Background
Important goals for treatment of patients with diabetes mellitus include suppression of macro- and microvascular complications and maintenance of good mortality related with these patients’ high risk for cardiovascular diseases (CVD) [
1]. Recent comprehensive care to avoid cardiovascular risk factors dramatically reduced diabetic complications [
2]; however, the mortality is still higher in patients with diabetes compared with that of those without [
3]. Recently it has been suggested that glucose fluctuation is closely related to endothelial cell damage [
4], known to be the first stage of atherosclerosis and a predictor of CVD [
5]. Moreover, mean amplitude of glycemic excursions (MAGE), which is a marker of daily blood glucose variability relating to higher postprandial blood glucose or hypoglycemia, is known to be an important factor in determining the severity of coronary artery disease, independent of HbA1c. It is also an independent predictor of mortality [
6]. Additionally, MAGE was also reported to correlate closely with oxidative stress in vivo [
7]. To overcome the risk of CVD, it would be important to manage glycemic fluctuation.
To date, several anti-hyperglycemic agents are available, but remedies that can suppress glucose variability are limited. One of such agents, dipeptidyl peptidase-4 (DPP-4) inhibitors, has been known to exert glucose level dependent hypoglycemic action [
8]. Additionally, combination therapy using insulin injection and DPP-4 inhibitors has reduced HbA1c levels and hypoglycemic events and also reduced glucose fluctuation such as the M value compared with insulin treatment alone [
9,
10]. However, some sodium–glucose co-transporter 2 (SGLT2) inhibitors have been shown to be potent suppressors of cardiovascular risks [
11,
12], but the effectiveness of SGLT2 inhibitors on suppressing glucose fluctuations in patients with type 2 diabetes mellitus, especially compared with DPP-4 inhibitors, has not been clarified. In this trial, we aimed to assess the effects of dapagliflozin, one of the SGLT2 inhibitors, on glucose fluctuation in patients with type 2 diabetes mellitus on insulin using a prospective, randomized parallel-group comparison study design.
Discussion
In this trial, we aimed to verify the superiority of dapagliflozin to therapy with DPP-4 inhibitors and insulin in type 2 diabetes patients for MAGE. To date, some clinical studies have been conducted on the relationship between glycemic fluctuation and macrovascular risks. The risk factors for cardiovascular events such as endothelial cell function, oxidative stresses, and intra-media thickness were shown to be strongly correlated with glycemic variability in patients with diabetes mellitus [
7,
16,
17]. There is no robust evidence that suppression of glycemic variability directly reverses cardiovascular events, but recently, some anti-diabetic remedies that can inhibit glucose fluctuation were shown to improve surrogate markers of cardiovascular risk factors [
18,
19]. Therefore, it is important to moderate not only HbA1c but also glycemic fluctuation.
Previous studies have shown that both DPP-4 inhibitors and SGLT2 inhibitors affect glucose fluctuation. DPP-4 inhibitors have a potent hypoglycemic effect during the hyperglycemic state via glucose-dependent insulin secretion by increasing the active serum GLP-1 and GIP concentration, or by reducing hypoglycemia by diminishing insulin secretion and cancelling glucagon suppression under normal to hypoglycemic conditions [
20]. GIP has been reported to act as a potent insulin releaser under hyperglycemic conditions. Other hand, GIP is also thought to be a physiological bifunctional blood glucose stabilizer because insulin secretion action does not occur and the glucagon response was improved under normal or hypo-glycemic conditions [
21]. These glucose level-dependent mechanisms of incretins suggest that DPP-4 inhibitors can improve glycemic control and reduce glucose fluctuations in patients with type 2 diabetes mellitus compared with other insulin secretagogues [
22]. Concerning the combination of the DPP-4 inhibitors with insulin therapy, meta-analysis revealed that co-administration of DPP-4 inhibitors and insulin injection achieved better glycemic control without increasing hypoglycaemia [
23].
