Abstract
Sodium‐glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on several cardiometabolic biomarkers, but this is not sufficient to fully explain the significant reduction in cardiovascular risk and mortality reported with SGLT2 inhibitor treatment in patients with diabetes mellitus. The 8‐week, randomized, open‐label SHIFT‐J study investigated the effects of adding canagliflozin vs intensified antihyperglycemic therapy on nocturnal home blood pressure (BP) in patients with poorly controlled type 2 diabetes and nocturnal BP on existing therapy. Patients were randomized to oral canagliflozin 100 mg/d or control (increased hypoglycemic dosage/addition of another hypoglycemic agent). The efficacy analysis included 78 patients (mean 69 years; 59% male). Nocturnal home systolic BP [HSBP] decreased by 5.23 mm Hg in the canagliflozin group and by 1.04 mm Hg in the control group (P = 0.078 for between‐group difference in change from baseline to week 8 [primary endpoint]); corresponding decreases in HSBP from baseline to week 4 were 5.08 and 1.38 mm Hg, respectively (P = 0.054). Reductions in morning HSBP from baseline to week 4 (−6.82 mm Hg vs −1.26 mm Hg, P = 0.038) and evening HSBP from baseline to week 8 (−8.74 mm Hg vs −2.36 mm Hg, P = 0.012) were greater in the canagliflozin group than in the control group. Body mass index (P < 0.001) and N‐terminal pro B‐type natriuretic peptide level (NT‐proBNP; P = 0.023) decreased more in the canagliflozin group than in the control group. Glycemic control improved comparably in both groups. Reduction of HSBP and NT‐proBNP level may be potential mechanism by which SGLT2 inhibitors reduce cardiovascular event risk.
Keywords: canagliflozin, cardiovascular risk, home blood pressure monitoring, nocturnal blood pressure, type 2 diabetes mellitus
1. INTRODUCTION
Both hypertension and diabetes mellitus are associated with increased risk of cardiovascular events and mortality.1, 2 These two conditions often co‐exist,3 which further increases the long‐term risk of vascular complications, including cardiovascular disease.4, 5, 6, 7
Data from large randomized controlled clinical trials showed that the rate of adverse cardiovascular outcomes in patients with type 2 diabetes can be significantly reduced by treatment with sodium‐glucose cotransporter 2 (SGLT2) inhibitors.8, 9 A number of potential mechanisms have been proposed for the beneficial effects of SGLT2 inhibitors on cardiovascular risk. These include reductions in body weight,10 glucose variability,11 blood pressure (BP),10, 12, 13 urinary albumin excretion,14, 15 and oxidative stress and inflammation.16, 17 While these are all plausible and probably contribute to the documented beneficial effects of SGLT2 inhibitors on cardiovascular risk, they do not fully explain the extent of the reduction in event risk that has been documented during SGLT2 inhibitor therapy.
Studies to date investigating the BP‐lowering effects of SGLT2 inhibitors have generally focused on clinic BP or 24‐hour BP rather than any more specific BP measures, such as nocturnal BP or BP variability. Uncontrolled nocturnal BP in particular has been shown to be associated with additional cardiovascular risk in patients with diabetes or heart failure with preserved ejection fraction.18, 19 The importance of nocturnal BP was highlighted by the results of a meta‐analysis of longitudinal prospective studies in patients with hypertension or general populations from Asia, Europe, or South America, which found that out‐of‐office night‐time systolic BP (SBP) was a better predictor of cardiovascular outcomes and total mortality than daytime SBP.20 Nocturnal BP is closely associated with circulating volume and is preferentially reduced by diuretics.21, 22
It is possible that SGLT2 inhibitors with relatively weak diuretic action have more specific effects on ambulatory BP parameters. Therefore, the study on beneficial effect on canagliflozin on nocturnal home blood pressure in Japanese type 2 diabetes patients (SHIFT‐J) determined the effects of canagliflozin on nocturnal home BP in patients with poorly controlled type 2 diabetes and nocturnal BP on existing therapy. The control group consisted of patients who had their antihyperglycemic dosage increased or an agent from a class other than SGLT2 inhibitors added.
2. METHODS
2.1. Study design
SHIFT‐J was a randomized, open‐label parallel‐group clinical trial. Patient was recruited at three centers in Japan over the period August 1, 2016, to May 31, 2017. This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by an ethics committee of the Jichi Medical University School of Medicine (Shimotsuke, Japan), and all patients provided written informed consent before study entry. The study is registered at UMIN‐CTR Clinical Trial (UMIN000023487).
