Quality measure and weight loss assessment in patients with type 2 diabetes mellitus treated with canagliflozin or dipeptidyl peptidase-4 inhibitors

Diabetes is a chronic condition characterized by high glucose levels in the blood. The American Diabetes Association (ADA) estimates that 9.3% of the US population have diabetes in 2012, among which 90–95% had type 2 diabetes mellitus (T2DM) [1]. Diabetes, including T2DM, can lead to several serious and sometimes life-threatening complications including microvascular conditions such as retinopathy and nephropathy, as well as cardiovascular disease [2].

Patients with better glycemic (e.g., glycylated hemoglobin [HbA1c]) and blood pressure (BP) control have better outcomes, including lower risks of complications and better survival, which in turn help to maintain quality of life and reduce complication-related treatment costs [3‐5]. Thus, monitoring for and managing high levels of HbA1c and BP as well as body weight (BW) are key components of the standard of care for patients with T2DM [6].

Although personalization of goals is recommended by the Healthcare Effectiveness Data and Information Set (HEDIS) and the ADA, both organizations suggest the following general goals for HbA1c management: HbA1c <7% for nonpregnant adults, and less stringent goals such as HbA1c <8% for those older than 65 or with complications (specifically, “history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes”) [6, 7]. The ADA also recommends an objective of BP <140/90 mmHg for all patients [6]. As reported by Bailey et al., various healthcare organizations and community quality improvement programs such as the Centers for Medicare & Medicaid Services: Accountable Care Organization, the Minnesota Community Measurement, the Wisconsin Collaborative for Healthcare Quality, and the Health Collaborative of Greater Cincinnati have established HbA1c goals below 8% and systolic BP <140 mmHg in diabetes patients [8]. Overweight and obesity are highly prevalent among patients with T2DM; [8] furthermore, managing obesity has been shown to have beneficial impacts on T2DM management [6]. Therefore, both the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) recommend to target a BW loss goal of ≥5% in this population [9].

Various antihyperglycemic agents have been developed to improve glycemic control as well as other vital signs in T2DM patients, as a complement to diet and lifestyle changes [10]. Sodium-glucose co-transporter 2 (SGLT2) inhibitors such as canagliflozin (Invokana® and Invokamet® [CANA]) are one class of agents that work to lower glucose levels by increasing the amount of glucose excreted by the kidneys. Due to their mechanism of action, SGLT2 inhibitors also contribute to reductions in BW and BP [11]. This insulin-independent mechanism of action makes CANA a candidate for add-on therapy with all other antihyperglycemic agents [12]. In recent Phase 3 clinical trials and real-world studies, CANA has been shown to improve HbA1c, BP, and BW in patients with T2DM [13‐21].

Another class of antihyperglycemic agents is dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors prevent the degradation of incretin hormones by inhibiting the DPP-4 enzyme. Incretin hormones exert their action by stimulation of insulin secretion and inhibition of glucagon release [22]. While DPP-4 inhibitors have been shown to improve HbA1c, only modest improvement in BP and no improvement in BW have been found [23, 24].

In clinical trials comparing CANA 100 mg and CANA 300 mg to sitagliptin 100 mg (a DPP-4 agent) [8, 15, 20], CANA 100 mg was shown to be non-inferior to sitagliptin in achieving diabetes-related quality measure goals for HbA1c, BP, and weight loss at week 52, while CANA 300 mg was shown to be statistically superior. Patients enrolled in these two trials and treated with CANA 100 mg or CANA 300 mg also showed significantly decreased BP and BW as compared to patients treated with sitagliptin.

Few studies have compared glycemic control, BP, and BW loss outcomes between patients initiated on CANA or a DPP-4 agent in a real-world setting [25]. Furthermore, no real-world study has assessed these outcomes over more than one year of follow-up. The aim of the present study was to expand on the clinical benefits mentioned in the clinical trials above and assess achievement of HbA1c, BP, and BW loss goals between a large sample of inadequately controlled patients initiated on CANA versus a DPP-4 agent in a real-world setting where patients can be observed for more than two years following the initiation. In addition, this study assessed the pre- and post-initiation use of antihyperglycemics, antihypertensives, and lipid-lowering agents for patients initiated on CANA versus a DPP-4 agent.