SGLT2 inhibitors also possess hypoglycemic actions and a preferable effect on glucose variability. The effects of SGLT2 inhibitors rely on the filtered load of glucose, and thus it is expected that their hypoglycemic action will work potently under hyperglycemic conditions [
24]. To avoid hypoglycemia under insufficient SGLT2 conditions, compensatory SGLT1 reabsorption prevents excessive glycosuria [
25] and excessive hypoglycemic action may be inhibited. In addition, increasing the plasma glucagon concentration [
26] and hepatic gluconeogenesis [
26], and enhancing lipolysis in patients with type 2 diabetes mellitus may also prevent hypoglycemia [
27]. A randomized controlled trial using CGM comparing luseogliflozin and a placebo with type 2 diabetes mellitus found significant improvements in glucose variability and mean blood glucose with luseogliflozin [
28]. Even in type 1 diabetes mellitus, dapagliflozin also reduced MAGE in a dose dependent manner [
15], which provided evidence of the beta-cell independent effect of SGLT2 inhibitors on glucose fluctuation. A recent prospective study comparing the efficacy of administration of SGLT2 inhibitor with a co-administration of DPP-4 inhibitor and SGLT2 inhibitor on multiple insulin injection therapy revealed that there were no significant changes in MAGE and SD on sensor glucose measurements among insulin therapy alone, or with the addition of DPP-4 inhibitors and/or SGLT2 inhibitor. However, night-time hypoglycaemia was significantly decreased in regimen including the SGLT2 inhibitor compared with insulin monotherapy [
29].
Our study showed as follows; accompanied with insulin, switching from DPP-4 inhibitors to dapagliflozin maintained an equivalent glucose fluctuation and all-day and nocturnal hypoglycaemia prevalence without significant insulin dosage change. However, we could not verify the superiority of dapagliflozin compared with DPP-4 inhibitors in MAGE, and HbA1c deteriorated only in the dapagliflozin group. As described above, the DPP-4 inhibitors’ potency in reducing glucose fluctuations has been shown. Switching to dapagliflozin did not show additional improvement on MAGE, which might be because baseline glucose variations were already suppressed in response to the DPP-4 inhibitors in insulin therapy. In addition, this result might be somewhat different if insulin titration was performed to maintain preferable glucose levels in the dapagliflozin group because generally glucose variation is influenced largely by mean blood glucose levels. That is, the higher the mean glucose levels are, the higher the glucose fluctuation will be. Even in DPP-4 continuation, glycemic control worsened in some participants. Our protocol did not allow participants to change the dosage or frequency of their DPP-4 inhibitors or other drugs taken for comorbidities in this group. Thus, deterioration of such changes observed in the DPP-4 inhibitor groups might be a result of adherence to dietary and exercise therapy. Taken together, combination therapy with SGLT2 inhibitors and insulin injection may be superior to insulin monotherapy in avoiding hypoglycaemia, and there seems to be no obvious differences between DPP-4 inhibitors and SGLT2 inhibitors as a partner of insulin in this context.
In addition, our study revealed that patients with improved MAGE after dapagliflozin administration possessed relatively preferable renal function. DPP-4 inhibitors are known to exert hypoglycemic action even with renal dysfunction [
30]. On the other hand, the hypoglycemic effects of SGLT2 inhibitors rely on proper renal function. In addition, a previous report which assessed the efficacy of luseogliflozin on individuals with different renal function using CGM revealed that patients with renal insufficiency showed not only attenuated glucose lowering effects but also a lack of SD improvement in the blood glucose [
31]. Taken together, the effect on glucose fluctuation of SGLT2 inhibitors may require relatively good renal function.