2.2. Study participants
Eligible outpatients were aged ≥20 years and had both hypertension (clinic sitting BP 130‐159/80‐99 mm Hg and use of stable antihypertensive medication [drugs and dosages] for ≥3 months) and type 2 diabetes mellitus (glycosylated hemoglobin [HbA1c] 6.5%‐10%) treated with one hypoglycemic agent (excluding combination agents) and were being considered for an increase in hypoglycemic dosage or the addition of another hypoglycemic agent due to poor glycemic control based on HbA1c. In addition, mean nocturnal home SBP over the 5‐day period up to baseline had to be at least 115 mm Hg. Patients were excluded if they were taking SGLT2 inhibitors, insulin, diuretics, or GLP‐1 receptor agonists, had a history of cerebral infarction or hypersensitivity to SGLT2 inhibitors, had advanced chronic kidney disease (stages G3b‐G5), were possible pregnant, pregnant or breastfeeding, were participating in another clinical trial, had a severe adverse event during the prestudy observation period, or had difficulty with home BP monitoring during the observation period. Changes in antihypertensive medication were not generally permitted during the study.
2.3. Study treatments
Eligible patients underwent a 1‐ to 4‐week prestudy observation period. Those who met all inclusion criteria and none of the exclusion criteria were then randomly assigned in a 1:1 ratio to the control group (increased hypoglycemic agent dosage or addition of another hypoglycemic agent other than an SGLT2 inhibitor) or to the addition of oral canagliflozin (Canaglu®) 100 mg/d given before or after breakfast. Antihypertensive treatment, nutritional, and exercise therapy were continued unchanged in all patients over the 8‐week treatment period.
2.4. Efficacy
2.4.1. Primary end point
The primary outcome measure was the change in nocturnal home BP from baseline to week 8.
2.4.2. Secondary end points
Secondary outcomes were change from baseline to week 8 in the following parameters: morning and evening home BP readings; office BP; day‐by‐day diurnal variations in nocturnal, morning, and evening home BP; HbA1c; body weight; body mass index (BMI); low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) cholesterol levels; uric acid (UA) levels; amino‐terminal pro B‐type natriuretic peptide (NT‐proBNP) levels; atrial natriuretic peptide (ANP) levels; magnesium levels; and the urinary albumin to creatinine ratio (UACR). Safety was also assessed based on laboratory findings, and the occurrence of adverse events and side effects.
2.4.3. Home BP measurement
Home BP measurement was performed using a cuff oscillometric device equipped with a mobile network communication function (HEM‐7080‐IC; Omron Healthcare Co., Ltd., Kyoto, Japan). Consistent with the Japanese Society of Hypertension 2014 Guidelines for the Management of Hypertension,23 patients were instructed to measure their morning home BP (twice within 1 hour after waking; both measurements taken after urination, before taking morning medications, and after 1‐2 minutes of seated rest), evening home BP (measured twice before bedtime after 1‐2 minutes of seated rest), and nocturnal home BP (at 2, 3, and 4 am during sleep)24, 25, 26, 27, 28 for five consecutive days before their next scheduled visit (at baseline, and 4 and 8 weeks). To measure nocturnal home BP, patients were instructed to wear the BP cuff and press the button to start the timer when they went to bed.
2.4.4. Clinic BP measurement
Clinic BP was measured after the patient had rested for ≥5 minutes and was seated in a chair with the arm cuff level with the heart.23 Smoking was prohibited 30 minutes before BP measurement. Several measurements were taken one after the other at intervals of ≥1 minutes, and the average of two measurements was used to define the clinic BP.
2.5. Statistical analyses
Based on an assumed between‐group difference in SBP of 5 mm Hg with a standard deviation (SD) of 7.5 mm Hg, it was calculated that 36 patients per group would be required to achieve 80% power with a two‐sided P‐value of 0.05. Allowing for a 30% dropout rate, it was planned to enroll 50 patients per group.
Patients who were noncompliant with the Ethical Guidelines for Clinical Research were excluded from all analyses (both efficacy and safety). The full analysis set (FAS) was defined as all enrolled participants who had received the assigned therapy at least once after randomization and who had measured their nocturnal home SBP at least once. The safety analysis set (SAS) was defined as all randomized participants who had received the assigned therapy at least once during the study period.
