The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA‐HF study

Abstract Background Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. Methods We conducted a double‐blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) slope (co‐primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2, ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12‐week follow‐up. Results The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM −1 min−1, P = .036), VAT (+1.5 mL kg−1 min−1, P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg−1 min−1, P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (−12.1, P = .018). Conclusions In this small and short‐term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2, VAT and quality of life.

Conclusions: In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO 2 or VE/VCO 2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO 2 , VAT and quality of life.

| INTRODUCTION
Heart failure (HF) remains one of the most common comorbidities in type 2 diabetes mellitus (T2DM). 1 The sodium-glucose cotransporter (SGLT)-2 inhibitors, canagliflozin, 2 dapagliflozin 3 and empagliflozin, 4 are the only glucose-lowering agents that reduce the incidence of HF and HF-related hospitalizations in patients with T2DM, and dapagliflozin also in patients without T2DM and established HF with reduced ejection fraction (HFrEF). 5 The mechanisms explaining these benefits appear, at least in part, independent of glycemic control.
The cardiovascular outcomes trials with the SGLT2 inhibitors canagliflozin and empagliflozin do not provide data on the forms of HF and HF-related events being prevented, with a small percentage of patients having HF at baseline. Dapagliflozin reduced the risk of worsening HF or death from cardiovascular causes in established HFrEF patients and improved quality of life (QoL) in patients with and without T2DM. 5 Exercise intolerance is a hallmark consequence of HF, typically defined as a reduction in cardiorespiratory fitness (CRF) measured as a reduced peak oxygen consumption (VO 2 ) during cardiopulmonary exercise testing (CPX) and largely responsible for the reduced QoL in HF. 6 Peak VO 2 is a strong prognostic factor in HFrEF, and its improvements have been associated with long-term reduction of clinical events, making it a strong surrogate outcome measure. 7 Despite several therapeutics able to improve CRF, 6,8 patients with HFrEF still present with a markedly reduced CRF. The effects of SGLT2 inhibitors on CRF in patients with established HF have been only minimally investigated, 9,10 and, to date, no randomized controlled trials comparing the effects of SGLT2 inhibitors on CRF with other glucoselowering agents have been performed.
We investigated whether canagliflozin improved peak VO 2 and ventilatory efficiency in patients with T2DM and HFrEF compared to sitagliptin, a dipeptidyl peptidase (DPP)4 inhibitor with proven cardiovascular safety with glucose-lowering efficacy similar to SGLT2 inhibitors. 11 We hypothesized that improvements in CRF would be independent of glycemic control.

| Cardiopulmonary exercise testing
At baseline and 12 weeks subjects underwent a symptom-limited CPX, using a metabolic cart interfaced with a treadmill utilizing a conservative ramping protocol wherein the speed and grade increased approximately 0.6 estimated metabolic equivalents every minute, as previously described. 14 Peak VO 2 was defined as the highest 10-second interval average during the last 30 seconds of exercise. 6 The VE/VCO 2 slope was calculated using 10-second averaged VE and VCO 2 data from the initiation of exercise to peak that was inserted into spreadsheet software (Microsoft Excel, Microsoft Corp., Bellevue, Washington) to calculate the slope via least squares linear regression. 6 The VE/VCO 2 slope is a marker of HF severity defined as minute ventilation/carbon dioxide production (VE/VCO 2 ) slope.

| Doppler echocardiography
At baseline and at 12 weeks we performed resting transthoracic Doppler echocardiography. 15 We measured LV end-diastolic and LV end-systolic volumes, LVEF, and early transmitral velocity (E) on pulsed-wave Doppler spectra and early mitral annular velocities by tissue Doppler averaged between the lateral and septal (E 0 ) annulus; these measures were used to calculate the E/E 0 ratio. We also measured deceleration time (DT) and calculated the E 0 velocity indexed by DT (E 0 DT ). 16

| Quality of life
We measured QoL at baseline and 12 weeks using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). The MLHFQ is a 21-item graded questionnaire used to assess the impairments in QoL in HF, higher scores reflect a greater HF symptom burden. 17 2.6 | Anthropometrics, fluid status and blood pressure We measured body weight and height to calculate body mass index (BMI) and waist circumference at baseline and at 12 weeks. 18 We assessed lean mass (LM) to calculate lean peak VO 2 using dual-energy X-Ray Absorptiometry (DEXA) (QDR 4500a, Hologic, Marlborough, Massachusetts) 19 and changes in fluid status: total body water (TBW), intracellular water (ICW) and extracellular water (ECW) using bioelectrical impedance analysis (BIA; Quantum IV, RJL System, Clinton Township, Michigan) at baseline and 12 weeks. Resting blood pressure was measured at baseline and after 12 weeks using a Tango automated blood pressure system (Suntech Medical, Morrisville, North Carolina).

