1C can be achieved. Dual add-on saxagliptin plus dapagliflozin to metformin resulted in a greater proportion of patients achieving NQF-endorsed HEDIS quality measures, as well as A1C < 7% (no longer an NQF-endorsed measure). As health care shifts to a more value-based payment structure, measuring quality outcomes will assume a greater role in guiding decision making and influence the care that patients receive. Understanding how antihyperglycemic medication regimens affect quality measures can help clinicians make informed decisions.

 

Corresponding author: Lawrence Blonde, MD, Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, LA.

Funding/support: This study was supported by AstraZeneca. Medical writing support for the preparation of this manuscript was provided by Lauren D’Angelo, PhD, and Janet Matsuura, PhD, from Complete Healthcare Communications, LLC (Chadds Ford, PA), with funding from AstraZeneca.

Financial disclosures: Dr. Blonde has received grant and research support from AstraZeneca, Jansen Pharmaceuticals, Lexicon Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis and has received honoraria for participating as a speaker from AstraZeneca, Janssen Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis as well as honoraria for consultant work from AstraZeneca, GlaxoSmithKline, Intarcia Therapeutics, Janssen Pharmaceuticals, Merck, Novo Nordisk, and Sanofi-Aventis. R. Garcia-Sanchez is an employee of AstraZeneca. J. Sheehan and Y. C. Barrett were employees of AstraZeneca at the time of this research.

References

1. National Quality Forum. ABCs of measurement. Accessed 11 Mar 2016 at www.qualityforum.org/Measuring_Performance/ABCs_of_Measurement.aspx.

2. National Committee for Quality Assurance. HEDIS measure development process. Accessed 14 Mar 2016 at www.ncqa.org/tabid/414/Default.aspx.

3. National Committee for Quality Assurance. HEDIS measures. Accessed 11 Mar 2016 at www.ncqa.org/HEDISQualityMeasurement/HEDISMeasures.aspx.

4. National Committee for Quality Assurance. About NCQA: overview. Accessed 14 Mar 2016 at www.ncqa.org/AboutNCQA.aspx.

5. National Committee for Quality Assurance. Health care program evaluations. Accessed 11 Mar 2016 at www.ncqa.org/Programs.aspx.

6. National Committee for Quality Assurance. HEDIS and Performance Measurement. Accessed 14 Mar 2016 at www.ncqa.org/HEDISQualityMeasurement.aspx.

7. National Committee for Quality Assurance. HEDIS 2015 technical specifications for ACO measurement. Washington, DC: National Committee for Quality Assurance; 2014.

8. National Quality Forum. Comprehensive diabetes care: hemoglobin A1c (HbA1c) poor control (> 9.0%). NQF identifier: 0059. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

9. National Quality Forum. Comprehensive diabetes care: hemoglobin A1c (HbA1c) control (< 8.0%). NQF identifier: 0575. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

10. National Quality Forum. Comprehensive diabetes care: blood pressure control (< 140/90 mm Hg). NQF identifier: 0061. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

11. Onglyza(saxagliptin). Full prescribing information. AstraZeneca, Wilmington, DE; 2014.

12. Farxiga (dapagliflozin). Full prescribing information. AstraZeneca, Wilmington, DE; March 2015.

13. Deacon CF, Holst JJ. Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Adv Ther 2009;26:488–99.

14. Kasichayanula S, Liu X, Lacreta F, et al. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet 2014;53:17–27.

15. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 2014;38:376–83.

16. Bailey CJ. SGLT2 inhibitors: glucuretic treatment for type 2 diabetes. British Journal of Diabetes & Vascular Disease 2010;10:193-9.

17. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens 2015;9:48–53.

18. 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;36:2271–9.

19. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1–45.

20. National Quality Forum. Comprehensive diabetes care (composite). NQF identifier: #0731. Accessed 11 Mar 2016 at www.qualityforum.org/QPS/QPSTool.aspx.

21. National Quality Forum. Optimal diabetes care (composite measure). NQF identifier: 0729. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

22. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007;298:194–206.

23. Monami M, Lamanna C, Desideri CM, Mannucci E. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther 2012;29:14–25.

24. Invokana(canagliflzoin). Full prescribing information. Janssen Pharmaceuticals, Titusville, NJ;  2013.

25. Jardiance(empagliflozin). Full prescribing information. Boehringer Ingelheim Pharmaceuticals and Eli Lilly, Ingelheim, Germany and Indianapolis, IN; 2014.

26. Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015;12:90–100.

27. American Diabetes Association. Standards of medical care in diabetes-2016. Diabetes Care 2016;39:S1–S119.

28. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care 2009;32:S151–S6.

29. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm -- 2016 executive summary. Endocr Pract 2016;22:84–113.

30. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89.

31. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53.

32. Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007;30:890–5.

33. National Quality Forum. Glycemic control: hypoglycemia. NQF identifier: 2363. Accessed 29 Oct 2015 at www.qualityforum.org/QPS/QPSTool.aspx.

