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Lowering of blood pressure and pulse rate by switching from DPP-4 inhibitor to luseogliflozin in patients with type 2 diabetes complicated with hypertension: A multicenter, prospective, randomized, open-label, parallel-group comparison trial (LUNA study)

  • Reina Hashimoto-Kameda
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Kyu Yong Cho
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan

    Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Hiroshi Nomoto
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Akinobu Nakamura
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Kazuno Omori
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • So Nagai
    Affiliations
    Division of Diabetes and Endocrinology, Department of Medicine, Sapporo Medical Center, NTT East Corporation, Minami 1, Nishi 15, Chuo-ku, Sapporo 060-0061, Japan
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  • Sachiko Edagawa
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Shinichiro Kawata
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Jun Takeuchi
    Affiliations
    Sapporo Diabetes, Thyroid Clinic, Kita 7, Nishi 2-8-1, Kita-ku, Sapporo 060-0807, Japan
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  • Hiraku Kameda
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Yoshio Kurihara
    Affiliations
    Kurihara Clinic, Atsubetsuchuo 3-5-7-28, Atsubetsu-ku, Sapporo 004-0053, Japan
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  • Shin Aoki
    Affiliations
    Aoki Clinic, Nangodori 1-Kita 1-1-5F, Shiroisi-ku, Sapporo 003-0023, Japan
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  • Tatsuya Atsumi
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • Hideaki Miyoshi
    Correspondence
    Corresponding author at: Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-8638, Japan.
    Affiliations
    Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan

    Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14, Nishi 5, Kita-ku, Sapporo 060-8648, Japan
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  • LUNA Study Investigators
Open AccessPublished:September 22, 2021DOI:https://doi.org/10.1016/j.diabres.2021.109069

      Highlights

      • The effect on nighttime BP of SGLT2i was investigated in patients with T2D and HT.
      • Switching from DPP-4i to luseogliflozin decreased nighttime BP, PP, and PR.
      • BP circadian rhythm was improved by the switching.

      Abstract

      Aims

      Sodium-glucose cotransporter-2 inhibitor (SGLT2i) reduces clinic blood pressure (BP), but the effects on BP circadian rhythm remain unclear. The present study aimed to determine the nighttime antihypertensive effect of SGLT2i compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) in patients with type 2 diabetes and hypertension.

      Materials and Methods

      In this randomized, open-label, parallel-group trial, patients treated with DPP-4i were either switched to luseogliflozin 2.5 mg/day (Luseo group; n = 30) or continued DPP-4i (DPP-4i group; n = 26). The patients undertook 24-h ambulatory BP monitoring before and 8 weeks after the group allocation. The primary endpoint was mean change in nighttime systolic BP (SBP).

      Results

      Nighttime SBP, as well as daytime SBP, was significantly reduced in the Luseo group compared with the DPP-4i group (nighttime, −4.0 ± 11.4 vs. 3.6 ± 10.7 mmHg, P = 0.01; daytime, −4.4 ± 10.9 vs. 3.7 ± 11.9 mmHg, P = 0.01). Similarly, nighttime pulse rate (PR) was significantly reduced in the Luseo group (−2.0 ± 4.8 vs. 0.9 ± 4.8 bpm, P = 0.03). The proportion of patients with abnormal BP circadian rhythms (non-dipper pattern plus riser pattern) was significantly lower in the Luseo group (36.6% vs. 56.7%, P < 0.05).

      Conclusions

      Switching from DPP-4i to luseogliflozin decreased nighttime SBP and PR; moreover, BP circadian rhythm was improved.

      Keywords

      1. Introduction

      Patients with type 2 diabetes are at high risk for cardiovascular disease and cardiovascular mortality [

      Emerging Risk Factors Collaboration; Sarwar N, Gao P, Kondapally Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010; 375: 2215-22.

      ]. Multidisciplinary interventions, including those for hyperglycemia, are required to reduce cardiovascular complications and mortality in type 2 diabetes patients [
      • Gæde P.
      • Vedel P.
      • Larsen N.
      • Jensen G.V.H.
      • Parving H.-H.
      • Pedersen O.
      Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.
      ,
      • Ueki K.
      • Sasako T.
      • Okazaki Y.
      • et al.
      J-DOIT3 Study Group. Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial.
      ]. In particular, hypertension is present in more than one-half of type 2 diabetes patients, approximately twice the prevalence in non-type 2 diabetes patients [
      • Colosia A.D.
      • Palencia R.
      • Khan S.
      Prevalence of hypertension and obesity in patients with type 2 diabetes mellitus in observational studies: a systematic literature review.
      ], and is closely associated with the elevated cardiovascular mortality in these patients [
      • Lewington S.
      • Clarke R.
      • Qizilbash N.
      • et al.
      Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
      ]. In the guideline for hypertension, the target values were sequentially set for clinical blood pressure (BP) and home BP measurements [
      • Umemura S.
      • Arima H.
      • Arima S.
      • Asayama K.
      • Dohi Y.
      • Hirooka Y.
      • et al.
      The Japanese society of hypertension guidelines for the management of hypertension (JSH 2019).
      ]; however, these measurements are not appropriate to identify nighttime hypertension, a strong predictor of cardiovascular disease in type 2 diabetes patients [

      Astrup AS, Nielsen FS, Rossing P, et al. Predictors of mortality in patients with type 2 diabetes with or without diabetic nephropathy: a follow-up study. J Hypertens 2007; 25: 2479–85.