The efficacy analyses for BP values were conducted in the FAS. Mixed‐effects model repeated measures (MMRM) analysis was used to compare the changes in nocturnal home SBP from baseline to week 8 in the canagliflozin and placebo groups. MMRM included the randomized study group, time point (0, 4, and 8 weeks), the interaction between the study group and time points as fixed effects, and ages and sex as covariates. These analyses were repeated with additional adjustment for changes in body weight during the study. Safety was determined in the SAS.
A 2‐sided test was used, and P‐values of <0.05 were considered statistically significant. Intergroup comparisons were tested with a t test for continuous variables, and Pearson’s chi‐squared test or Fisher’s exact test was used for dichotomous data. Data were analyzed using SAS version 9.4 (SAS Institute, Cary, NC, USA) at the Jichi Medical University Center of Global Home and Ambulatory BP Analysis (GAP), Shimotsuke, Japan.
3. RESULTS
3.1. Study patients
A total of 104 patients entered the pretrial observation period, and 84 were randomized (42 each to the control and canagliflozin groups). One patient in the control group withdrew during the study leaving 83 patients in the SAS, and a further five (four in the control group and one in the canagliflozin group) were excluded from the FAS (Figure 1). There were no statistically significant differences in baseline characteristics in the two treatment groups (Table 1).
Figure 1.
SHIFT‐J study flow chart. Abbreviations: BP, blood pressure; FAS, full analysis set
Table 1.
Demographic and baseline characteristics of study patients
| Control (n = 37) | Canagliflozin (n = 41) | P‐value | |
|---|---|---|---|
| Age, y | 67.8 ± 9.8 | 70.4 ± 9.5 | 0.242 |
| Male, % | 51.4 | 65.9 | 0.194 |
| BMI, kg/m2 | 26.3 ± 4.1 | 25.5 ± 3.3 | 0.333 |
| Smoking, % | 13.5 | 12.2 | 1.000 |
| Drinking, % | 59.5 | 51.2 | 0.465 |
| Dyslipidemia, % | 67.6 | 56.1 | 0.299 |
| Coronary artery disease, % | 5.4 | 12.2 | 0.436 |
| Stroke, % | 8.1 | 9.8 | 1.000 |
| Chronic kidney disease, % | 27.0 | 19.5 | 0.432 |
| Antihypertensive drugs, % | |||
| ACE inhibitor | 0.0 | 2.4 | 1.000 |
| ARB | 78.4 | 63.4 | 0.148 |
| CCB | 78.4 | 58.5 | 0.061 |
| Diuretics | 5.4 | 0.0 | 0.222 |
| β‐blocker | 8.1 | 2.4 | 0.341 |
| Antidiabetic drugs 4 wk before baseline, % | |||
| Sulfonylureas | 32.4 | 39.0 | 0.545 |
| α‐glucosidase inhibitor | 8.1 | 4.9 | 0.664 |
| DPP‐4 inhibitor | 73.0 | 82.9 | 0.288 |
| Metformin | 18.9 | 36.6 | 0.083 |
| Thiazolidinedione | 18.9 | 7.3 | 0.179 |
| Glinide | 5.4 | 7.3 | 1.000 |
| Increased dosage of, or addition of agent to, antidiabetic therapy, % | |||
| SGLT2 inhibitor | – | 100.0 | – |
| Sulfonylurea | 21.6 | – | – |
| α‐glucosidase inhibitor | 8.1 | – | – |
| DPP‐4 inhibitor | 37.8 | – | – |
| Metformin | 27.0 | – | – |
| Thiazolidinedione | 2.7 | – | – |
| Glinide | 5.4 | – | – |
| Nocturnal home SBP, mm Hg | 130.4 ± 10.5 | 133.7 ± 13.8 | 0.237 |
| Nocturnal home DBP, mm Hg | 70.2 ± 6.7 | 70.3 ± 7.1 | 0.944 |
| Nocturnal home PR, beats/min | 63.9 ± 8.4 | 63.3 ± 9.0 | 0.763 |
| Morning home SBP, mm Hg | 146.8 ± 11.6 | 147.5 ± 14.3 | 0.826 |
| Morning home DBP, mm Hg | 80.1 ± 9.9 | 79.1 ± 9.2 | 0.685 |
| Morning home PR, beats/min | 69.6 ± 9.8 | 67.3 ± 10.6 | 0.339 |
| Evening home SBP, mm Hg | 139.9 ± 11.4 | 138.6 ± 14.3 | 0.665 |
| Evening home DBP, mm Hg | 74.7 ± 9.1 | 71.9 ± 9.5 | 0.185 |
| Evening home PR, beats/min | 74.8 ± 11.4 | 74.1 ± 12.3 | 0.799 |
| Clinic SBP, mm Hg | 138.1 ± 11.7 | 142.8 ± 13.6 | 0.104 |
