Advances in Food Technology and Nutritional Sciences

Open journal

ISSN 2377-8350

Comparison of Diuretic Effects between Empagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor With Osmotic Diuresis, and Tolvaptan, a Water Diuretic, in Two Type 2 Diabetic Patients Taking Sodium Diuretics

Yuji Aoki*

Received: October 14th, 2016 Accepted: October 28th, 2016 Published: October 28th, 2016

INTRODUCTION

The recent EMPA-REG OUTCOME trial has demonstrated that empagliflozin, one of sodiumglucose co-transporter 2 (SGLT2) inhibitors, in addition to standard care had beneficial effects on cardiovascular morbidity and mortality in patients with type 2 diabetes at high risk for cardiovascular events.1 Moreover, the secondary microvascular outcome has revealed that the use of empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo.2 It is suggested that the mechanisms behind these benefits of empagliflozin include osmotic diuresis, reductions in arterial stiffness and the rate pressure product, and direct renovascular effects through activating tubuloglomerular feedback.2,3 Unlike strong osmotic diuretics such as intravenously administered mannitol,4 SGLT2 inhibitors seem to be rather close to that of tolvaptan, a selective oral vasopressin V2 -receptor antagonist,5 to promote water diuresis (excretion of electrolyte-free water).6,7 Urinary sodium excretion was shown to slightly increase only early after the administration of SGLT2 inhibitors in experimental animals.8,9 Two cases are presented in this short communication, where distinct changes in urinary water and sodium excretion were seen immediately after replacing tolvaptan with empagliflozin. Osmotic diuresis–related effects of SGLT2 inhibitors will be discussed.

CASES

Case 1 (Table 1) was a 93-year-old woman with type 2 diabetes, hypertension and heart failure. She was hospitalized due to the worsening of heart failure. She was 141 cm in height and 48 kg in weight. Her HbA1c level was 5.8% on diet therapy alone. She was intermittently treated with tolvaptan in the presence of sodium diuretics. After the 3rd treatment with 7.5 mg tolvaptan for 7 days, it was replaced with 10 mg empagliflozin. Changes in urinary excretion of water, glucose and electrolytes are shown in Table 1. Since an indwelling urethral catheter was placed, urinary creatinine excretion was not measured to estimate the accuracy of 24-hour urine volume. After the replacement of tolvaptan with empagliflozin, urine volume was slightly decreased from 1650 to 1500 ml/day (mean value for two days; the ratio, 0.91), and urinary sodium excretion was apparently decreased from 72.6 to 47.8 mM/day (0.66). Before and after the 4-day measurement period, serum levels of albumin, urea nitrogen, creatinine, sodium and potassium were 2.9 and 2.6 g/dL, 30 and 33 mg/ dL, 1.19 and 1.48 mg/dL, 139 and 140 mM/L, and 4.5 and 4.3 mM/L, respectively.

Table 1: Urinary data and oral diuretics in Case 1 (see the section of Cases).

Four consecutive hospital days 1 2 3 4
Urine Volume (ml/day) 1800 1500 1400 1600
Urine Glucose (g/day) <0.1 <0.1 4.7 10.0
Urine Sodium (mM/day) 70.2 75.0 47.6 48.0
Urine Chlorine (mM/day) 59.4 64.5 40.6 43.2
Urine Potassium (mM/day) 21.6 18.6 18.5 22.1
Tolvaptan 7.5 mg 7.5 mg
Empagliflozin 10 mg 10 mg
Furosemide 10 mg 10 mg 10 mg 10 mg

Case 2 (Table 2) was a 44-year-old man with type 2 diabetes, hypertension and nephrotic syndrome. He was referred and admitted to our hospital due to severe edema. He was 167 cm in height and 71 kg in weight. His HbA1c level was 6.5% under the treatment with a dipeptidyl peptide-4 inhibitor. After 20 days’ treatment with 7.5 mg tolvaptan in the presence of sodium diuretics, it was replaced with 10 mg empagliflozin. Changes in urinary excretion of water, creatinine, glucose, electrolytes and protein are shown in Table 2. After the replacement of tolvaptan with empagliflozin, urine volume was increased from 1250 to 1550 ml/day (mean value for two days; the ratio, 1.24), and urinary sodium excretion was apparently increased from 66.9 to 107.1 mM/day (1.60). In addition, the amount of urine protein was decreased from 7.6 to 6.8 g/day (0.89). Before and after the 4-day measurement period, serum levels of albumin, urea nitrogen, creatinine, sodium and potassium were 1.9 and 2.6 g/dL, 24 and 28 mg/dL, 2.67 and 2.60 mg/dL, 142 and 139 mM/L, and 4.4 and 4.7 mM/L, respectively.