      ,

      Bouhanick B, Bongard V, Amar J, et al. Prognostic value of nocturnal blood pressure and reverse-dipping status on the occurrence of cardiovascular events in hypertensive diabetic patients. Diabetes Metab. 2008; 34: 560–7.

      ]. Evaluation of 24-h BP using ambulatory blood pressure monitoring (ABPM) devices can detect nighttime hypertension [
      • O’Brien E.
      • Parati G.
      • Stergiou G.
      Ambulatory blood pressure measurement what is the international consensus?.
      ] in individual patients, as well as relevant information including BP variability over 24 h. In healthy individuals, the BP profiles during sleep are > 10% lower than those during daytime because of the decreased physical activity. Disappearance or reversal of the physiological BP variability can potentially cause hypertensive target organ damage even though the daytime BP is normotensive [
      • Hansen T.W.
      • Li Y.
      • Boggia J.
      • Thijs L.
      • Richart T.
      • Staessen J.A.
      Predictive role of the nighttime blood pressure.
      ]. ABPM also provides information on pulse rate (PR), given that elevated nighttime PR was identified as an independent risk for cardiovascular mortality in hypertensive patients with normal daytime PR [
      • Palatini P.
      • Reboldi G.
      • Beilin L.J.
      • et al.
      Masked tachycardia. A predictor of adverse outcome in hypertension.
      ].
      A selective sodium-glucose cotransporter-2 inhibitor (SGLT2i) blocks glucose reabsorption in the proximal tubules of the kidney and increases glucosuria, as well as blocking sodium resorption and leading to sodium excretion in the urine [
      • Kim Y.
      • Babu A.R.
      Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes.
      ]. A recent series of mega-scale clinical trials for SGLT2i versus placebo indicated cardioprotective effects of SGLT2i [
      • Zinman B.
      • Wanner C.
      • Lachin J.M.
      • Fitchett D.
      • Bluhmki E.
      • Hantel S.
      • et al.
      EMPA-REG OUTCOME investigators: empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
      ,
      • Neal B.
      • Perkovic V.
      • Mahaffey K.W.
      • de Zeeuw D.
      • Fulcher G.
      • Erondu N.
      • et al.
      CANVAS program collaborative group: canagliflozin and cardiovascular and renal events in type 2 diabetes.
      ,
      • Wiviott S.D.
      • Raz I.
      • Bonaca M.P.
      • et al.
      Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
      ]. Although several studies have reported a lowering effect of SGLT2i on clinical BP, most of the studies did not focus on nighttime BP. One study that evaluated the change in nighttime BP as a primary endpoint has recently been reported [
      • Kario K.
      • Okada K.
      • Kato M.
      • et al.
      24-Hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study.
      ]. In the study, addition of empagliflozin effectively reduced nighttime BP, but the change did not reach significance compared with addition of placebo.
      Dipeptidyl peptidase-4 inhibitors (DPP-4is) are widely used because of their effectiveness for glycemic control and acceptable safety. Unlike SGLT2is, DPP-4is do not affect BP [
      • Mita T.
      • Katakami N.
      • Shiraiwa T.
      • Yoshii H.
      • Onuma T.
      • Kuribayashi N.
      • et al.
      Collaborators on the sitagliptin preventive study of intima-media thickness evaluation (SPIKE) trial. Sitagliptin attenuates the progression of carotid intima-media thickening in insulin-treated patients with type 2 diabetes: the sitagliptin preventive study of intima-media thickness evaluation (SPIKE): A randomized controlled trial.
      ,
      • Zhang X.
      • Zhao Q.
      Effect of dipeptidyl peptidase-4 inhibitors on blood pressure in patients with type2 diabetes: A systematic review and meta-analysis.
      ] or reduce the prevalence of cardiovascular events [
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • Steg P.G.
      • Davidson J.
      • Hirshberg B.
      • et al.
      SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      ,
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • et al.
      CARMELINA investigators.
      ]. However, the outcomes of switching from DPP-4i to SGLT2i on the variation of BP and PR have not been fully evaluated based on 24-h BP monitoring and PR data.
      The present study investigated the significance of switching from DPP-4i to luseogliflozin on the changes in ABPM parameters in patients with type 2 diabetes complicated with hypertension in a randomized clinical trial (RCT) (LUNA study) [
      • Kameda R.
      • Nomoto H.
      • Cho K.Y.
      • Kawata S.
      • Omori K.
      • Takeuchi J.
      • et al.
      Effects of switching from a dipeptidyl peptidase-4 inhibitor to luseogliflozin on nocturnal blood pressure in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, blinded endpoint parallel-group comparison study.
      ].