| Clinic DBP, mm Hg | 75.8 ± 10.1 | 76.9 ± 10.8 | 0.630 |
| Clinic PR, beats/min | 74.3 ± 10.3 | 74.5 ± 13.3 | 0.929 |
| HbA1c, % | 7.2 ± 0.6 | 7.4 ± 0.7 | 0.131 |
| LDL, mg/dL | 110.5 ± 24.6 | 103.4 ± 27.7 | 0.234 |
| HDL, mg/dL | 55.4 ± 14.4 | 55.0 ± 18.4 | 0.913 |
| UA, mg/dL | 5.5 ± 1.1 | 5.0 ± 1.2 | 0.064 |
| MG, mg/dL | 2.2 ± 0.2 | 2.1 ± 0.3 | 0.451 |
| NT‐proBNP, pg/mL | 37.7 (24.4, 98.9) | 69.2 (29.9, 108.0) | 0.465 |
| ANP, pg/mL | 16.9 (12.3, 30.2) | 21.4 (14.6, 28.9) | 0.609 |
| UACR, mg/g・Cre | 24.8 (11.0, 67.9) | 34.3 (9.2, 98.5) | 0.985 |
ANP, atrial natriuretic peptide; BMI, body mass index; DBP, diastolic BP; HbA1c, glycosylated hemoglobin; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; Mg, magnesium; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; PR, pulse rate; SBP, systolic BP; UA, uric acid; UACR, urinary albumin/creatinine ratio.
Data are shown as mean ± SD, median (interquartile range), or percent patients.
3.2. Nocturnal home BP
The number of nocturnal home BP measurements also did not differ significantly between the canagliflozin and control groups (36.1 ± 7.0 vs 36.0 ± 7.4, P = 0.929). Nocturnal home systolic BP decreased by 5.23 mm Hg in the canagliflozin group and by 1.04 mm Hg in the control group (P = 0.078 for between‐group difference in change from baseline to week 8 [primary endpoint]); corresponding decreases in HSBP from baseline to week 4 were 5.08 and 1.38 mm Hg, respectively (P = 0.054; Figure 2A). Changes from baseline in nocturnal home DBP (Figure 2B) and pulse rate (Figure 2C) were similar in the two treatment groups. Findings were similar in the analysis adjusting for change in body weight during treatment (Figure S1).
Figure 2.
Change in nocturnal systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), and pulse rate (C) for patients in the full analysis set. Each point represents mean ± standard error in a mixed‐effects model repeated measures analysis, adjusted for age and gender. 1) P‐values are for the between‐group difference in change from baseline
3.3. Morning home BP
There were no statistically significant between‐group differences in change from baseline to week 8 in morning home SBP, DBP, and pulse rate (Figure 3A–C), although the reduction of morning home SBP from baseline to week 4 was significantly greater in the canagliflozin group compared with the control group (−6.82 mm Hg vs −1.26 mm Hg, P = 0.038; Figure 3A). Adjustment for change in body weight from baseline did not significantly alter the results (Figure S2).
Figure 3.
Change in morning and evening home blood pressures: A, Morning home systolic blood pressure (SBP), B, Morning home diastolic blood pressure (DBP), C, Morning home pulse rate, D, Evening home SBP, E, Evening home DBP, and F, Evening home pulse rate. Each point represents mean ± standard error in a mixed‐effects model repeated measures analysis of full analysis set, adjusted for age and gender. 1) P‐values are for the between‐group difference in change from baseline
3.4. Evening home BP
The decrease from baseline to week 8 in evening home SBP was significantly greater in the canagliflozin group compared with the control group (139.2‐130.5 mm Hg and 139.9‐137.5 mm Hg, respectively; P = 0.012 for between‐group difference in the change from baseline; Figure 3D). Changes from baseline in evening home DBP (Figure 3E) and pulse rate (Figure 3F) were similar in the two treatment groups. All results were similar when adjusted for body weight change during the study (Figure S2).
