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Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes
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Available online at
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Short Report
Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes§ S.H. Min a,1, T.J. Oh a,b,1, S.-I. Baek a, D.-H. Lee a,b, K.M. Kim a,b, J.H. Moon a,b, S.H. Choi a,b, K.S. Park a, H.C. Jang a,b, S. Lim a,b,* a
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300, Gumi-dong, Bundang-gu, Seongnam-city 463-070, South Korea
b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 August 2017 Received in revised form 22 September 2017 Accepted 25 September 2017 Available online xxx
Background. – Euglycaemic ketoacidosis has been reported after sodium–glucose cotransporter 2 (SGLT2) inhibitor treatment. However, the degree of ketonaemia and its metabolic effects have not been well investigated. Our study examined the degree of ketonaemia induced by SGLT2 inhibition and its association with metabolic profiles in type 2 diabetes mellitus (T2DM). Methods. – Biochemical parameters, including insulin, glucagon, free fatty acid (FFA), b-hydroxybutyrate (BHB) and acetoacetate (ACA) levels, were measured in 119 T2DM patients after dapagliflozin treatment for > 3 months, and compared with a matched control group. Results. – Levels of total ketones, BHB and ACA were significantly higher in the dapagliflozin group than in the control group: 283.7 311.0 vs 119.8 143.8 mmol/L; 188.3 226.6 vs 78.0 106.7 mmol/L; and 94.1 91.3 vs 41.8 39.1 mmol/L, respectively (all P < 0.001). After dapagliflozin treatment, BHB was higher than the upper limit of normal (> 440 mmol/L) in 13 (10.9%) patients who had no relevant symptoms. BHB level after dapagliflozin treatment correlated positively with HbA1c (r = 0.280), FFA levels (r = 0.596) and QUICKI (r = 0.238), and negatively with BMI (r = 0.222), insulin-to-glucagon ratio (r = 0.199) and HOMAIR (r = 0.205; all P < 0.05). On multivariable linear regression analysis, QUICKI was independently associated with BHB level. Conclusion. – Ketone levels were higher in T2DM patients treated with dapagliflozin than in controls, but with no clinical symptoms or signs of ketonaemia. Low-grade ketonaemia after dapagliflozin treatment may also be associated with improved insulin sensitivity.
C 2017 Published by Elsevier Masson SAS.
Keywords: Acetoacetate b-hydroxybutyrate Free fatty acid Insulin sensitivity Ketone body SGLT2 inhibitor
Introduction Sodium–glucose cotransporter 2 (SGLT2) inhibitors are recently developed oral antidiabetic drugs for the treatment of type 2 diabetes mellitus (T2DM). Along with improving glycaemic § Data from this study were presented in part at the American Diabetes Association 2017 Scientific Sessions, San Diego, California, 9–12 June 2017. Abbreviations: ACA, acetoacetate; Adipo-IR, adipose tissue insulin resistance; BMI, body mass index; eGFR, estimated glomerular filtration; FFA, free fatty acid; HOMA, homoeostasis model assessment; IR, insulin resistance; SD, standard deviation; SGLT2, sodium–glucose cotransporter 2; SNUBH, Seoul National University Bundang Hospital; QUICKI, quantitative insulin sensitivity check index. * Corresponding author. Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300, Gumi-dong, Bundang-gu, Seongnam-city 463-070, South Korea. E-mail address: [email protected] (S. Lim). 1 Se Hee Min and Tae Jung Oh contributed equally to this study.
control, SGLT2 inhibitors provide additional desirable effects for the management of T2DM, such as reducing body weight and blood pressure without increasing the risk of hypoglycaemia [1]. Furthermore, in the recently reported trial of cardiovascular outcome events in T2DM patients (EMPA-REG OUTCOME), empagliflozin treatment reduced major adverse cardiovascular events by 14% [2], and attenuated the progression of nephropathy by 39% compared with a placebo in T2DM patients [3]. Another recent study (CANVAS Program) showed similar beneficial effects [4]. These clinical benefits of SGLT2 inhibitors have generated increasing interest as regards the management of T2DM. In 2015, the US Food and Drug Administration warned physicians and patients of an increased risk of ketoacidosis associated with the use of SGLT2 inhibitors [5]. However, the degree of ketonaemia after using SGLT2 inhibitors has never been investigated in everyday clinical practice. In addition, the clinical hazards and benefits of ketonaemia after treatment with SGLT2
https://doi.org/10.1016/j.diabet.2017.09.006 C 2017 Published by Elsevier Masson SAS. 1262-3636/
Please cite this article in press as: Min SH, et al. Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes. Diabetes Metab (2017), https://doi.org/10.1016/j.diabet.2017.09.006
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inhibitors have never been revealed either. In the present study, it was hypothesized that attenuation of insulin resistance (IR) might be related to chronic low-grade ketonaemia in patients with T2DM receiving SGLT2 inhibitor treatment. Thus, the degree of ketonaemia after treatment with the SGLT2 inhibitor dapagliflozin was assessed and compared with other oral antidiabetic drugs in T2DM patients, while the relationships between the key factors related to ketonaemia and IR were also investigated.
Materials and methods
achieve normal distributions. A paired t test was used to evaluate differences in variables between the dapagliflozin group and matched control group, and between before and after dapagliflozin in the treatment group. Pearson correlation analysis was used to assess the associations between variables. Multivariable linear regression analysis was used to evaluate the association between serum BHB concentration and other variables considered significant in a simple correlation analysis performed in the dapagliflozin treatment group. Values of P < 0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 20 (IBM Corp., Armonk, NY, USA).