| Study endpoints
The co-primary endpoints for the study were changes from baseline in peak VO 2 and the VE/VCO 2 slope after 12 weeks of treatment with canagliflozin 100 mg daily or sitagliptin 100 mg daily. We measured QoL using the MLHFQ and additional CRF variable: ventilatory anaerobic threshold (VAT), and DEXA-measured lean peak VO 2 . 6,21 Lean peak VO 2 has been proposed to be superior to peak VO 2 in determining prognosis in patients with HFrEF, especially in patients with obesity, in which peak VO 2 may underestimate the overall level of CRF. 6

| Baseline characteristics
No statistically significant differences were found between the two groups at baseline, except for peak RER, which was significantly lower in the sitagliptin group compared to canagliflozin (Table 1). Patients randomized to canagliflozin tended to be more likely to receive insulin, had a lower BMI, and lower NTproBNP, although the differences did not reach statistical significance. Patients were followed for a mean follow-up of 93 days.

| Cardiorespiratory fitness
We did not observe any statistically significant improvements in the coprimary endpoints of the study in any of the groups ( Table 2). We did not detect any significant within-group differences in the canagliflozin 13.1 ± 2.3 mL kg −1 min −1 , P = .004; sitagliptin within group: from 11.7 ± 3.0 to 11.8 ± 2.9 mL kg −1 min −1 , P = .93; Figure 3).