      2. Subjects, materials and methods

      2.1 Study design

      The LUNA study is a multicenter, prospective, randomized, open-label, blind-endpoint, parallel-group comparative study, the design and rationale of which were reported previously [
      • Kameda R.
      • Nomoto H.
      • Cho K.Y.
      • Kawata S.
      • Omori K.
      • Takeuchi J.
      • et al.
      Effects of switching from a dipeptidyl peptidase-4 inhibitor to luseogliflozin on nocturnal blood pressure in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, blinded endpoint parallel-group comparison study.
      ]. The study is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000031451) and the Japan Registry of Clinical Trials (jRCTs011180019). The study protocol was approved by the Hokkaido University Certified Review Board and the study was carried out in accordance with the principles of the Declaration of Helsinki and its amendments. All participants provided written informed consent prior to enrollment. Participant randomization and data management were conducted by a third-party entity for minimization of bias.

      2.2 Study population

      Enrollment began in March 2018 and ended in May 2020. Eligible participants were Japanese patients with type 2 diabetes who attended hospitals (five sites in Japan) that cooperated with the study. The key inclusion criteria were as followed: age of 20–85 years; HbA1c level of 6.0%–9.0% (46–79 mmol/mol); ≥4 weeks of DPP-4i treatment with exception of once-weekly agents; and diagnosis of hypertension (BP > 130/80 mm Hg) before enrollment. The subjects were excluded according to the following key criteria : previous treatment with SGLT2i unless a 4-week washout period had been completed; SGLT2i intolerance; unstable diabetic retinopathy; complication with severe hepatopathy or nephropathy; definite or suspected pregnancy; severe ketosis, diabetic coma, or precoma; severe infection, trauma, or perioperative period; impaired insulin secretion; BMI of < 22 kg/m2; and estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73 m2. Participants who worked at night or had undetermined work shifts were also excluded.

      2.3 Randomization and study intervention

      After informed consent was obtained, the participants were randomly assigned in a 1:1 ratio to continue their DPP-4i or switch to luseogliflozin 2.5 mg/day [
      • Rosenstock J.
      • Perkovic V.
      • Johansen O.E.
      • et al.
      CARMELINA investigators.
      ]. The randomization was performed using a computer-based dynamic allocation method by a specialized center that was independent of the participating sites. Allocation factors included age, BMI, and HbA1c. The doses of medications against hypertension and hyperglycemia, including DPP-4i and luseogliflozin, were not adjusted for the trial. However, the doses of sulfonylureas and insulin could be reduced if there was a risk of hypoglycemia [
      • Takahashi K.
      • Cho K.Y.
      • Nakamura A.
      • Miya A.
      • Miyoshi A.
      • Yamamoto C.
      • et al.
      Should sulfonylurea be discontinued or maintained at the lowest dose when starting ipragliflozin? A multicenter observational study in Japanese patients with type 2 diabetes.
      ]. At visit 1 (screening, enrollment), background characteristics and clinical information (age, body weight, complications, medications) were collected (Supplemental Fig. 1). The minimum observation period between visits 2 and 3 was 8 weeks (up to 12 weeks). Immediately before visits 2 and 3, the participants carried out 24-h BP monitoring by ABPM twice on the term, comprising a total of four times in the study. For this purpose, a TM 2433 device (A&D Medical, Tokyo, Japan) was used to record BP and PR every 30 min for 24 h. During the measurement period, the participants recorded their times of waking, going to bed, and meal consumption in a logbook to define their individual times for daytime and nighttime. In the present study, daytime was defined as the time from waking up to before going to bed, and nighttime was defined as the time from going to bed to before waking up [
      • Kario K.
      • Okada K.
      • Kato M.
      • et al.
      24-Hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study.
      ,
      • Kameda R.
      • Nomoto H.
      • Cho K.Y.
      • Kawata S.
      • Omori K.
      • Takeuchi J.
      • et al.
      Effects of switching from a dipeptidyl peptidase-4 inhibitor to luseogliflozin on nocturnal blood pressure in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, blinded endpoint parallel-group comparison study.
      ]. At both visit 2 (baseline) and visit 3 (end of study), fasting blood and urine samples were collected in addition to the measurements gathered.