Study population Results Patients with T2DM who attended the endocrinology clinic of Seoul National University Bundang Hospital (SNUBH) in 2015– 2016 were consecutively enrolled. Inclusion criteria were age 20– 75 years with inadequately controlled, SGLT2-inhibitor-naı¨ve T2DM who subsequently received dapagliflozin treatment for > 3 months. Patients who had type 1 diabetes or were using insulin therapy were excluded. Also excluded were those diagnosed with malignancy within the past five years, and those who had a medical history of severe liver or renal disease [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2], poor compliance based on prescription refill records or experienced diabetic ketoacidosis. To compare clinical and biochemical data between dapagliflozin users and non-users, patients taking other oral antidiabetic medications (except SGLT2 inhibitors) were included as a control group. Based on propensity scores, they were matched on a 1:1 ratio for age, gender, body mass index (BMI), HbA1c levels and duration of diabetes as variables. Data driven by non-users were not used in the correlation analysis. The study protocol was approved by the institutional (ethics) review board of SNUBH (IRB No. B-1608/358-304). Measurement of anthropometric and biochemical parameters Height and body weight were measured, and BMI was calculated by dividing weight by height squared (kg/m2). Medical records were reviewed comprehensively to obtain data for duration of diabetes and comorbidities such as hypertension and dyslipidaemia. Blood samples were obtained after an overnight fast. However, data from subjects whose fasting time was > 12 h or who had drunk alcohol the day before the examination were excluded. Biochemical analysis was performed according to standard procedure at the SNUBH laboratory. Serum concentrations of total ketones, acetoacetate (ACA) and b-hydroxybutyrate (BHB) were measured, using an enzymatic immunoassay kit (Nittobo Medical Co., Ltd., Tokyo, Japan). Of the different types of ketone bodies, data for BHB were primarily analyzed because it constitutes around 80% of circulating ketones and is more stable in blood than ACA or acetone [6]. Ketosis was defined as when total ketone and BHB levels were over the upper limit of normal, values of 530 mmol/L and 440 mmol/L, respectively [7]. IR index and pancreatic b-cell function were assessed according to homeostasis model assessment for IR (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI) and index of adipose tissue insulin resistance (Adipo-IR) [8–10]. Statistical analysis Data are presented as means standard deviation (SD) or as numerical counts and percentages. Variables with non-normal distributions, such as concentrations of triglycerides, glucagon, free fatty acid (FFA), total ketones, BHB and ACA were log-transformed to
Patients’ characteristics, and clinical and biochemical parameters after dapagliflozin treatment Of the 165 patients initially screened, 119 patients were ultimately enrolled in the dapagliflozin group after consideration of exclusion criteria, and the same number of matched participants out of 310 control patients were included as the control group. The patients’ anthropometric and biochemical characteristics and changes after dapagliflozin treatment are presented in Table 1. The mean SD age of the study participants in the dapagliflozin and control groups was 53.2 9.4 years and 53.9 9.4 years, respectively, and the duration of diabetes was 9.5 6.5 years and 9.1 7.4 years, respectively. The mean duration of study follow-up was 6.1 4.8 months. Mean HbA1c levels did not differ between groups [7.7% 1.1% (61 12 mmol/mol) vs 7.6% 1.1% (60 12 mmol/mol); P = 0.194]. These data indicate that the participants in both groups were well matched, as intended. Fasting plasma glucose (FPG) concentration, renal function, liver function, lipid profiles, HOMA-IR and HOMA-b (for b-cell function) values also did not differ between the two groups. All participants in the dapagliflozin group and 91.6% in the control group were taking metformin. However, more patients in the control group were taking a dipeptidyl peptidase (DPP)-4 inhibitor and thiazolidinedione (60.5% and 18.5%, respectively; Table S1; see supplementary materials associated with this article online). Dapagliflozin treatment decreased body weight by 2.8 2.9 kg, and systolic and diastolic blood pressure by 5.0 14.8 mmHg and 2.7 10.8 mmHg, respectively. After dapagliflozin treatment, HbA1c also decreased, from 8.4% 1.2% (68 13.1 mmol/mol) to 7.7% 1.1% (61 12.0 mmol/mol), and FPG decreased from 173.9 47.7 mg/dL to 141.4 32.6 mg/dL. In addition, triglyceride concentration decreased by 18.2 61.3 mg/dL, and high-density lipoprotein (HDL) cholesterol increased by 2.2 6.6 mg/dL, whereas low-density lipoprotein (LDL) cholesterol did not change significantly. Notably, HOMA-IR decreased significantly while QUICKI increased significantly following dapagliflozin treatment: from 5.6 3.9 to 3.4 1.9, and from 0.31 0.03 to 0.33 0.03, respectively (both P < 0.05). In contrast, HOMA-b and Adipo-IR did not change after dapagliflozin treatment (Table 1). Degree of ketonaemia, and correlations between BHB and other clinical parameters After dapagliflozin treatment, total ketone concentration was significantly higher in the dapagliflozin group than in the control group. Levels of BHB and ACA, major components of ketone bodies, were also higher in the dapagliflozin than in the control group (Table 1). Ketosis was detected in 13 patients (10.9%) in the dapagliflozin group and in four (3.4%) in the control group (P = 0.023). However, none presented with clinical symptoms such as nausea, vomiting, difficulty breathing, fatigue or confusion.