Both DPP-4 inhibitors and SGLT2 inhibitors have been reported to have some pleiotropic effects on metabolisms other than the hypoglycemic action. Previous reports verified that incretin agents including DPP-4 inhibitors exert renal protective effects in vitro and in vivo against increased renal oxidative stress under hyperglycemia [
32]. The pooled analysis of prospective clinical trials using linagliptin resulted in significant improvement in albuminuria in patients with type 2 diabetes mellitus and renal dysfunction independent of changes in blood glucose and blood pressure [
33]. Our study showed that albuminuria improved only in the dapagliflozin group after switching from DPP-4 inhibitors, but not between group comparison in the absence of a change in glucose fluctuation and blood pressure. The impact of SGLT2 inhibitors on renal protection has recently attracted much attention. In the diabetic state, the tubuloglomerular feedback system is known to break down and to result in causing glomerular hyper-filtration. It has been revealed that SGLT2 inhibitors reduced the reabsorption of glucose in the proximal tubule resulting in normalized tubuloglomerular feedback and glomerular hyper-filtration [
34]. Although there are only a few large-scale clinical trials that have focused on the impact of SGLT2 inhibitors on renal protection, one of the SGLT2 inhibitors, empagliflozin, was reported to be associated with slower progression of kidney disease and lower rates of clinically relevant renal events in patients with type 2 diabetes mellitus [
35].
Our data also showed significant elevation of hemoglobin and hematocrit with dapagliflozin treatment. These phenomena were thought to be due to up-regulation of erythropoietin rather than dehydration as previously reported [
36], and such hematopoietic action might in part exert favorable effects on diabetic kidneys [
37].
Finally, dapagliflozin significantly reduced BMI and liver enzyme as expected. Previously, we investigated the effects of ipragliflozin on body composition in Japanese patients with type 2 diabetes mellitus and revealed that body weight loss accompanied with improvement of liver dysfunction was driven mainly by reducing visceral fat mass and reducing water volume [
38]. Even with co-administration of SGLT2 inhibitors and insulin injection, a recent meta-analysis reported that this combination resulted in significantly lower HbA1c, body weight and insulin dosage compared with placebo [
39]. Considering that DPP-4 inhibitors do not affect body weight and insulin therapy tends to increase it, switching from DPP-4 inhibitors to dapagliflozin might possess merits from this point of view.
The strengths of our study are as follows: this was the first randomized controlled trial directly comparing DPP-4 inhibitors and an SGLT2 inhibitor on glucose fluctuation in insulin therapy; there were no significant biases in the pre-treatment for type 2 diabetes mellitus in both study arms; and we could assess the relationship between glucose fluctuations and other metabolic parameters. However, our small sample size may limit our ability to draw a conclusion. Other major limitations of this study were a lack of double blinding, the short study duration, and a lack of dietary uniformity because of the ambulatory care setting. In addition, some participants withdrew their consent after study inclusion and randomization. To resolve these potential issues, our findings need to be validated with a larger scaled, long term, dietary-controlled double-blind trial.
Authors’ contributions
HN contributed in writing the manuscript. HN and KO contributed to the data analysis. HN, HM, SY, MO, HS, and AN contributed to patient enrolment. HM, AN, and TA contributed to the discussion, and reviewed and edited the manuscript. HM designed and performed the research and wrote the manuscript. HM is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. All authors read and approved the final manuscript.
Competing interests
HM has received honoraria for lectures from Astellas Pharma Inc., AstraZeneca, Dainippon Pharma Co., Eli Lilly, Kissei, Mitsubishi Tanabe Pharma Co., MSD, Novo Nordisk Pharma, and Sanofi, and has received research funding from Astellas Pharma Inc., AstraZeneca, Eli Lilly, Mitsubishi Tanabe Pharma Co.
AN has received honoraria for lectures from Sanofi.
TA has received honoraria for lectures from Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd, Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd, Pfizer Inc., and AbbVie Inc., and has received research funding from Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, and Otsuka Pharmaceutical Co., Ltd.
HN, HS, KO, SY, and MO have no competing interests to declare.