34. National Quality Forum. Glycemic control: hyperglycemia. NQF identifier: 2362. Accessed 11 Mar 2016 at www.qualityforum.org/QPS/QPSTool.aspx.

35. Bailey CJ, Day C. Fixed-dose single tablet antidiabetic combinations. Diabetes Obes Metab 2009;11:527–33.

36. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499–508.

37. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509–14.

38. Hansen L, Iqbal N, Ekholm E, et al. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy. Endocr Pract 2014;20:1187–97.

References

1. National Quality Forum. ABCs of measurement. Accessed 11 Mar 2016 at www.qualityforum.org/Measuring_Performance/ABCs_of_Measurement.aspx.

2. National Committee for Quality Assurance. HEDIS measure development process. Accessed 14 Mar 2016 at www.ncqa.org/tabid/414/Default.aspx.

3. National Committee for Quality Assurance. HEDIS measures. Accessed 11 Mar 2016 at www.ncqa.org/HEDISQualityMeasurement/HEDISMeasures.aspx.

4. National Committee for Quality Assurance. About NCQA: overview. Accessed 14 Mar 2016 at www.ncqa.org/AboutNCQA.aspx.

5. National Committee for Quality Assurance. Health care program evaluations. Accessed 11 Mar 2016 at www.ncqa.org/Programs.aspx.

6. National Committee for Quality Assurance. HEDIS and Performance Measurement. Accessed 14 Mar 2016 at www.ncqa.org/HEDISQualityMeasurement.aspx.

7. National Committee for Quality Assurance. HEDIS 2015 technical specifications for ACO measurement. Washington, DC: National Committee for Quality Assurance; 2014.

8. National Quality Forum. Comprehensive diabetes care: hemoglobin A1c (HbA1c) poor control (> 9.0%). NQF identifier: 0059. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

9. National Quality Forum. Comprehensive diabetes care: hemoglobin A1c (HbA1c) control (< 8.0%). NQF identifier: 0575. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

10. National Quality Forum. Comprehensive diabetes care: blood pressure control (< 140/90 mm Hg). NQF identifier: 0061. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

11. Onglyza(saxagliptin). Full prescribing information. AstraZeneca, Wilmington, DE; 2014.

12. Farxiga (dapagliflozin). Full prescribing information. AstraZeneca, Wilmington, DE; March 2015.

13. Deacon CF, Holst JJ. Saxagliptin: a new dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Adv Ther 2009;26:488–99.

14. Kasichayanula S, Liu X, Lacreta F, et al. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clin Pharmacokinet 2014;53:17–27.

15. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 2014;38:376–83.

16. Bailey CJ. SGLT2 inhibitors: glucuretic treatment for type 2 diabetes. British Journal of Diabetes & Vascular Disease 2010;10:193-9.

17. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens 2015;9:48–53.

18. 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;36:2271–9.

19. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129:S1–45.

20. National Quality Forum. Comprehensive diabetes care (composite). NQF identifier: #0731. Accessed 11 Mar 2016 at www.qualityforum.org/QPS/QPSTool.aspx.

21. National Quality Forum. Optimal diabetes care (composite measure). NQF identifier: 0729. Accessed 14 Mar 2016 at www.qualityforum.org/ProjectMeasures.aspx?projectID=73652.

22. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007;298:194–206.

23. Monami M, Lamanna C, Desideri CM, Mannucci E. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther 2012;29:14–25.

24. Invokana(canagliflzoin). Full prescribing information. Janssen Pharmaceuticals, Titusville, NJ;  2013.

25. Jardiance(empagliflozin). Full prescribing information. Boehringer Ingelheim Pharmaceuticals and Eli Lilly, Ingelheim, Germany and Indianapolis, IN; 2014.

26. Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015;12:90–100.

27. American Diabetes Association. Standards of medical care in diabetes-2016. Diabetes Care 2016;39:S1–S119.

28. Fonseca VA. Defining and characterizing the progression of type 2 diabetes. Diabetes Care 2009;32:S151–S6.

29. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm -- 2016 executive summary. Endocr Pract 2016;22:84–113.

30. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–89.

31. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53.

32. Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 2007;30:890–5.

33. National Quality Forum. Glycemic control: hypoglycemia. NQF identifier: 2363. Accessed 29 Oct 2015 at www.qualityforum.org/QPS/QPSTool.aspx.

34. National Quality Forum. Glycemic control: hyperglycemia. NQF identifier: 2362. Accessed 11 Mar 2016 at www.qualityforum.org/QPS/QPSTool.aspx.

35. Bailey CJ, Day C. Fixed-dose single tablet antidiabetic combinations. Diabetes Obes Metab 2009;11:527–33.

36. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499–508.

37. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509–14.

38. Hansen L, Iqbal N, Ekholm E, et al. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy. Endocr Pract 2014;20:1187–97.

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Journal of Clinical Outcomes Management - SEPTEMBER 2016, VOL. 23, NO. 9
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Quality Measure Attainment After Add-on Therapy of Both Saxagliptin and Dapagliflozin to Metformin Versus Single Add-On of Saxagliptin or Dapagliflozin
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