Please cite this article in press as: Min SH, et al. Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes. Diabetes Metab (2017), https://doi.org/10.1016/j.diabet.2017.09.006
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Table 1 Clinical and biochemical parameters at baseline and follow-up of dapagliflozin-treated and control patient groups. Dapagliflozin (n = 119)
Variable
Men, n (%) Age (years) Diabetes duration (years) Body weight (kg) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) HbA1c (%) HbA1c (mmol/mol) Fasting plasma glucose (mg/dL) Creatinine (mg/dL) eGFR (mL/min/1.73 m2) AST (IU/L) ALT (IU/L) Total cholesterol (mg/dL) Triglycerides (mg/dL)b HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Insulin (mIU/mL) C-peptide (ng/mL) Glucagon (pmol/L)b,c Free fatty acid (mmol/L)c Insulin-to-glucagon ratio (mol/mol)c Total ketone (mmol/L)b,c b-hydroxybutyrate (mmol/L)b,c Acetoacetate (mmol/L)b,c HOMA-IR HOMA-b QUICKI Adipo-IR (mmol/L mIU/mL)
Before
After
61 (51.3) 53.2 9.4 9.5 6.5 74.8 14.5 27.3 3.6 131.9 14.4 78.1 10.9 8.4 1.2 68.0 13.1 173.9 47.7 0.78 0.21 98.0 16.1 31.7 18.0 38.8 27.7 164.1 35.5 166.3 96.3 47.2 10.2 92.2 26.8 13.5 10.9 3.00 1.38 67.7 37.4 617.1 262.0 1.7 1.4 110.3 83.2 68.9 55.6 49.5 54.3 5.6 3.9 56.9 95.3 0.31 0.03 7.9 5.1
– – 71.9 14.0 26.3 3.3 127.3 13.7 75.6 10.5 7.7 1.1 61.0 12.0 141.4 32.6 0.80 0.24 97.8 17.9 25.9 11.2 30.4 23.2 162.6 37.9 148.1 84.6 49.3 10.3 91.0 26.7 9.7 4.7 2.77 1.27 62.7 29.0 730.2 233.5 1.3 0.9 282.7 311.0 188.3 226.6 94.1 91.3 3.4 1.9 50.7 29.3 0.33 0.03 7.0 4.0
Pd
Controlsa (n = 119)
Pe
< 0.001 < 0.001 < 0.001 0.008 < 0.001 < 0.001 < 0.001 0.525 0.709 < 0.001 < 0.001 0.710 0.001 0.001 0.468 < 0.001 0.017 0.217 0.006 0.121 < 0.001 < 0.001 0.002 < 0.001 0.527 < 0.001 0.350
62 (52.1) 53.9 9.4 9.1 7.4 69.5 11.7 26.1 3.4 129.0 13.8 76.3 10.5 7.6 1.1 60 12.0 151.2 50.7 0.79 0.19 95.7 16.3 27.9 13.1 30.5 17.7 163.8 37.3 141.1 83.7 49.2 11.1 91.4 26.2 10.9 6.9 3.07 2.29 62.8 40.1 599.3 222.3 1.7 1.3 119.8 143.8 78.0 106.7 41.8 39.1 4.0 2.7 56.6 45.2 0.32 0.03 6.3 4.1
0.897 0.547 0.712 0.110 0.741 0.339 0.570 0.482 0.482 0.069 0.634 0.362 0.216 0.976 0.801 0.435 0.897 0.911 0.102 0.212 0.223 < 0.001 0.025 < 0.001 < 0.001 < 0.001 0.047 0.216 0.177 0.183
Values are presented as means standard deviation (SD) for continuous variables or as n (%) for categorical variables. eGFR: estimated glomerular filtration rate; AST/ALT: aspartate/alanine aminotransferase; HDL/LDL: high-density/low-density lipoprotein; HOMA-IR/b: homoeostasis model assessment for insulin resistance/beta-cell function; QUICKI: quantitative insulin sensitivity check index; Adipo-IR: adipose tissue insulin resistance. a Propensity-matched for age, body mass index, HbA1c, duration of type 2 diabetes. b Log-transformed values used for analysis. c Baseline values measured in subgroup (n = 39). d Difference between before and after dapagliflozin treatment by paired t test or chi-square test. e Difference between dapagliflozin group after treatment and matched control group by paired t test or chi-square test. Table 2 Multivariable linear regression analysis: independent associations between log b-hydroxybutyrate concentration and clinical and biochemical variables. Variable
b
SE
P
b
SE
P
Body mass index (kg/m2) HbA1c (%) Free fatty acid (mmol/L) HOMA-IR QUICKI
0.034 0.002 0.002 0.070 –
0.021 0.067 0.000 0.036 –
0.110 0.976 <0.001 0.058 –
0.026 0.002 0.002 – 6.294
0.021 0.066 0.000 – 2.438
0.223 0.973 <0.001 – 0.011
HOMA-IR: homeostasis model assessment of insulin resistance; QUICKI: quantitative insulin sensitivity check index.