Table 2: Urinary data and oral diuretics in Case 2 (see the section of Cases).

Four consecutive hospital days 1 2 3 4
Urine Volume (ml/day) 1300 1200 1500 1600
Urine Creatinine (g/day) 0.93 1.07 0.90 0.93
Urine Glucose (g/day) 2.7 3.0 13.3 14.3
Urine Sodium (mM/day) 68.9 64.8 99.0 115.2
Urine Chlorine (mM/day) 49.4 40.8 87.0 99.2
Urine Potassium (mM/day) 19.4 20.5 23.3 25.8
Urine protein (g/day) 7.3 7.8 6.9 6.6
Tolvaptan 7.5 mg 7.5 mg
Empagliflozin 10 mg 10 mg
Furosemide 20 mg 20 mg 20 mg 20 mg
Azosemide 60 mg 60 mg 60 mg 60 mg
Spironolactone 25 mg 25 mg 25 mg

25 mg

Case 3 as a reference case (Table 3) was a 67-year-old women with type 2 diabetes, hypertension and renal insufficiency. She was hospitalized due to shortness of breath caused by obesity and asthma. She was 155 cm in height and 102 kg in weight. Her HbA1c level was 7.4 % under the treatment with 500 mg metformin and a dipeptidyl peptide-4 inhibitor. Empagliflozin was added to her treatment in the absence of diuretics when her weight was 99 kg and serum levels of albumin, urea nitrogen, creatinine, sodium and potassium were 3.3 g/dL, 18 mg/dL, 1.64 mg/dL, 143 mM/L and 4.3 mM/L, respectively.

Table 3: Urinary data in Case 3, a reference case with empagliflozin in the absence of diuretics (see the section of Cases).

Four consecutive hospital days 1 2 3 4
Urine Volume (ml/day) 2400 2300 2700 2900
Urine Creatinine (g/day) 0.92 0.75 0.77 0.86
Urine Glucose (g/day) 0.2 0.2 9.2 12.7
Urine Sodium (mM/day) 134.4 87.4 113.4 110.2
Urine Chlorine (mM/day) 100.8 57.5 75.6 69.6
Urine Potassium (mM/day) 22.6 16.1 18.9 20.3
Empagliflozin 10 mg 10 mg

Changes in urinary excretion of water, creatinine, glucose and electrolytes are shown in Table 3. After the addition of empagliflozin, urine volume was increased from 2350 to 2800 ml/day (mean value for two days; the ratio, 1.19), and urinary sodium excretion was very slightly increased from 110.9 to 111.8 mM/ day (1.01). An increase in glycosuria (approximately 10 g/day) after the administration of empagliflozin was small because of renal insufficiency, and was similar to that seen in Cases 1 and 2.

DISCUSSION

Because the effect of SGLT2 inhibitors on glycosuria is depending on glomerular filtration rate in its mechanism,10,11 the amount of glycosuria induced by empagliflozin (approximately 10 g/day) in 3 patients with renal insufficiency presented here was small compared with that by SGLT2 inhibitors (approximately 50 to 100 g/day) reported in type 2 diabetic patients without renal insufficiency.12,13,14 In Case 3, the administration of empagliflozin in the absence of diuretics caused an increase in urine volume with almost no change in urinary sodium excretion. Such osmotic diuresis as seen in familial renal glycosuria5,15,16 seems to be close to water diuresis of tolvaptan,6,7 which has been shown to be effectively used in patients with decompensated heart failure.17,18 However, during two days after replacing tolvaptan with empagliflozin, Case 1 showed a large decrease in urinary sodium excretion with a slight descrease in urine volume. By contrast, Case 2 showed a large increase in urinary sodium excretion with a small increase in urine volume. The different changes in urinary water and sodium excretion were due probably to distinct diuretic effects of empagliflozin and tolvaptan in the presence of sodium diuretics as well as distinct pathological conditions.