3.5. Clinic BP
There were no statistically significant between‐group differences in change from baseline to week 8 in clinic SBP, DBP, and pulse rate, although reductions in DBP and pulse rate tended to be greater in the canagliflozin group vs the control group (P = 0.056 and P = 0.063, respectively; Figure 4), with similar results after adjustment for change in body weight (Figure S4).
Figure 4.
Change in clinic systolic blood pressure (SBP) (A), diastolic blood pressure (DBP) (B), and pulse rate (C). Each point represents mean ± standard error in a mixed‐effects model repeated measures analysis of the full analysis set, adjusted for age and gender. 1) P‐values are for the between‐group difference in change from baseline
3.6. Other secondary endpoints
Glycemic control improved to a similar extent in the canagliflozin and control groups (Table 2). Changes from baseline to week 8 in body weight, BMI, magnesium, and NT‐proBNP (−5.45% vs +19.49%, P = 0.02) levels were significantly greater in the canagliflozin group compared with the control group (Table 2, Figure S4A). Reductions in NT‐proBNP were similar when also adjusted for change from baseline in body weight during the study (Figure S4B). Both LDL cholesterol and HDL cholesterol were increased to a significantly greater extent with canagliflozin vs control (Table 2). There were no other statistically significant between‐group differences in change from baseline for other secondary endpoint parameters (Table 2).
Table 2.
Primary and secondary endpoint parameters
| Change from baseline to week 8 (95% CI) | Between‐group difference | P‐value | ||||
|---|---|---|---|---|---|---|
| Control | Canagliflozin | |||||
| n | n | |||||
| Nocturnal home SBP, mm Hg | 37 | −1.04 (−4.43, 2.34) | 41 | −5.23 (−8.44, −2.01) | −4.18 (−8.85, 0.48) | 0.078 |
| Nocturnal home DBP, mm Hg | 37 | 0.33 (−1.82, 2.49) | 41 | −1.45 (−3.49, 0.60) | −1.78 (−4.75, 1.19) | 0.237 |
| Nocturnal home PR, beats/min | 37 | 0.32 (−1.37, 2.02) | 41 | 0.21 (−1.40, 1.82) | −0.11 (−2.45, 2.23) | 0.924 |
| Morning home SBP, mm Hg | 37 | −3.29 (−7.41, 0.84) | 40 | −6.96 (−10.93, −2.99) | −3.67 (−9.40, 2.06) | 0.205 |
| Morning home DBP, mm Hg | 37 | −1.90 (−3.87, 0.08) | 40 | −1.31 (−3.22, 0.60) | 0.59 (−2.16, 3.33) | 0.672 |
| Morning home PR, beats/min | 37 | −1.30 (−3.28, 0.67) | 40 | −0.21 (−2.12, 1.69) | 1.09 (−1.66, 3.84) | 0.432 |
| Evening home SBP, mm Hg | 37 | −2.36 (−5.89, 1.17) | 40 | −8.74 (−12.18, −5.29) | −6.38 (−11.31, −1.45) | 0.012 |
| Evening home DBP, mm Hg | 37 | −1.66 (−3.54, 0.22) | 40 | −3.32 (−5.15, −1.49) | −1.66 (−4.28, 0.97) | 0.213 |
| Evening home PR, beats/min | 37 | 1.93 (0.06, 3.81) | 40 | 1.20 (−0.63, 3.03) | −0.73 (−3.35, 1.89) | 0.579 |
| Clinic SBP, mm Hg | 37 | −3.55 (−7.24, 0.14) | 41 | −6.55 (−10.05, −3.04) | −2.99 (−8.08, 2.09) | 0.245 |
| Clinic DBP, mm Hg | 37 | −0.16 (−2.98, 2.65) | 41 | −3.94 (−6.61, −1.26) | −3.78 (−7.66, 0.11) | 0.056 |
| Clinic PR, beats/min | 37 | 1.45 (−1.34, 4.23) | 41 | −2.20 (−4.84, 0.45) | −3.64 (−7.48, 0.20) | 0.063 |
| HbA1c, % | 36 | −0.34 (−0.50, −0.18) | 41 | −0.37 (−0.53, −0.21) | −0.03 (−0.25, 0.19) | 0.793 |
| Weight, kg | 37 | −0.08 (−0.47, 0.31) | 41 | −1.70 (−2.08, −1.32) | −1.62 (−2.16, −1.09) | <0.001 |
| BMI, kg/m2 | 37 | −0.05 (−0.20, 0.10) | 41 | −0.67 (−0.81, −0.52) | −0.61 (−0.82, −0.41) | <0.001 |