Therefore, no patients stopped or changed their medication. In those treated with dapagliflozin (n = 39) whose baseline ketone levels had been measured, mean concentrations of total ketones, BHB and ACA increased significantly after dapagliflozin treatment (all P < 0.05); the increase in BHB from baseline tended to be negatively correlated with HOMA-IR (r = 0.327, P = 0.073), but positively correlated with QUICKI (r = 0.311, P = 0.054). In the dapagliflozin-treated group, serum BHB concentration significantly correlated with BMI (r = 0.222, P = 0.015), HbA1c (r = 0.280, P = 0.002), FFA levels (r = 0.596, P < 0.001), insulin-toglucagon ratio (r = 0.199, P = 0.033), HOMA-IR (r = 0.205, P = 0.026), QUICKI (r = 0.238, P = 0.010) and HOMA-b (r = 0.309, P = 0.001) in the follow-up evaluation. Our study also evaluated whether serum BHB was independently associated with clinical and biochemical variables following dapagliflozin treatment. As shown in Table 2, serum BHB concentration was only marginally associated with HOMA-IR
(b = 0.070, P = 0.058), but significantly associated with QUICKI (b = 6.294, P = 0.011), after adjusting for BMI, HbA1c and FFA levels. Discussion The present study found that ketone levels increased after about six months of treatment with dapagliflozin compared with other oral antidiabetic drugs. It has also confirmed the clinical benefits of dapagliflozin, such as reductions in glucose, blood pressure and body weight. Notably, mild ketonaemia after dapagliflozin treatment had no clinical symptoms, but was significantly associated with improved insulin sensitivity. Although the exact physiological mechanism responsible for ketogenesis induced by SGLT2 inhibition has not been fully elucidated, the higher insulin-to-glucagon ratio and substrate shift from glucose to lipid have been suggested to play a role [11–13]. In the present study, both the insulin-to-glucagon ratio and plasma FFA level correlated significantly with BHB level. Given that a relative insulin-deficient status stimulates lipolysis, FFA overflow could be induced by dapagliflozin treatment, and this may drive ketogenesis [14]. Taken altogether, our results support the idea that dapagliflozin treatment stimulates lipolysis and induces mild ketogenesis in patients with T2DM. Interestingly, recent data have suggested that ketone bodies may play a role as signaling metabolites [15]. In the present study, serum BHB level showed a negative correlation with HOMA-IR and a positive correlation with QUICKI. A study in vitro reported that BHB increases adiponectin secretion [16] and inhibits the NOD-like
Please cite this article in press as: Min SH, et al. Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes. Diabetes Metab (2017), https://doi.org/10.1016/j.diabet.2017.09.006
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receptor family, pyrin domain-containing (NLRP)-3 inflammasome in adipocytes [17]. Another study showed that BHB inhibits class I histone deacetylases and reduces oxidative stress [18]. Our group recently reported that chronic administration of empagliflozin reduces atheroma in the aorta and that the extent of the change is strongly correlated with amelioration of IR, modulation of inflammatory markers and levels of adiponectin in atherosclerosis-prone mice [19]. These results could translate into the improved cardiovascular outcomes reported in the EMPA-REG OUTCOME trial [2]. Thus, this recent evidence, including ours, suggests that the increase in ketone bodies after SGLT2 inhibitor treatment may be associated with improved insulin sensitivity as well as favourable cardiovascular outcomes. Nevertheless, further mechanistic studies are still needed to prove the causative role of ketone bodies in insulin sensitivity and cardiovascular events. The present study has several limitations. First, because the study was retrospective and not a prospective randomized controlled trial, confounding factors may have affected our findings. However, our attempt to overcome this limitation involved selecting a control group matched for clinically important variables. Second, because of the limited number of participants with known baseline ketone levels, evaluation of the associations between change in BHB level and change in relevant parameters was incomplete. Third, the study results were restricted to dapagliflozin only and the treatment duration was relatively short, which prevents their generalization to other SGLT2 inhibitors and to long-term results with this class of drugs. However, this study also had several strengths. First, concentrations of the main components of ketone bodies, such as total ketones, BHB and ACA, were measured. Second, FFA and glucagon levels, which were not routinely measured in other studies, were also measured. Third, any symptoms related to ketonaemia were meticulously examined. In conclusion, chronic treatment with dapagliflozin induced lowgrade ketonaemia without causing severe symptomatic ketoacidosis, and also improved insulin sensitivity. These results suggest that the mild increase in concentration of ketones (metabolic intermediates) after SGLT2 inhibition is associated with improvement in insulin sensitivity in T2DM patients. Role of the funding source This work was supported by a grant from the Seoul National University Bundang Hospital. Contributors S.H.M., T.J.O. and S.L. contributed to the study conception and design, data collection, statistical analysis and writing of the manuscript. S.-I.B. and D.-H.L. contributed to the data analysis and interpretation. K.M.K., J.H.M., S.H.C., K.S.P., H.C.J. and S.L. contributed to the critical revisions for intellectual content. All authors critically reviewed the manuscript and approved the publication of the final version of the manuscript. S.L. 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. Disclosure of interest The authors declare that they have no competing interest.
Acknowledgments We thank the Medical Research Collaborating Center of SNUBH for statistical support.
Appendix A. Supplementary data Supplementary data (Tables S1–S8) associated with this article can be found in the online version, at http://www.sciencedirect. com at http://dx.doi.org/10.1016/j.diabet.2017.09.006. References [1] Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol 2012;8:495–502. [2] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. [3] Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323–34. [4] Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 Diabetes. N Engl J Med 2017;377:644–57. [5] Administration USFaD. Drug safety communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood; 2015 [Internet, 15 May]. [6] Sacks DB, Arnold M, Bakris GL, Bruns DE, Horvath AR, Kirkman MS, et al. Position statement executive summary: guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 2011;34:1419–23. [7] Lee K, Jun S-H, Lee KW, Han M, Song SH, Park KU, et al. Evaluation of the T-KB-H and 3-HB kits for the measurement of serum ketone and b-hydroxybutyric acid. Lab Med Online 2014;4:22–7. [8] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. [9] Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402–10. [10] Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology 2009;50:1087–93. [11] Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499–508. [12] Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190–5. [13] Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care 2016;39:2036–41. [14] Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev 1999;15:412– 26. [15] Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab 2014;25(1):42–52. [16] Plaisance EP, Lukasova M, Offermanns S, Zhang Y, Cao G, Judd RL. Niacin stimulates adiponectin secretion through the GPR109A receptor. Am J Physiol Endocrinol Metab 2009;296:E549–58. [17] Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 2015;21:263–9. [18] Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 2013;339:211–4. [19] Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, et al. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE / mice fed a western diet. Diabetologia 2017;60:364–76.