      2.4 Primary and secondary endpoints

      The primary endpoint was the mean change in nighttime systolic blood pressure (SBP) measured by ABPM. The secondary endpoints included the mean changes in nighttime diastolic blood pressure (DBP), daytime SBP and DBP, daytime and nighttime PR, laboratory parameters indicative of glucose and lipid metabolism, liver enzymes and renal function. In addition, nighttime SBP decrease (%) was calculated as 100 × [1–(nighttime SBP)/(daytime SBP)] and the participants were classified into three subcategories based on their ABPM data [
      • O'Brien E.
      • Sheridan J.
      • O'Malley K.
      Dippers and non-dippers.
      ]: dipper, ≥10% reduction in nighttime SBP compared with daytime SBP; non-dipper, <10% reduction in nighttime SBP compared with daytime SBP; and riser, increased nighttime SBP compared with daytime SBP.

      2.5 Sample size and statistical analysis

      The sample size was calculated based on the assumption that the improvement in mean ± SD change in nighttime SBP with luseogliflozin would be 10.7 ± 11.3 mmHg, as shown in a previous small-group, single-arm, pilot ABPM study in Japanese type 2 diabetes patients [
      • Shirabe S.
      • Maeda H.
      • Koike Y.
      • et al.
      Analysis of the effect of luseogliflozin on patients with type 2 diabetes and hypertension using ambulatory blood pressure monitoring.
      ]. It was determined that 25 patients would be needed in each group to detect a significant difference, with 90% power and 0.05 significance level for superiority. The sample size was set at 30 individuals to include 5 dropouts per group.
      Analyses of data for the primary and secondary endpoints were performed on the full analysis set (FAS), which included all subjects enrolled in the study and assigned to the treatment groups. Results are presented as mean ± SD, median (interquartile range), or n (%). Differences in baseline characteristics between the two groups were evaluated using an unpaired t-test or the Mann–Whitney U test for continuous variables, and the chi-square test or Fisher’s exact test for categorical variables. The Kolmogorov–Smirnov test for normality was used as the appropriate statistical test for continuous variables. The results within each group were compared using a paired-sample t-test or the Wilcoxon signed-rank test. Data were analyzed using JMP Pro version 14.1.1 software (SAS Institute, Cary, NC, USA). Values of P < 0.05 were considered to indicate statistical significance.

      3. Results

      3.1 Patients

      A total of 68 patients with type 2 diabetes complicated with hypertension were enrolled in the study. One patient was excluded after withdrawal of consent, thus 67 patients met the criteria and were randomized to the DPP-4i group (n = 33) and Luseo group (n = 34) (Fig. 1). Finally, 56 patients completed the study and were included in the FAS (DPP-4i group, n = 26; Luseo group, n = 30). There were two cases with symptoms during this study (mild sickness in the DPP-4i group and intermittent body pain in the Luseo group). Body pain in the Luseo group was observed prior to the initiation of luseogliflozin. Both cases were not serious and resolved with appropriate treatment. The user rates and kinds of antihypertensive drugs were similar between the two groups (Table 1). Thirteen participants did not take any antihypertensive drugs (six in the Luseo group; seven in the DPP-4i group). One patient in the DPP-4i group had his antihypertension drug dosage increased at the doctor’s discretion.
      Table 1Clinical characteristics of the study cohort.
      VariablesDPP-4i (n = 26)Luseo (n = 30)P-value
      Age (years)68.3 ± 8.169.6 ± 9.00.59
      Male sex20 (76.9)19 (63.3)0.27
      BMI (kg/m2)25.4 ± 2.926.3 ± 3.90.29
      Duration of diabetes (years)0.36
       <55 (19.2)6 (20.0)
       5≤, <104 (15.4)5 (16.7)
       10≤, <156 (23.1)5 (16.7)
       15≤11 (42.3)14 (46.7)
      Smoking status0.05
       Current smoker10 (38.5)4 (13.3)
       Former smoker11 (42.3)13 (43.3)
      Alcohol drinking status12 (46.2)8 (26.7)0.13
      Diabetic retinopathy6 (23.1)11 (36.7)0.27
      Diabetic nephropathy13 (50.0)12 (40.0)0.45
       Microalbuminuria9 (34.6)9 (30.0)
       Macroalbuminuria4 (15.4)3 (10.0)
      Atherosclerotic vascular disease4 (15.4)5 (17.2)1.00
      Dyslipidemia21 (80.8)22 (73.3)0.51
      Fatty liver4 (15.4)5 (16.1)1.00
      Sleep apnea syndrome0 (0)2 (6.7)0.49
      Treatment for diabetes mellitus
       DPP-4i0.92
       Vildagliptin9 (34.2)6 (20.0)
       Teneligliptin6 (23.1)7 (23.3)
       Sitagliptin4 (15.4)7 (23.3)
       Linagliptin3 (11.5)4 (13.3)
       Alogliptin2 (7.7)3 (10.0)
       Anagliptin2 (7.7)2 (6.7)
       Saxagliptin0 (0.0)1 (3.3)
      Other oral antidiabetic drug
       Biguanide21 (80.8)18 (60.0)0.09
       Sulfonylurea4 (15.4)5 (16.7)0.90
       Glinide3 (11.5)7 (23.3)0.31
       α-GI2 (7.7)8 (26.7)0.09
       Pioglitazone1 (3.9)2 (6.7)1.00
       Insulin1 (3.9)5 (16.7)0.20
      Treatment for hypertension
      ACE inhibitor/ARB17 (65.4)21 (70.0)0.71
      Calcium channel blocker16 (61.5)16 (53.3)0.54
      Beta-blocker1 (3.9)4 (13.3)0.36
      Diuretic3 (11.5)4 (13.3)1.00
      Other treatment
      Statin16 (61.5)19 (63.3)0.89
      Fibrate4 (15.4)1 (3.3)0.17
      Ezetimibe3 (11.5)3 (10.0)1.00
      Drug for hyperuricemia1 (3.9)4 (13.3)0.36
      Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide-1; α-GI, α-glucosidase inhibitor.
      Data are shown as mean ± SD or n (%).
      P-values: Luseo group vs. DPP-4i group.
      The baseline demographic characteristics were well matched between the two groups (Table 1). At the end of the study, there were no significant differences in the clinical manifestations and laboratory data between the two groups, although body weight, abdominal circumference, clinical SBP, clinical DBP, PR, and uric acid were decreased and HbA1c was increased in the Luseo group during the study (Supplemental Table 1). No participants had worsening of renal function in the Luseo group. No changes in urinary albumin-to-creatinine ratio and eGFR were observed in either group throughout the study period.