SGLT2 mediates glucose reabsorption in the kidney by catalysing the active transport of glucose with sodium at 1:1 stoichiometry across the luminal membrane. The inward sodium gradient across the luminal epithelium is maintained by ATPdriven active extrusion of sodium (Na+ /K+ -ATPase) across the basolateral membrane into the blood.19 Glucose and sodium molecules increased by the inhibition of SGLT2 (low affinity, high capacity) located in the early proximal tubule deliver to the later renal tubule. The excess of glucose can be partially reabsorbed by SGLT1 (high affinity, low capacity) located in the late proximal tubule, and that of sodium can be reabsorbed to a larger extent in the late proximal tubule, the loop of Henle, the distal tubule and the collecting tubule (Figure 1). Therefore, urinary sodium excretion is presumed not to be practically increased by the SGLT2 inhibition, as seen in Case 3 and elsewhere.8,9,20 In the case of mannitol as an osmotic diuretic, mannitol filtered from glomerulus acts to retain water and to dilute sodium, and then decreases the numbers of sodium-absorbing sites of the tubular cells that are exposed to sodium, leading to urinary sodium loss.4 Mannitol, a monosaccharide like glucose, is usually administered intravenously in a dose of ~100 g over ~60 min,21 the urinary excretion of which is expected to be much larger than that of glucose induced by SGLT2 inhibitors. This is inferred to make a difference in their effects on urinary sodium excretion.

Figure 1: A diagram of nephron and action sites of diuretics in parentheses, including SGLTs (sodium-glucose co-transporters) 1 and 2.

Then, diuresis with SGLT2 inhibitors seems to be close to that with tolvaptan, a water diuretic. However, in the presence of sodium diuretics acting on the renal tubule later than the proximal tubule, SGLT2 inhibitors are considered to increase urinary sodium excretion greater than that increased by loop diuretics, thiazides, and/or spironolactone alone (Figure 1). Therefore, Cases 1 and 2 did not show similar urine data after the replacement of tolvaptan with empagliflozin. In Case 2 treated with stronger sodium diuretics, 10 mg empagliflizin appeared to be more potent than 7.5 mg tolvaptan as a diuretic. In addition, it was worthy of note that the amount of urine protein was reduced immediately after the replacement. Inhibiting SGLT2 might have saved energy inside the proximal tubular cells for other proximal tubular functions such as renal protein reabsorption. Canagliflozin, another SGLT2 inhibitor, has recently been reported to decrease urinary albumin-to-creatinine ratio independently of its glycemic effects from the early stage of the trial in type 2 diabetic patients with the baseline ratio more than 30 mg/g.22 SGLT2 inhibitors would be expected to have the potential to exert some beneficial effects other than lowering blood glucose levels by increasing urinary glucose excretion.

CONFLICTS OF INTEREST

The author declares that he has no conflicts of interest.

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373: 2117-2128. doi: 10.1056/NEJMoa1504720

2. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016; 375: 323-334. doi: 10.1056/NEJMoa1515920

3. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: Results of the EMPA-REG OUTCOME trial. Eur Heart J. 2016; 37(19): 1526-1534. doi: 10.1093/eurheartj/ehv728

4. Bernstein LM, Blumberg B, Arkin MC. Osmotic diuretic treatment of refractory edema. Circulation. 1958; 17: 1013-1020. doi: 10.1161/01.CIR.17.6.1013

5. Aoki Y. Administration of sodium-glucose co-transporter 2 inhibitors could accelerate dehydration in poorly-controlled diabetic patients, proposing an option not to increase glucosuria but to decrease carbohydrate intake during hyperglycemia. Diabetes Res Open J. 2015;1: 72-74. doi: 10.17140/DROJ-1-111

6. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2 -receptor antagonist, for hyponatremia. N Engl J Med. 2006; 355: 2099-2112.

7. Aoki Y. Surprising results of the EMPA-REG OUTCOME study have brought a new insight into use of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes. Trop Med Surg. 2015; 3: 199. doi: 10.4172/2329-9088.1000199

8. Katsuno K, Fujimori Y, Takemura Y, et al. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose reabsorption and modulates plasma glucose level. J Pharmacol Exp Ther. 2007; 320: 323-330. doi: 10.1124/jpet.106.110296

9. Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014; 13: 148. doi: 10.1186/s12933-014-0148-1

10. Kasichayanula S, Liu X, Pe Benito M, et al. The influence of kidney function on dapagliflozin exposure, metabolism and pharmacodynamics in healthy subjects and in patients with type 2 diabetes mellitus. Br J Clin Pharmacol. 2013; 76: 432-444. doi: 10.1111/bcp.12056

11. Sarashina A, Ueki K, Sasaki T, et al. Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in Japanese patients with type 2 diabetes mellitus. Clin Ther. 2014; 36: 1606-1615. doi: 10.1016/j.clinthera.2014.08.001

12. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodiumglucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009; 32: 650-657. doi: 10.2337/dc08-1863

13. Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol. 2013; 53: 601-610. doi: 10.1002/jcph.88

14. Kanada S, Koiwai K, Taniguchi A, Sarashina A, Seman L, Woerle HJ. Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks’ treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus. J Diabetes Invest. 2013; 4: 613-617. doi: 10.1111/jdi.12110

15. Scholl-Buergi S, Santer R, Ehrich JHH. Long-term outcome of renal glucosuria type 0: the original patient and his natural history. Nephrol Dial Transplant. 2004; 19: 2394-2396. doi: 10.1093/ndt/gfh366

16. Calado J, Sznajer Y, Metzger D, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. 2008; 23: 3874- 3879. doi: 10.1093/ndt/gfn386

17. Matsuzaki M, Hori M, Izumi T, Fukunami M. Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study). Cardiovasc Drugs Ther. 2011; 1: S33-S45. doi: 10.1007/s10557-011-6304-x

18. Patra S, Kumar B, Harlalka KK, et al. Short term efficacy and safety of low dose tolvaptan in patients with acute decompensated heart failure with hyponatremia: A prospective observational pilot study from a single center in South India. Heart Views. 2014; 15: 1-5. doi: 10.4103/1995-705X.132136

19. Chao EC, Henry RR. SGLT2 inhibition – anovel strategy for diabetes treatment. Nat Rev Drug Discov. 2010; 9: 551-559. doi: 10.1038/nrd3180

20. Cherney DZI, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014; 129: 587-597. doi: 10.1161/CIRCULATIONAHA.113.005081

21. Shawkat H, Westwood M-M, Mortimer A. Mannitol: A review of its clinical uses. Contin Educ Anaesth Crit Care Pain. 2012; 1-4. doi: 10.1093/bjaceaccp/mkr063

22. Heerspink HJL, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2016; 28. doi: 10.1681/ASN.2016030278

LATEST ARTICLES

Prevalence and Risk Factors of Subclinical Mastitis of Goats in Banadir Region, Somalia

Omar M. Salah*, Yasin H. Sh-Hassan, Moktar O. S. Mohamed, Mohamed A. Yusuf and Abas S. A. Jimale

doi.10.17140/VMOJ-9-184

Use of Black Soldier Fly (Hermetia illucens) Prepupae Reared on Organic Waste

Maggot Debridement Therapy: A Natural Solution for Wound Healing

Isayas A. Kebede*, Haben F. Gebremeskel and Gelan D. Dahesa,

doi.10.17140/VMOJ-9-183

Figure 11. Risk Map for the Introduction of Ruminant Diseases at Borders

Ovine Network in Morocco: Epizootics Spread Prevention and Identification of the At-Risk Areas for “Peste des Petits Ruminants” and “Foot and Mouth Disease”

Yassir Lezaar*, Mehdi Boumalik, Youssef Lhor, Moha El-Ayachi, Abelilah Araba and Mohammed Bouslikhane

doi.10.17140/EPOJ-8-131

The Impact of Family Dynamics on Palliative Care at the End-of-Life

Neil A. Nijhawan*, Rasha Mustafa and Aqeela Sheikh

doi.10.17140/PMHCOJ-10-154

Long-Term Follow-Up After Laparoscopic Radical Prostatectomy for Localized and Locally Advanced Prostate Cancer

Shrenik J. Shah*, Abhishek Jha, Chirag Davara, Rushi Mistry and Kapil Kachhadiya

doi.10.17140/UAOJ-7-147

Mindfulness, Sustained Attention and Post-Traumatic Stress in Tsunami Survivors

Christina Hagen*, Lars Lien, Edvard Hauff and Trond Heir

doi.10.17140/PCSOJ-2-115

Treatment and Control Methods of Bovine Mastitis: A Review

Isayas A. Kebede* and Gelan D. Dahesa

doi.10.17140/VMOJ-9-182

LATEST ARTICLES

Original Research

2024 Mar

Omar M. Salah*, Yasin H. Sh-Hassan, Moktar O. S. Mohamed, Mohamed A. Yusuf and Abas S. A. Jimale
Use of Black Soldier Fly (Hermetia illucens) Prepupae Reared on Organic Waste

review

2024 Mar

Isayas A. Kebede*, Haben F. Gebremeskel and Gelan D. Dahesa,