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Short Report
Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes§ S.H. Min a,1, T.J. Oh a,b,1, S.-I. Baek a, D.-H. Lee a,b, K.M. Kim a,b, J.H. Moon a,b, S.H. Choi a,b, K.S. Park a, H.C. Jang a,b, S. Lim a,b,* a
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300, Gumi-dong, Bundang-gu, Seongnam-city 463-070, South Korea
b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 4 August 2017 Received in revised form 22 September 2017 Accepted 25 September 2017 Available online xxx
Background. – Euglycaemic ketoacidosis has been reported after sodium–glucose cotransporter 2 (SGLT2) inhibitor treatment. However, the degree of ketonaemia and its metabolic effects have not been well investigated. Our study examined the degree of ketonaemia induced by SGLT2 inhibition and its association with metabolic profiles in type 2 diabetes mellitus (T2DM). Methods. – Biochemical parameters, including insulin, glucagon, free fatty acid (FFA), b-hydroxybutyrate (BHB) and acetoacetate (ACA) levels, were measured in 119 T2DM patients after dapagliflozin treatment for > 3 months, and compared with a matched control group. Results. – Levels of total ketones, BHB and ACA were significantly higher in the dapagliflozin group than in the control group: 283.7 311.0 vs 119.8 143.8 mmol/L; 188.3 226.6 vs 78.0 106.7 mmol/L; and 94.1 91.3 vs 41.8 39.1 mmol/L, respectively (all P < 0.001). After dapagliflozin treatment, BHB was higher than the upper limit of normal (> 440 mmol/L) in 13 (10.9%) patients who had no relevant symptoms. BHB level after dapagliflozin treatment correlated positively with HbA1c (r = 0.280), FFA levels (r = 0.596) and QUICKI (r = 0.238), and negatively with BMI (r = 0.222), insulin-to-glucagon ratio (r = 0.199) and HOMAIR (r = 0.205; all P < 0.05). On multivariable linear regression analysis, QUICKI was independently associated with BHB level. Conclusion. – Ketone levels were higher in T2DM patients treated with dapagliflozin than in controls, but with no clinical symptoms or signs of ketonaemia. Low-grade ketonaemia after dapagliflozin treatment may also be associated with improved insulin sensitivity.
C 2017 Published by Elsevier Masson SAS.
Keywords: Acetoacetate b-hydroxybutyrate Free fatty acid Insulin sensitivity Ketone body SGLT2 inhibitor
Introduction Sodium–glucose cotransporter 2 (SGLT2) inhibitors are recently developed oral antidiabetic drugs for the treatment of type 2 diabetes mellitus (T2DM). Along with improving glycaemic § Data from this study were presented in part at the American Diabetes Association 2017 Scientific Sessions, San Diego, California, 9–12 June 2017. Abbreviations: ACA, acetoacetate; Adipo-IR, adipose tissue insulin resistance; BMI, body mass index; eGFR, estimated glomerular filtration; FFA, free fatty acid; HOMA, homoeostasis model assessment; IR, insulin resistance; SD, standard deviation; SGLT2, sodium–glucose cotransporter 2; SNUBH, Seoul National University Bundang Hospital; QUICKI, quantitative insulin sensitivity check index. * Corresponding author. Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, 300, Gumi-dong, Bundang-gu, Seongnam-city 463-070, South Korea. E-mail address: [email protected] (S. Lim). 1 Se Hee Min and Tae Jung Oh contributed equally to this study.
control, SGLT2 inhibitors provide additional desirable effects for the management of T2DM, such as reducing body weight and blood pressure without increasing the risk of hypoglycaemia [1]. Furthermore, in the recently reported trial of cardiovascular outcome events in T2DM patients (EMPA-REG OUTCOME), empagliflozin treatment reduced major adverse cardiovascular events by 14% [2], and attenuated the progression of nephropathy by 39% compared with a placebo in T2DM patients [3]. Another recent study (CANVAS Program) showed similar beneficial effects [4]. These clinical benefits of SGLT2 inhibitors have generated increasing interest as regards the management of T2DM. In 2015, the US Food and Drug Administration warned physicians and patients of an increased risk of ketoacidosis associated with the use of SGLT2 inhibitors [5]. However, the degree of ketonaemia after using SGLT2 inhibitors has never been investigated in everyday clinical practice. In addition, the clinical hazards and benefits of ketonaemia after treatment with SGLT2
https://doi.org/10.1016/j.diabet.2017.09.006 C 2017 Published by Elsevier Masson SAS. 1262-3636/
Please cite this article in press as: Min SH, et al. Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes. Diabetes Metab (2017), https://doi.org/10.1016/j.diabet.2017.09.006
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inhibitors have never been revealed either. In the present study, it was hypothesized that attenuation of insulin resistance (IR) might be related to chronic low-grade ketonaemia in patients with T2DM receiving SGLT2 inhibitor treatment. Thus, the degree of ketonaemia after treatment with the SGLT2 inhibitor dapagliflozin was assessed and compared with other oral antidiabetic drugs in T2DM patients, while the relationships between the key factors related to ketonaemia and IR were also investigated.