| LDL, mg/dL | 36 | −2.64 (−7.97, 2.69) | 40 | 7.18 (1.22, 13.13) | 9.81 (1.95, 17.67) | 0.015 |
| HDL, mg/dL | 36 | −1.97 (−4.90, 0.96) | 41 | 2.32 (0.12, 4.52) | 4.29 (0.68, 7.90) | 0.020 |
| UA, mg/dL | 37 | −0.11 (−0.32, 0.10) | 41 | −0.45 (−0.74, −0.16) | −0.34 (−0.69, 0.01) | 0.057 |
| Mg, mg/dL | 25 | 0.00 (−0.08, 0.08) | 30 | 0.11 (0.04, 0.18) | 0.11 (0.01, 0.21) | 0.034 |
| NT‐proBNP, % | 37 | 19.49 (3.41, 38.07) | 41 | −5.45 (−18.15, 9.22) | – | 0.023 |
| ANP, % | 37 | 8.41 (−8.19, 28.00) | 41 | 0.75 (−11.03, 14.09) | – | 0.477 |
| UACR, % | 37 | −21.66 (−40.61, 3.32) | 40 | −28.29 (−44.43, −7.45) | – | 0.636 |
ANP, atrial natriuretic peptide; BMI, body mass index; CI, confidence interval; HbA1c, glycosylated hemoglobin; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; Mg, magnesium; NT‐proBNP, N‐terminal pro B‐type natriuretic peptide; UA, uric acid; UACR, urinary albumin/creatinine ratio.
Values are expressed as mean (95% confidence interval [CI]). NT‐proBNP, ANP, and UACR values were % change from baseline, back‐transformed from natural log. P‐values are for the comparison of between‐group differences in changes from baseline to week 8.
3.7. Safety
Canagliflozin was well tolerated; no serious adverse events occurred during treatment. Nonserious adverse events occurred in 7% of patients in the canagliflozin group and 12% of patients in the control group (Table S1). Only three events in each group were considered to be related to treatment (Table S1).
4. DISCUSSION
This is the first study to investigate the effects of an SGLT2 inhibitor on home BP, facilitated by use of a new home BP monitoring device capable of determining nocturnal home BP. The results showed that, as well as providing good glycemic control, the addition of canagliflozin to standard antihyperglycemic therapy for 8 weeks marginally reduced nocturnal SBP (primary endpoint) and significantly reduced morning and evening home SBP and serum NT‐proBNP levels, compared with other antihyperglycemics targeted to achieve strict glycemic control in diabetic patients with uncontrolled nocturnal hypertension. These differences between the canagliflozin and placebo groups persisted after adjustment for change from baseline in body weight during the study and represent potential mechanisms by which canagliflozin could contribute to reducing the risk of cardiovascular events in patients with diabetes.
The reduction in nocturnal home SBP from baseline to week 8 in the canagliflozin group was 5.23 mm Hg. The statistical significance of this reduction was marginal compared with the control group (P = 0.078). The difference in reduction of nocturnal home SBP from baseline to week 4 was also of marginal statistical significance (P = 0.054). However, this nocturnal BP reduction may be one potential mechanism for the cardioprotective action of SGLT2 inhibitors, because the lowering of nocturnal BP could act synergistically with treatment‐related reductions in circulating volume29 (as shown by an increase in hematocrit during empagliflozin treatment in the EMPA‐REG OUTCOME trial9). This would result in reductions in both preload and afterload, contributing to lower risk of heart failure. It is interesting to note that, as reported previously,11 reductions in BP seen during canagliflozin therapy were not accompanied by a compensatory increase in heart rate.