| Adverse events
As expected, the overall number of adverse events was low ( Canagliflozin was associated with a significant improvement in QoL and additional CPX variables that have been found to consistently predict prognosis in patients with HF, and have proven to be more sensitive than peak VO 2 , such as lean peak VO 2 and VAT. 6 Treatment with canagliflozin was associated with a significant reduction in the MLHFQ, indicating improved QoL related to improvements in HF-related symptoms. In patients with HF, lean peak VO 2 may be a stronger prognosticator than peak VO 2 , particularly in individuals with obesity, in which peak VO 2 adjusted by total body mass may result in an underestimate of CRF. 21,24 Of note, 86% of the patients enrolled in the study had obesity at baseline, 22% had class III obesity (BMI ≥ 40 kg/m 2 ) and 100% had either overweight or obesity. VAT allows the quantification of the ability to sustain submaximal physical activity for prolonged periods, which approximates levels associated with activities of daily living in individuals with HF, who rarely perform higher intensity activities. 6 At the 12-week visit, many subjects had a reduction in peak RER, which further reduced the power of our study to detect changes in peak VO 2 . Of note, an assessment of peak VO 2 adjusted per RER showed a significant improvement with canagliflozin. It is unclear as to why subjects in the canagliflozin group exercised to a lower peak RER post-intervention. This may be related to the imbalance in RER at baseline, with higher values in the canagliflozin group, but it could be related to other factors such as improved cardiac function allowing the individuals to reach the same or higher effort level while maintaining a greater cardiac reserve. It is indeed noteworthy that although canagliflozin patients tended to have lower RER at follow-up this did not negatively affect the peak VO 2 , as it is was not F I G U R E 2 Effects of treatments on peak oxygen consumption (VO 2 ) and minute ventilation/carbon dioxide production slope (VE/VCO 2 slope). Treatment with canagliflozin nor sitagliptin did not result in significant changes in peak VO 2 , A and VE/VCO 2 slope, B. Data are presented as mean ± SD F I G U R E 3 Effects of treatments on exploratory cardiopulmonary exercise testing (CPX) variables. Canagliflozin resulted in significant improvements in lean peak oxygen consumption (VO 2 ), A, ventilatory anaerobic threshold (VAT), B, and RER-matched VO 2 , C, compared to sitagliptin in a time_x_group interaction. Data are presented as mean ± SD. LM, lean mass measured with dual-energy X-ray absorptiometry; MD, mean difference between groups reduced from baseline. It is possible that in this cohort of HFrEF patients with obesity and deconditioning, a treatment that improves cardiac function may fall short in improving peak VO 2 due to supervening secondary limitation to maximal aerobic capacity. 25 On the other hand, the VE/VCO 2 slope, an effort-independent CPX variable, was not affected by either treatment. Of note, while peak VO 2 was clearly reduced in the investigated population (64% ± 12% of predicted), offering room for significant improvements, the mean VE/VCO 2 slope was only mildly elevated (33.3 ± 7), with 11 subjects (31%) presenting with a normal VE/VCO 2 slope (<30), potentially minimizing the ability to detect significant changes with the intervention.
Canagliflozin was associated with greater LVEF at 12 weeks compared to baseline, while sitagliptin had neutral effects, however, the time_x_group analysis was not statistically significant. Importantly, prior studies have shown favourable changes in systolic function (ie, LVEF and echocardiography-derived strains) in preclinical models of HF. 26 In addition to LVEF, we observed a small reduction in DT with canagliflozin compared to sitagliptin, which may reflect an improvement in myocardial relaxation. Of note, other more robust measures of cardiac diastolic function and estimate of filling pressures, such as E/E 0 , were not improved by canagliflozin.
These effects appear to be independent of glycemic control, which did not differ between the two groups. We did not observe significant changes in biomarkers of myocardial wall stress and renal function, such as NTproBNP and GFR, respectively. The lack of changes may be related to the study being underpowered to detect significant changes in such variables and/or short duration of treatment.
No changes in blood pressure and fluid status were found. While this may appear surprising, the baseline blood pressure and fluid status were within normal ranges, likely due to the fact that patients were required to be on maximally tolerated optimal medical therapy and stable without evidence of fluid overload prior to enrolment. We cannot exclude the possibility, however, that in this population, the blood pressure lowering effects of SGLT2 inhibitors 27 may not be as pronounced, due to concomitant therapies and perhaps require a larger sample size to detect a significant change. 5 We did not report any significant dietary changes in terms of daily caloric and sodium intake. We finally reported the safety profile of canagliflozin com- F I G U R E 5 Effects of treatments on cardiac function. Canagliflozin was associated with improved systolic and diastolic function compared to baseline. Specifically, we observed improvements in left ventricular ejection fraction (LVEF), A, and deceleration time (DT), B. When compared to sitagliptin at time_x_group interaction analysis, however, the difference in LVEF was no longer statistically significant, while the difference with DT remained statistically significant. Data are presented as mean ± SD for LVEF, and median and interquartile ranges for DT. MD, mean difference between groups the limited number of adverse events in the two groups, and the short duration of follow-up.
Canagliflozin and other SGLT2 inhibitors have been shown to reduce hospitalizations for HF and renal events 2-5 in patients with T2DM and recently also in patients without T2DM. 5,28 Canagliflozin was shown to reduce cardiovascular and renal events, including hospitalizations for HF, even in patients with chronic kidney disease and albuminuria, 29 further supporting its role in patients with T2DM to reduce cardiovascular events. In small studies, canagliflozin has been associated with improved diastolic function in patients with T2DM, 30 however, its role on CRF and cardiac function in patients with established HF has not been previously investigated. We have previously shown that empagliflozin was associated with reduced E/E 0 in patients with HFrEF 9 suggesting a reduction in filling pressures and improvements in peak VO 2 when patients where concomitantly treated with loop diuretics. Empagliflozin has also been associated with improved peak VO 2 in other non-randomized studies in patients with established HF. 10 The recent EMPERIAL-Preserved and EMPERIAL Reduced trials, 31 however, suggested no improvements in functional capacity measured with 6-minute walk test distance with empagliflozin.
Of note, the EMPERIAL trials did not investigate the effects of SGLT2 inhibitors on CRF, particularly on peak VO 2 , like we attempted to do in our trial. Peak VO 2 is a more sensitive parameter of exercise capacity than 6-minute walk test distance, which instead estimates functional capacity and does not provide insights on the determinants of reduced CRF. 6 Due to early interruption of our study, however, we cannot make definite conclusion on the effects of SGLT2 inhibitors on peak VO 2 , while we hope that ongoing clinical trials, such as the EMPA-TROPISM will provide a final answer, also in patients without T2DM. 32 The mechanisms responsible for such effects are largely unknown. The hearts of patients with HF present with metabolic dysregulation resulting in reduced ability to utilize carbohydrates as an energetic substrate, with a resulting compensatory increased utilization of fatty acids and ketone bodies. By increasing fatty acid oxidation, ultimately increasing the production of ketone bodies, SGLT2 inhibitors, may increase the availability and utilization of these newly preferred energetic substrates in the setting of HF.
Sitagliptin was neutral on CRF, QoL, cardiac function and biomarkers, confirming its safety profile explored in a large cardiovascular outcome trial. 11 The study is not without limitations. In addition to the early termination, there were some differences in the baseline characteristics of the patients, which could have potentially affected the overall results of the study. Moreover, the small sample size of the study does not allow to definitely confirm the lack of differences of the safety profile of the two agents in the investigated population.

| CONCLUSION
Despite the early interruption in enrolment and the failure to show differences in the primary endpoints of peak VO 2 and VE/VCO 2 , we report for the first time that in patients with T2DM and HFrEF canagliflozin was associated with improvements in several measures of CRF such as lean peak VO 2 , VAT and RER-matched VO 2 , and an improvement in the MLHFQ score reflecting a reduced HF symptom burden compared to sitagliptin, despite no significant differences in glycemic and hemodynamic control.