Materials and methods
achieve normal distributions. A paired t test was used to evaluate differences in variables between the dapagliflozin group and matched control group, and between before and after dapagliflozin in the treatment group. Pearson correlation analysis was used to assess the associations between variables. Multivariable linear regression analysis was used to evaluate the association between serum BHB concentration and other variables considered significant in a simple correlation analysis performed in the dapagliflozin treatment group. Values of P < 0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics version 20 (IBM Corp., Armonk, NY, USA).
Study population Results Patients with T2DM who attended the endocrinology clinic of Seoul National University Bundang Hospital (SNUBH) in 2015– 2016 were consecutively enrolled. Inclusion criteria were age 20– 75 years with inadequately controlled, SGLT2-inhibitor-naı¨ve T2DM who subsequently received dapagliflozin treatment for > 3 months. Patients who had type 1 diabetes or were using insulin therapy were excluded. Also excluded were those diagnosed with malignancy within the past five years, and those who had a medical history of severe liver or renal disease [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2], poor compliance based on prescription refill records or experienced diabetic ketoacidosis. To compare clinical and biochemical data between dapagliflozin users and non-users, patients taking other oral antidiabetic medications (except SGLT2 inhibitors) were included as a control group. Based on propensity scores, they were matched on a 1:1 ratio for age, gender, body mass index (BMI), HbA1c levels and duration of diabetes as variables. Data driven by non-users were not used in the correlation analysis. The study protocol was approved by the institutional (ethics) review board of SNUBH (IRB No. B-1608/358-304). Measurement of anthropometric and biochemical parameters Height and body weight were measured, and BMI was calculated by dividing weight by height squared (kg/m2). Medical records were reviewed comprehensively to obtain data for duration of diabetes and comorbidities such as hypertension and dyslipidaemia. Blood samples were obtained after an overnight fast. However, data from subjects whose fasting time was > 12 h or who had drunk alcohol the day before the examination were excluded. Biochemical analysis was performed according to standard procedure at the SNUBH laboratory. Serum concentrations of total ketones, acetoacetate (ACA) and b-hydroxybutyrate (BHB) were measured, using an enzymatic immunoassay kit (Nittobo Medical Co., Ltd., Tokyo, Japan). Of the different types of ketone bodies, data for BHB were primarily analyzed because it constitutes around 80% of circulating ketones and is more stable in blood than ACA or acetone [6]. Ketosis was defined as when total ketone and BHB levels were over the upper limit of normal, values of 530 mmol/L and 440 mmol/L, respectively [7]. IR index and pancreatic b-cell function were assessed according to homeostasis model assessment for IR (HOMA-IR), the quantitative insulin sensitivity check index (QUICKI) and index of adipose tissue insulin resistance (Adipo-IR) [8–10]. Statistical analysis Data are presented as means standard deviation (SD) or as numerical counts and percentages. Variables with non-normal distributions, such as concentrations of triglycerides, glucagon, free fatty acid (FFA), total ketones, BHB and ACA were log-transformed to
Patients’ characteristics, and clinical and biochemical parameters after dapagliflozin treatment Of the 165 patients initially screened, 119 patients were ultimately enrolled in the dapagliflozin group after consideration of exclusion criteria, and the same number of matched participants out of 310 control patients were included as the control group. The patients’ anthropometric and biochemical characteristics and changes after dapagliflozin treatment are presented in Table 1. The mean SD age of the study participants in the dapagliflozin and control groups was 53.2 9.4 years and 53.9 9.4 years, respectively, and the duration of diabetes was 9.5 6.5 years and 9.1 7.4 years, respectively. The mean duration of study follow-up was 6.1 4.8 months. Mean HbA1c levels did not differ between groups [7.7% 1.1% (61 12 mmol/mol) vs 7.6% 1.1% (60 12 mmol/mol); P = 0.194]. These data indicate that the participants in both groups were well matched, as intended. Fasting plasma glucose (FPG) concentration, renal function, liver function, lipid profiles, HOMA-IR and HOMA-b (for b-cell function) values also did not differ between the two groups. All participants in the dapagliflozin group and 91.6% in the control group were taking metformin. However, more patients in the control group were taking a dipeptidyl peptidase (DPP)-4 inhibitor and thiazolidinedione (60.5% and 18.5%, respectively; Table S1; see supplementary materials associated with this article online). Dapagliflozin treatment decreased body weight by 2.8 2.9 kg, and systolic and diastolic blood pressure by 5.0 14.8 mmHg and 2.7 10.8 mmHg, respectively. After dapagliflozin treatment, HbA1c also decreased, from 8.4% 1.2% (68 13.1 mmol/mol) to 7.7% 1.1% (61 12.0 mmol/mol), and FPG decreased from 173.9 47.7 mg/dL to 141.4 32.6 mg/dL. In addition, triglyceride concentration decreased by 18.2 61.3 mg/dL, and high-density lipoprotein (HDL) cholesterol increased by 2.2 6.6 mg/dL, whereas low-density lipoprotein (LDL) cholesterol did not change significantly. Notably, HOMA-IR decreased significantly while QUICKI increased significantly following dapagliflozin treatment: from 5.6 3.9 to 3.4 1.9, and from 0.31 0.03 to 0.33 0.03, respectively (both P < 0.05). In contrast, HOMA-b and Adipo-IR did not change after dapagliflozin treatment (Table 1). Degree of ketonaemia, and correlations between BHB and other clinical parameters After dapagliflozin treatment, total ketone concentration was significantly higher in the dapagliflozin group than in the control group. Levels of BHB and ACA, major components of ketone bodies, were also higher in the dapagliflozin than in the control group (Table 1). Ketosis was detected in 13 patients (10.9%) in the dapagliflozin group and in four (3.4%) in the control group (P = 0.023). However, none presented with clinical symptoms such as nausea, vomiting, difficulty breathing, fatigue or confusion.