      3.2 Blood pressure and pulse rate

      Table 2 shows the changes in BP and PR between the two groups. Both nighttime SBP and daytime SBP was significantly reduced in the Luseo group compared with the DPP-4i group (nighttime SBP, −4.0 ± 11.4 vs. 3.6 ± 10.7 mmHg, P < 0.01; daytime SBP, −4.4 ± 10.9 vs. 3.7 ± 11.9 mmHg, P < 0.01; Fig. 2). Daytime DBP was significantly decreased in the Luseo group compared with the DPP-4i group (−2.4 ± 5.5 vs. 1.0 ± 6.1 mmHg, P = 0.03), while nighttime DBP showed a similar pattern in the absence of statistical significance (−2.2 ± 6.1 vs. 0.8 ± 5.7 mmHg, P = 0.06) (Supplemental Fig. 2). Pulse pressure (PP), defined as the difference between SBP and DBP, was significantly reduced for both nighttime and daytime in the Luseo group compared with the DPP-4i group (nighttime, −2.8 ± 7.3 vs. 2.8 ± 6.3 mmHg, P = 0.02; daytime, −2.0 ± 6.7 vs. 2.7 ± 6.9 mmHg, P = 0.01) (see Table 2, Table 3).
      Figure thumbnail gr2
      Fig. 2Comparisons of SBP obtained from 24-h ABPM data in the Luseo and DPP-4i groups. **P < 0.01, mean change from baseline to end of study (unpaired t-test).
      Table 2Comparisons of systolic blood pressure, diastolic blood pressure, pulse pressure, and pulse rate based on the 24-h ABPM data in the DPP-4i and Luseo groups.
      VariablesDPP-4iLuseoP-value
      BaselineEndChangeBaselineEndChange
      SBP (mmHg)
      Daytime144.9 ± 11.1148.6 ± 14.33.7 ± 11.9146.5 ± 17.5142.0 ± 13.3−4.4 ± 10.9<0.01
      Nighttime128.1 ± 10.5131.7 ± 13.53.6 ± 10.7132.2 ± 19.6128.2 ± 18.3−4.0 ± 11.4<0.01
      DBP (mmHg)
      Daytime80.6 ± 9.881.6 ± 9.11.0 ± 6.180.6 ± 10.878.2 ± 8.3−2.4 ± 5.50.03
      Nighttime71.0 ± 6.771.8 ± 6.90.8 ± 5.771.6 ± 9.369.4 ± 7.6−2.2 ± 6.10.06
      PP (mmHg)
      Daytime64.3 ± 10.267.0 ± 11.32.7 ± 6.965.8 ± 12.063.8 ± 11.0−2.0 ± 6.70.01
      Nighttime57.2 ± 10.860.0 ± 11.92.8 ± 6.860.6 ± 13.958.7 ± 13.6−2.8 ± 7.30.02
      PR (bpm)
      Daytime74.8 ± 8.276.8 ± 9.71.9 ± 5.772.1 ± 7.772.4 ± 7.40.4 ± 4.40.30
      Nighttime67.1 ± 8.168.0 ± 9.70.9 ± 4.863.7 ± 7.361.7 ± 7.8 *−2.0 ± 4.80.03
      Abbreviations: ABPM, ambulatory blood pressure monitoring; DBP, diastolic blood pressure; DPP-4i, dipeptidyl peptidase-4 inhibitor; PP, pulse pressure; PR, Pulse rate; SBP, systolic blood pressure.
      P-values: mean change between baseline and end of study (Welch’s t-test or Mann–Whitney U test) in the DPP-4i and Luseo group. *P < 0.05, between baseline and end of study (paired-sample t-test) in each group.
      In the Luseo group, 13 patients were classified as dipper type (43.3%), 15 as non-dipper type (50.0%), and 2 as riser type (6.7%) at baseline. After treatment, the number of non-dipper type decreased to 7 patients (23.3%) (P < 0.05) (Table 3). In the DPP-4i group, the numbers of patients classified as dipper type, non-dipper type and riser type did not change significantly from baseline to end of study: 18 (69.2%) to 17 (65.3%), 5 (19.2%) to 6 (23.0%), and 3 (11.5%) to 3 (11.5%), respectively.
      Table 3Changes in types of blood pressure variability in the Luseo group.
      VariablesBaselineEndChange
      Dipper13 (43.3)19 (63.3)6 (20.0)
      Non-dipper15 (50.0)7 (23.3)−8 (−26.6)
      Riser2 (6.7)4 (13.3)2 (6.6)
      Data are shown as n (%).
      PR showed differences between nighttime and daytime. Nighttime PR was significantly reduced in the Luseo group during the study (−2.0 ± 4.8 vs. 0.9 ± 4.8 bpm, P = 0.03), while daytime PR was not (0.4 ± 4.4 vs. 1.9 ± 5.7 bpm, P = 0.30) (Supplemental Fig. 3).