In this study of EMRs collected between March 2012 to October 2015 including 28,381 T2DM patients initiated on CANA or DPP-4 agents, patients initiated on CANA were more likely to attain HbA1c measurements of <7% or 8% during the observation period compared to patients initiated on a DPP-4 agent. Patients initiated on CANA were also significantly more likely to achieve BW reduction of at least 5% and reduction of systolic BP below 140 mmHg compared with patients initiated on a DPP-4 agent. Patients initiated on CANA were as likely as patients initiated on DPP-4 agents to reach a diastolic BP lower than 90 mmHg, this result was expected because greater reductions in systolic BP than diastolic BP were observed in clinical trials for CANA [35]. Overall, attainment of diabetes-related quality measure goals was more likely in CANA patients than in DPP-4 patients despite the fact that a higher proportion of DPP-4 patients added or switched to a new antihyperglycemic agent during the follow-up period, which may have improved quality measure attainment among DPP-4 patients and reduced observed differences between cohorts.

These results were obtained using IPTW to account for observable differences in patients’ characteristics at treatment initiation or over the baseline period. Before weighting, many patient demographic and clinical characteristics were found to be significantly different between the CANA and DPP-4 patient cohorts. Compared to patients initiated on DPP-4: CANA patients were younger; had used a higher number of antihyperglycemic agents at baseline; suffered more from neuropathy, but less from nephropathy; were more often obese, with on average almost 15 more pounds in terms of BW; and had higher baseline HbA1c values, but similar systolic BP. Such differences were also observed in other retrospective studies comparing patients initiated on CANA and patients initiated on sitagliptin, the most commonly prescribed DPP-4 agent [36, 37]. In particular, Grabner et al. found that patients initiated on CANA were on average younger compared to patients initiated on sitagliptin, suffered more from neuropathy and obesity, and had a higher initial HbA1c [36]. However, after applying IPTW, the weighted populations of the current study were well balanced.

This study adds to the growing body of literature reporting on comparisons of CANA and DPP-4s in terms of quality measures [8, 15, 20, 25, 37‐39]. Of particular interest, two clinical trials assessed the efficacy and safety of CANA versus sitagliptin over 52 weeks, respectively on background antihyperglycemic treatment with metformin [15] and metformin plus sulfonylurea [20]. Significant differences in favor of CANA 100 mg were identified compared to sitagliptin 100 mg at 52 weeks (12 months) in terms of HbA1c < 8%, BP, BMI and BW loss measure achievement, while no difference was found in terms of HbA1c < 7% [39]. When pooling results from both trials, significant differences in favor of CANA 300 mg were found for the same endpoints, including HbA1c < 7%, when compared to sitagliptin 100 mg [39].

In the present study and following weighting to balance characteristics between patient populations, modest but statistically significant differences between all CANA and DPP-4 patients reaching an HbA1c < 7% appeared at 6 months post-index date, and were observed for those with up to 24 months of follow-up (weighted KM rates respectively 42.8% and 40.3% for CANA and DPP-4, P < 0.001). Among patients younger than 65, significant differences in the proportion of patients reaching an HbA1c < 7% were also found as early as 6 months after treatment initiation and consistently for up to 24 months (42.2% vs. 38.7% respectively for CANA and DPP-4 patients, P < 0.001). Consistent and numerically larger differences were also found as early as 6 months after treatment initiation and up to 24 months in the proportion of patients reaching HbA1c <8% between CANA and DPP-4 cohorts, although no difference was found in the subgroup of patients aged 65 years or older. However, it is important to consider the clinical context of these older patients when interpreting this finding. Specifically, older age is associated with lower eGFR [40], which may impact dosing considerations. Improving renal and other outcomes (as opposed to targeting HbA1c) may also be of higher priority in older patients, particularly given the promising findings reported for SGLT2s and renal outcomes that have been recently reported [41, 42]. Therefore, future investigations may benefit from exploring other clinical endpoints in older sub-populations of patients. Also of note, although SGLT2 inhibition lowers glucose starting on the first day of initiation, differences with DPP-4 agents are not likely to be found prior to 6 months post-index because HbA1c is likely measured at 6-month intervals among patients with stable glycemic control, as per treatment guidelines (3-month intervals for those not meeting treatment goals) [43].