Please cite this article in press as: Min SH, et al. Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes. Diabetes Metab (2017), https://doi.org/10.1016/j.diabet.2017.09.006
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Table 1 Clinical and biochemical parameters at baseline and follow-up of dapagliflozin-treated and control patient groups. Dapagliflozin (n = 119)
Variable
Men, n (%) Age (years) Diabetes duration (years) Body weight (kg) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) HbA1c (%) HbA1c (mmol/mol) Fasting plasma glucose (mg/dL) Creatinine (mg/dL) eGFR (mL/min/1.73 m2) AST (IU/L) ALT (IU/L) Total cholesterol (mg/dL) Triglycerides (mg/dL)b HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Insulin (mIU/mL) C-peptide (ng/mL) Glucagon (pmol/L)b,c Free fatty acid (mmol/L)c Insulin-to-glucagon ratio (mol/mol)c Total ketone (mmol/L)b,c b-hydroxybutyrate (mmol/L)b,c Acetoacetate (mmol/L)b,c HOMA-IR HOMA-b QUICKI Adipo-IR (mmol/L mIU/mL)
Before
After
61 (51.3) 53.2 9.4 9.5 6.5 74.8 14.5 27.3 3.6 131.9 14.4 78.1 10.9 8.4 1.2 68.0 13.1 173.9 47.7 0.78 0.21 98.0 16.1 31.7 18.0 38.8 27.7 164.1 35.5 166.3 96.3 47.2 10.2 92.2 26.8 13.5 10.9 3.00 1.38 67.7 37.4 617.1 262.0 1.7 1.4 110.3 83.2 68.9 55.6 49.5 54.3 5.6 3.9 56.9 95.3 0.31 0.03 7.9 5.1
– – 71.9 14.0 26.3 3.3 127.3 13.7 75.6 10.5 7.7 1.1 61.0 12.0 141.4 32.6 0.80 0.24 97.8 17.9 25.9 11.2 30.4 23.2 162.6 37.9 148.1 84.6 49.3 10.3 91.0 26.7 9.7 4.7 2.77 1.27 62.7 29.0 730.2 233.5 1.3 0.9 282.7 311.0 188.3 226.6 94.1 91.3 3.4 1.9 50.7 29.3 0.33 0.03 7.0 4.0
Pd
Controlsa (n = 119)
Pe
< 0.001 < 0.001 < 0.001 0.008 < 0.001 < 0.001 < 0.001 0.525 0.709 < 0.001 < 0.001 0.710 0.001 0.001 0.468 < 0.001 0.017 0.217 0.006 0.121 < 0.001 < 0.001 0.002 < 0.001 0.527 < 0.001 0.350
62 (52.1) 53.9 9.4 9.1 7.4 69.5 11.7 26.1 3.4 129.0 13.8 76.3 10.5 7.6 1.1 60 12.0 151.2 50.7 0.79 0.19 95.7 16.3 27.9 13.1 30.5 17.7 163.8 37.3 141.1 83.7 49.2 11.1 91.4 26.2 10.9 6.9 3.07 2.29 62.8 40.1 599.3 222.3 1.7 1.3 119.8 143.8 78.0 106.7 41.8 39.1 4.0 2.7 56.6 45.2 0.32 0.03 6.3 4.1
0.897 0.547 0.712 0.110 0.741 0.339 0.570 0.482 0.482 0.069 0.634 0.362 0.216 0.976 0.801 0.435 0.897 0.911 0.102 0.212 0.223 < 0.001 0.025 < 0.001 < 0.001 < 0.001 0.047 0.216 0.177 0.183
Values are presented as means standard deviation (SD) for continuous variables or as n (%) for categorical variables. eGFR: estimated glomerular filtration rate; AST/ALT: aspartate/alanine aminotransferase; HDL/LDL: high-density/low-density lipoprotein; HOMA-IR/b: homoeostasis model assessment for insulin resistance/beta-cell function; QUICKI: quantitative insulin sensitivity check index; Adipo-IR: adipose tissue insulin resistance. a Propensity-matched for age, body mass index, HbA1c, duration of type 2 diabetes. b Log-transformed values used for analysis. c Baseline values measured in subgroup (n = 39). d Difference between before and after dapagliflozin treatment by paired t test or chi-square test. e Difference between dapagliflozin group after treatment and matched control group by paired t test or chi-square test. Table 2 Multivariable linear regression analysis: independent associations between log b-hydroxybutyrate concentration and clinical and biochemical variables. Variable
b
SE
P
b
SE
P
Body mass index (kg/m2) HbA1c (%) Free fatty acid (mmol/L) HOMA-IR QUICKI
0.034 0.002 0.002 0.070 –
0.021 0.067 0.000 0.036 –
0.110 0.976 <0.001 0.058 –
0.026 0.002 0.002 – 6.294
0.021 0.066 0.000 – 2.438
0.223 0.973 <0.001 – 0.011
HOMA-IR: homeostasis model assessment of insulin resistance; QUICKI: quantitative insulin sensitivity check index.