The reduction in nocturnal BP seen in this study is consistent with the suggestion that changes in BP during treatment with an SGLT2 inhibitor restore disrupted circadian BP rhythms, shifting patients with hypertension and diabetes from a nondipper to a dipper pattern.30, 31 Given the association between disrupted circadian BP patterns and cardiovascular events,32, 33, 34, 35 this is one plausible mechanism for the beneficial effects of SGLT2 inhibitor treatment on cardiovascular risk.
Another important finding of the SHIFT‐J study was that clinically relevant reductions were found in morning and evening home systolic BP values. This highlights the importance of out‐of‐office BP monitoring compared with clinic‐based measurements. There is increasing recognition of the importance of out‐of‐clinic BP (home BP and ambulatory BP) compared with clinic BP, and these approaches are recommended by several international hypertension guidelines.23, 36, 37 In particular, a home BP‐guided approach is recommended in clinical practice.
The reduction in clinic SBP from baseline to week 8 in the canagliflozin group was 6.55 mm Hg, which was not significantly different from the change in the control group. Meta‐analysis data have shown that the risk of major cardiovascular events and heart failure decreased by 20% and 28%, respectively, for each 10‐mm Hg reduction in clinic SBP, and these effects were consistent across patients with a range of comorbid conditions.38 The clinical benefits of a reduction in home BP with an SGLT2 inhibitor would be greater than those associated with a reduction in clinic BP.
In the SHIFT‐J study, canagliflozin reduced NT‐proBNP levels to a significantly greater extent compared with the control group over 8 weeks’ treatment and were independent of change in body weight during the study. B‐type natriuretic peptide (BNP) is an important biomarker of cardiac overload for predicting heart failure.39 Reductions in natriuretic peptide levels in heart failure patients indicate improved clinical condition. Baseline levels of the biomarker NT‐proBNP were within the normal range in the SHIFT‐J study. Even small increases in plasma BNP levels have also been shown to be associated with increasing nocturnal BP.40 Data from the Framingham Offspring Study in patients without heart failure and with BNP levels in the normal range showed that each 1 SD increase in log BNP levels was associated with a 28% increase in the risk of a first CV event (P = 0.03), a 53% increase in the risk of transient ischemic attack or stroke (P = 0.002), and a 27% increase in the risk of death (P = 0.009).41 Therefore, decreases in NT‐proBNP within the normal range, as seen with canagliflozin in the current study, would be expected to reduce the risk of death and CV events and are therefore clinically meaningful. The reduction of NT‐proBNP even within the normal range may partly account for the results from the CANVAS program, which showed that the risk of hospitalization for heart failure was significantly reduced by canagliflozin compared with placebo (hazard ratio 0.67, 95% confidence interval 0.52‐0.87).8 This was similar for primary and secondary prevention,42 which is consistent with our findings of reductions in NT‐proBNP. Empagliflozin, another SGLT2 inhibitor, has also been shown to significantly reduce the rate of hospitalization for heart failure vs placebo when added to standard care in type 2 diabetes patients at high cardiovascular risk.9
5. STUDY STRENGTHS
A key strength of this study is the use of objective study endpoints. Nocturnal and daytime home BP was measured using a validated information and communication technology (ICT)‐based home BP monitoring device, and all BP readings were taken using standardized methodology.
6. STUDY LIMITATIONS
The main weakness of this study was the relatively small number of patients, which may have limited the statistical power for some comparisons. In addition, the open‐label study design means that sources of bias could not be completely eliminated.
7. CONCLUSIONS
The SHIFT‐J study identified a number of possible mechanisms for the reduction in cardiovascular risk associated with canagliflozin therapy in patients with diabetes mellitus. Clinically meaningful reductions were observed in home systolic BP measurements and levels of the cardiac biomarker NT‐proBNP. The ability of SGLT2 inhibitors to control home BP and improve circulatory parameters is likely to contribute to the cardioprotective effects of this drug class in heart failure.
CONFLICT OF INTEREST
This study was funded by Mitsubishi Tanabe Pharma Corporation. Medical writing assistance was provided by Nicola Ryan, independent medical writer.
Supporting information
ACKNOWLEDGMENTS
This work was supported by Mitsubishi Tanabe Pharma Corporation.
Kario K, Hoshide S, Okawara Y, et al. Effect of canagliflozin on nocturnal home blood pressure in Japanese patients with type 2 diabetes mellitus: The SHIFT‐J study. J Clin Hypertens. 2018;20:1527–1535. 10.1111/jch.13367
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