To the best of our knowledge, only a single study has compared changes in HbA1c and proportions of patients achieving HbA1c <8% and <7% among patients with T2DM treated with CANA versus DPP-4 inhibitors, using data from the real-world setting [25]. In particular, Thayer et al identified that among matched CANA and DPP-4 inhibitor cohorts of 2,776 patients each, change in HbA1c was greater among patients in the CANA cohort than for those in the DPP-4 inhibitor cohort (−0.92% vs. −0.63%, P < 0.001), and greater percentages of the CANA cohort relative to the DPP-4 inhibitor cohort achieved HbA1c < 7% (35.4% vs. 29.9%, P = 0.022) over a 9 month follow-up [25]. The shorter time to reach the endpoint compared to our study can potentially be explained by the relatively younger population (mean age 56 years vs. 58 years in our study). The aim of the present study was to additionally expand on the clinical benefits other than HbA1c and compare achievement BP, and BW loss goals between a large sample of inadequately controlled patients initiated on CANA or a DPP-4 agent in a real-word setting where patients can be observed for more than two years post-index.

This study was subject to some limitations. First, the data used came from EMRs with a physician centric perspective without any link to healthcare claims. As a consequence, there was no direct link to secondary care data which means that information on hospital visits was not collected. Second, this study relied on prescription data without any knowledge of whether the medication was filled and taken as prescribed. Third, although the CANA prescribing information recommends that patients be initiated on a daily dose of 100 mg [44], a minority of patients in the present study had their first CANA prescription for 300 mg. Two possible explanations for this observation could be that patients were actually initiated on 300 mg, which is consistent with some clinical trials, or that they received samples of CANA 100 mg prior to the index date, which would not have been observed in this database. Fourth, although the study took appropriate measures to reduce confounding, there remains a risk of residual confounding due to unmeasured confounders, which is inherent to observational studies. For instance, sociodemographic characteristics such as economic status and type of insurance coverage were not available while waist circumference and serum creatinine were available for less than 1% of patients. Fifth, the current study assessed goal attainment using recommended thresholds from various healthcare organizations. However, not every patient has the same goals based on his/her demographic and clinical profile; therefore personalization of goals remains important. Sixth, 75% of the study population was White; consequently, results from the current study may not be generalizable to other races/ethnicities. Finally, adverse events were not assessed in this study given that our data source does not allow tracking of patients across different providers and does not include direct link to secondary care data such as hospital visits. Authors believe that the evaluation of adverse events would be impacted by this limitation. As a consequence, it was not possible to evaluate the impact that such adverse events may have had on the outcomes observed in this study. Although the findings should be interpreted in the context of these limitations, large observational studies such as the one currently presented provide a rich insight into real-world clinical populations and practices.

This real-world retrospective study showed that inadequately controlled patients initiated on CANA were more likely to achieve diabetes-related quality measure goals (HbA1c <7%, HbA1c <8%, BW loss ≥5%, and systolic BP <140 mmHg) compared to patients initiated on a DPP-4 agent. These findings suggest that compared to DPP-4 inhibitors, CANA may be a more effective therapeutic option for improving quality measure goals, which is relevant both for patient outcomes as well as for providers and payers, especially given the importance of quality measure achievement on provider evaluation and reimbursement in the US.