      4. Discussion

      The LUNA study is the first RCT to investigate the changes in nighttime BP after switching from DPP-4i to SGLT2i luseogliflozin in patients with type 2 diabetes and hypertension. We found that the switching strategy had several benefits, by decreasing not only daytime but also nighttime SBP, PP, and PR. Moreover, improvement of BP circadian rhythm was shown in the present study.
      There have been several phase 2 or phase 3 clinical trials on SGLT2i versus placebo to compare the changes in 24-hour ambulatory BP as secondary outcomes. Some showed that SGLT2i significantly reduced nighttime BP compared with placebo, while others showed only a trend toward reduction. A meta-analysis of those trials found that SGLT2i caused decreases of −2.61 mmHg (95% CI, −3.08 to −2.14) in nighttime SBP and −1.49 mmHg (95% CI, −2.20 to −0.78) in nighttime DBP [
      • Baker W.L.
      • Buckley L.F.
      • Kelly M.S.
      • Bucheit J.D.
      • Parod E.D.
      • Brown R.
      • et al.
      Effects of sodium-glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis.
      ,
      • Tikkanen I.
      • Narko K.
      • Zeller C.
      • Green A.
      • Salsali A.
      • Broedl U.C.
      • et al.
      Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension.
      ,
      • Chilton R.
      • Tikkanen I.
      • Hehnke U.
      • Woerle H.J.
      • Johansen O.E.
      Impact of empagliflozin on blood pressure in dipper and non-dipper patients with type 2 diabetes mellitus and hypertension.
      ]. The SACRA study designed to determine the beneficial effects of empagliflozin on nighttime BP compared with placebo showed a trend toward reduction in SBP (−4.3 mmHg, P = 0.159) [
      • Kario K.
      • Okada K.
      • Kato M.
      • et al.
      24-Hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study.
      ]. It was hypothesized in a review that a robust reduction in nighttime SBP with SGLT2i could be caused by a greater body weight at baseline [
      • Kario K.
      • Ferdinand K.C.
      • O'Keefe J.H.
      Control of 24-hour blood pressure with SGLT2 inhibitors to prevent cardiovascular disease.
      ]. However, no correlations between the change in weight and the changes in nighttime SBP or circadian rhythm were observed in the Luseo group in the present study (data not shown). In the present study, luseogliflozin significantly reduced not only daytime SBP but also nighttime SBP compared with DPP-4i (−7.6 mmHg, P < 0.001). The minor difference in nighttime SBP between the SACRA study and the present study could arise from differences in the characteristics of the participants, although the baseline BMIs were similar (26.1 vs. 26.3 kg/m2). The present study also found that luseogliflozin affected the BP circadian rhythm and reduced abnormal patterns. The reduction in nighttime BP with patients with diabetes has been attributed to increased vagal activity during sleep associated with diabetic neuropathy, and also to vascular complications [
      • Nakano S.
      • Uchida K.
      • Kigoshi T.
      • Azukizawa S.
      • Iwasaki R.
      • Kaneko M.
      • et al.
      Circadian rhythm of blood pressure in normotensive NIDDM subjects. Its relationship to microvascular complications.
      ]. Although the mechanisms for the BP-lowering effect of SGLT2i, especially for nighttime hypertension, have not been fully elucidated, the increases in sodium excretion and urinary volume caused by inhibition of sodium and glucose reabsorption at proximal tubules are considered to comprise one of the main mechanisms for lowering BP under SGLT2i [
      • DeFronzo R.A.
      • Norton L.
      • Abdul-Ghani M.
      Renal, metabolic and cardiovascular considerations of SGLT2 inhibition.
      ]. We previously showed in the RCT that SGLT2i significantly decreased the level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) by optimization of excess fluid retention and improvement of albuminuria [
      • Cho K.Y.
      • Nakamura A.
      • Omori K.
      • Takase T.
      • Miya A.
      • Manda N.
      • et al.
      Effect of switching from pioglitazone to the sodium glucose co-transporter-2 inhibitor dapagliflozin on body weight and metabolism-related factors in patients with type 2 diabetes mellitus: An open-label, prospective, randomized, parallel-group comparison trial.
      ]. In addition, SGLT2i prevented the elevation of BP observed in diabetic rats treated with a high-salt diet [
      • Osorio H.
      • Bautista R.
      • Rios A.
      • et al.
      Effect of phlorizin on SGLT2 expression in the kidney of diabetic rats.
      ]. It was reported that salt restriction and use of diuretics in hypertensive patients with high salt sensitivity improved their nighttime hypertension pattern from non-dipper to dipper, indicating that excess of sodium contributes to the abnormal circadian rhythm in nighttime BP [
      • Fujii T.
      • Uzu T.
      • Nishimura M.
      • Takeji M.
      • Kuroda S.
      • Nakamura S.
      • et al.
      Circadian rhythm of natriuresis is disturbed in nondipper type of essential hypertension.
      ]. A significant improvement in nighttime BP and circadian rhythm was demonstrated by switching from DPP-4i to luseogliflozin in the present study. There was also a significant reduction in PP in both daytime and nighttime in the present study. The increase of PP results in more stress in arteries, which leads to increased elastic component fatigue and fracture and weakens the lining of blood vessels [
      • Zheng J.
      • Sun Z.
      • Guo X.
      • Xie Y.
      • Sun Y.
      • Zheng L.
      Blood pressure predictors of stroke in rural Chinese dwellers with hypertension: a large-scale prospective cohort study.
      ]. PP is a well-established independent predictor of stroke incidence among normotensive individuals [
      • Zheng J.
      • Sun Z.
      • Guo X.
      • Xie Y.
      • Sun Y.
      • Zheng L.
      Blood pressure predictors of stroke in rural Chinese dwellers with hypertension: a large-scale prospective cohort study.
      ,