Therefore, no patients stopped or changed their medication. In those treated with dapagliflozin (n = 39) whose baseline ketone levels had been measured, mean concentrations of total ketones, BHB and ACA increased significantly after dapagliflozin treatment (all P < 0.05); the increase in BHB from baseline tended to be negatively correlated with HOMA-IR (r = 0.327, P = 0.073), but positively correlated with QUICKI (r = 0.311, P = 0.054). In the dapagliflozin-treated group, serum BHB concentration significantly correlated with BMI (r = 0.222, P = 0.015), HbA1c (r = 0.280, P = 0.002), FFA levels (r = 0.596, P < 0.001), insulin-toglucagon ratio (r = 0.199, P = 0.033), HOMA-IR (r = 0.205, P = 0.026), QUICKI (r = 0.238, P = 0.010) and HOMA-b (r = 0.309, P = 0.001) in the follow-up evaluation. Our study also evaluated whether serum BHB was independently associated with clinical and biochemical variables following dapagliflozin treatment. As shown in Table 2, serum BHB concentration was only marginally associated with HOMA-IR
(b = 0.070, P = 0.058), but significantly associated with QUICKI (b = 6.294, P = 0.011), after adjusting for BMI, HbA1c and FFA levels. Discussion The present study found that ketone levels increased after about six months of treatment with dapagliflozin compared with other oral antidiabetic drugs. It has also confirmed the clinical benefits of dapagliflozin, such as reductions in glucose, blood pressure and body weight. Notably, mild ketonaemia after dapagliflozin treatment had no clinical symptoms, but was significantly associated with improved insulin sensitivity. Although the exact physiological mechanism responsible for ketogenesis induced by SGLT2 inhibition has not been fully elucidated, the higher insulin-to-glucagon ratio and substrate shift from glucose to lipid have been suggested to play a role [11–13]. In the present study, both the insulin-to-glucagon ratio and plasma FFA level correlated significantly with BHB level. Given that a relative insulin-deficient status stimulates lipolysis, FFA overflow could be induced by dapagliflozin treatment, and this may drive ketogenesis [14]. Taken altogether, our results support the idea that dapagliflozin treatment stimulates lipolysis and induces mild ketogenesis in patients with T2DM. Interestingly, recent data have suggested that ketone bodies may play a role as signaling metabolites [15]. In the present study, serum BHB level showed a negative correlation with HOMA-IR and a positive correlation with QUICKI. A study in vitro reported that BHB increases adiponectin secretion [16] and inhibits the NOD-like
Please cite this article in press as: Min SH, et al. Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes. Diabetes Metab (2017), https://doi.org/10.1016/j.diabet.2017.09.006
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receptor family, pyrin domain-containing (NLRP)-3 inflammasome in adipocytes [17]. Another study showed that BHB inhibits class I histone deacetylases and reduces oxidative stress [18]. Our group recently reported that chronic administration of empagliflozin reduces atheroma in the aorta and that the extent of the change is strongly correlated with amelioration of IR, modulation of inflammatory markers and levels of adiponectin in atherosclerosis-prone mice [19]. These results could translate into the improved cardiovascular outcomes reported in the EMPA-REG OUTCOME trial [2]. Thus, this recent evidence, including ours, suggests that the increase in ketone bodies after SGLT2 inhibitor treatment may be associated with improved insulin sensitivity as well as favourable cardiovascular outcomes. Nevertheless, further mechanistic studies are still needed to prove the causative role of ketone bodies in insulin sensitivity and cardiovascular events. The present study has several limitations. First, because the study was retrospective and not a prospective randomized controlled trial, confounding factors may have affected our findings. However, our attempt to overcome this limitation involved selecting a control group matched for clinically important variables. Second, because of the limited number of participants with known baseline ketone levels, evaluation of the associations between change in BHB level and change in relevant parameters was incomplete. Third, the study results were restricted to dapagliflozin only and the treatment duration was relatively short, which prevents their generalization to other SGLT2 inhibitors and to long-term results with this class of drugs. However, this study also had several strengths. First, concentrations of the main components of ketone bodies, such as total ketones, BHB and ACA, were measured. Second, FFA and glucagon levels, which were not routinely measured in other studies, were also measured. Third, any symptoms related to ketonaemia were meticulously examined. In conclusion, chronic treatment with dapagliflozin induced lowgrade ketonaemia without causing severe symptomatic ketoacidosis, and also improved insulin sensitivity. These results suggest that the mild increase in concentration of ketones (metabolic intermediates) after SGLT2 inhibition is associated with improvement in insulin sensitivity in T2DM patients. Role of the funding source This work was supported by a grant from the Seoul National University Bundang Hospital. Contributors S.H.M., T.J.O. and S.L. contributed to the study conception and design, data collection, statistical analysis and writing of the manuscript. S.-I.B. and D.-H.L. contributed to the data analysis and interpretation. K.M.K., J.H.M., S.H.C., K.S.P., H.C.J. and S.L. contributed to the critical revisions for intellectual content. All authors critically reviewed the manuscript and approved the publication of the final version of the manuscript. S.L. 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. Disclosure of interest The authors declare that they have no competing interest.
Acknowledgments We thank the Medical Research Collaborating Center of SNUBH for statistical support.
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Please cite this article in press as: Min SH, et al. Degree of ketonaemia and its association with insulin resistance after dapagliflozin treatment in type 2 diabetes. Diabetes Metab (2017), https://doi.org/10.1016/j.diabet.2017.09.006