      Okada K, Iso H, Cui R, et al. Pulse pressure is an independent risk factor for stroke among middle-aged Japanese with normal systolic blood pressure: the JPHC study. J Hypertens. 2011; 29: 319-24.

      ] and was shown to have higher relevance to stroke etiology than SBP and DBP in patients with type 2 diabetes [

      Buda VA, Ciobanu DM, Roman G. Pulse pressure is more relevant than systolic and diastolic blood pressure in patients with type 2 diabetes and cardiovascular disease. Clujul Med. 2018; 91: 408-13.

      ]. Among several previous studies on SGLT2i, one study showed that addition of dapagliflozin significantly decreased PP for 8 weeks [
      • Kinguchi S.
      • Wakui H.
      • Ito Y.
      • Kondo Y.
      • Azushima K.
      • Osada U.
      • et al.
      Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study).
      ].
      We found a decrease in nighttime PR after switching to luseogliflozin in the present study. Epidemiologic studies identified high resting PR as a risk factor for cardiovascular mortality in hypertensive patients [
      • Paul L.
      • Hastie C.E.
      • Li W.S.
      • Harrow C.
      • Muir S.
      • Connell J.M.C.
      • et al.
      Resting heart rate pattern during follow-up and mortality in hypertensive patients.
      ]. In a 24-week observational study, the SGLT2i empagliflozin reduced 24-h PR and nighttime PR [
      • Kario K.
      • Okada K.
      • Kato M.
      • et al.
      24-Hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: results from the randomized, placebo-controlled SACRA study.
      ,
      • Chilton R.
      • Tikkanen I.
      • Cannon C.P.
      • Crowe S.
      • Woerle H.J.
      • Broedl U.C.
      • et al.
      Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.
      ]. Suppression of sympathetic nerve activity is a well-known hypothesis for the effect of SGLT2i on PR modulation. Addition of empagliflozin for 1 week affected renal sympathetic nerve activity and baroreflexes in diabetic rabbits [
      • Gueguen C.
      • Burke S.L.
      • Barzel B.
      • Eikelis N.
      • Watson A.M.D.
      • Jha J.C.
      • et al.
      Empagliflozin modulates renal sympathetic and heart rate baroreflexes in a rabbit model of diabetes.
      ], while ketone bodies suppressed sympathetic activity through binding to free fatty acid receptors [
      • Newman J.C.
      • Verdin E.
      Ketone bodies as signaling metabolites.
      ]. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) increased nighttime PR by affecting the sympathovagal balance or stimulating sino-atrial node myocytes [
      • Kumarathurai P.
      • Anholm C.
      • Larsen B.S.
      • Olsen R.H.
      • Madsbad S.
      • Kristiansen O.
      • et al.
      Effects of liraglutide on heart rate and heart rate variability: a randomized, double-blind, placebo-controlled crossover study.
      ,

      Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014; 155(4): 1280-90.

      ]. DPP-4is were employed in the present study, and the findings suggest that they had similar effects to GLP-1 RAs and may have led to the significant difference in PR.
      The present study had four limitations. First, the medication was open-label in clinical practice although the ABPM data were blinded. Second, all of the participants were Japanese, and thus the findings require confirmation in different ethnicities. Third, an inexplicable mild increase in BP was observed in the DPP-4i group. One of the possible reasons for this finding is that more than one-half of the participants in both groups finished the study in fall and winter. It is well known that blood pressure increases with decreasing temperature [

      Qiong W, Changchang L, Yanfang G, et al. Environmental ambient temperature and blood pressure in adults: A systematic review and meta-analysis. Sci Total Environ 2016; 575: 276-86.

      ]. Further studies aligned with the seasons may provide the answer to this question. Fourth, although improvement of sleep apnea syndrome (SAS) can alter BP circadian rhythm and BP, we did not exclude this disease from the present study and this may have been another limitation. There were two participants complicated with SAS among the total participants. Both of these patients were assigned to the Luseo group. Of these two patients, one showed improvement of BP circadian rhythm, while the other showed no change. SAS should be excluded in future studies that examine BP.
      In conclusion, luseogliflozin improved nighttime and daytime SBP, and showed optimization of BP circadian rhythm compared with DPP-4i in diabetes and hypertension. Moreover, the switching strategy from DPP-4i to luseogliflozin decreased PP and nighttime PR. These changes would contribute, in part, to the cardiovascular event suppression confirmed in several large-scale cardiovascular trials on SGLT2i.

      Declaration of Competing Interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nakamura A, Kurihara Y, Atsumi T, and Miyoshi H have received honoraria for lectures and received research funding from some organizations as described below. The other authors declare no conflict of interest. Nakamura A has received has obtained research support from Mitsubishi Tanabe Pharma, Daiichi Sankyo, MSD, Novo Nordisk Pharma, Novartis Pharma, AstraZeneca, Life Scan Japan, and Taisho Pharmaceutical Co., Ltd. Kurihara Y has received honoraria for lectures from Astellas Pharma Inc., AstraZeneca, Mitsubishi Tanabe Pharma Co., MSD K.K., Ono Pharmaceutical Co., Ltd., Sanofi, Shionogi & Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Atsumi T has received honoraria for lectures from Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., AbbVie Inc., Eisai Co. Ltd., Daiichi Sankyo Co., Bristol‐Myers Squibb Co., UCB Japan Co. Ltd., Eli Lilly Japan K.K., and has received research funding from Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., and Alexion Inc. Miyoshi H has received honoraria for lectures from Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Co., MSD K.K., Novo Nordisk Pharma Ltd., Kowa Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Sanofi, and has received research funding from Daiichi Sankyo Co., Sumitomo Dainippon Pharma Co. Ltd., Taisho Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Novo Nordisk Pharma, Kowa Pharmaceutical Co., Ltd., Abbott Japan Co., Nippon Boehringer Ingelheim Co., Ltd., Life Scan Japan Inc., and Ono Pharmaceutical Co.

      Acknowledgments

      The authors thank Naoki Nishimoto, PhD, for advice on the statistical analyses, and Alison Sherwin, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

      Funding Information

      Taisho Pharmaceutical Co. Ltd.

      Author Contributions

      Miyoshi H conceived and designed this study. Kameda R, Cho KY and Miyoshi H wrote the manuscript. Nakamura A, Omori K, Nagai So, Edawaga S, Takeuchi J, Kawata S, Kurihara Y, Aoki S, and Miyoshi H recruited participants and helped with data collection. Kameda R and Cho KY analyzed the data. Nomoto H, Kameda H, Nakamura A, Atsumi T, and Miyoshi H reviewed and edited the manuscript. All authors approved the final version of the report and take full responsibility for the content. Miyoshi H is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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