Possible Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors for Reducing Effects of Blood Glucose and also Blood Pressure

Bando H

doi:10.36502/2020/ASJBCCR.6210

Asploro Journal of Biomedical and Clinical Case Reports
ISSN: 2582-0370
Article Type: Editorial
DOI: 10.36502/2020/ASJBCCR.6210
Asp Biomed Clin Case Rep. 2020 Aug 28;3(3):186-90

Possible Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors for Reducing Effects of Blood Glucose and also Blood Pressure

Bando H^1,2*
¹Tokushima University / Medical Research, Tokushima, Japan
²Japan Low Carbohydrate Diet Promotion Association, Kyoto, Japan

Corresponding Author: Hiroshi Bando, MD, Ph.D., FACP ^{ORCID ID}
Address: Tokushima University /Medical Research, Nakashowa 1-61, Tokushima 770-0943, Japan.
Received date: 25 July 2020; Accepted date: 20 August 2020; Published date: 28 August 2020

Citation: Bando H. Possible Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors for Reducing Effects of Blood Glucose and also Blood Pressure. Asp Biomed Clin Case Rep. 2020 Aug 28;3(3):186-90.

Copyright © 2020 Bando H. This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium provided the original work is properly cited.

Keywords: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors, Phlorizin, Antihypertensive Agents (AHA), Cardiovascular Event, Blood Pressure

Abbreviations: CANVAS: Canagliflozin cardioVascular Assessment Study, CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, DECLARE-TIMI 58: Dapagliflozin Effect on CardiovascuLAR Events-TIMI 58, EMPA-REG OUTCOME: The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose study

Abstract

Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) has been in focus for the pharmacotherapy of diabetes. SGLT2i contributes to decreasing blood pressure (BP) to some degree. BP changes were analyzed in 4 well-known mega-studies. They are Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) study, Canagliflozin cardioVascular Assessment Study (CANVAS), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) and Dapagliflozin Effect on CardiovascuLAR Events (DECLARE)-TIMI 58. The ultimate goal of antihypertensive and hypoglycemic agents is not the achievement of target values, but the suppression of cardiovascular events. SGLT-2i show excellent strategy for event suppression and adjunct method for hypertension.

Diabetes is a medical and social problem in every country and region worldwide [1,2]. One of the basic treatment methods is adequate diet [3,4]. The authors have applied a low carbohydrate diet (LCD) to thousands of patients for years and have reported its significant effects [5,6]. Specifically, we have promoted 3 types of LCDs, which are super-LCD, standard-LCD, and petite-LCD. Further, we have socially promoted the social movement of LCD through Japan LCD Promotion Association (JLCDPA) [7]. On the other hand, the other treatment method is pharmacotherapy. Recently, Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) has been introduced to clinical practice [8]. The mechanism of the agent had not been seen formerly, and its excellent effect has been widely known.

As a matter of fact, LCD and SGLT2i have something valuable in common. The former means trying not to put sugar-rich foods into the body through the mouth. On the other hand, the latter means a mechanism of excreting a large amount of sugar from the body through the urinary tract. The common idea is to avoid involvement with carbohydrate metabolism [9]. In recent years, there have been various studies concerning the adverse effects of carbohydrates on the human body. Carbohydrate load increases the risk of non-communicable diseases (NCDs) such as obesity, diabetes, hypertension, and dyslipidemia. SGLT2i has been reported to have the function of lowering blood sugar in diabetes and also lowering blood pressure [10]. In this article, a general overview of SGLT2i and the effect on blood pressure would be described.

From a historical point of view, the technology for extracting the medicinal component was advanced such as alkaloid from the plant in the 19th century. Among them, phlorizin contained in the bark of apple was clinically used as an antipyretic drug in a small dose [11]. After that, a high dose was proved to excrete sugar from urine. In the latter 20th century, the presence of sodium-glucose co-transporter (SGLT) in the proximal tubules of the small intestine and kidney was proposed. Successively, SGLT-1 in the small intestine and SGLT-2 in the proximal tubule was discovered [12]. Consequently, the physical action point of phlorizin was clarified, and the development of hypoglycemic agent due to the urinary glucose excretion was started related to phlorizin.

SGLT-2 inhibitor is a type of glycoside similar to phlorizin because of its chemical structure. It has glucose as a part of its structural formula and inhibits SGLT-2, which has glucose as an in-vivo organ, from the tubular side in a reversible and glucose competitive manner. Due to this structural formula and high SGLT-2 selectivity, it is considered that there is no site of action other than SGLT-2 in the proximal tubule at clinical pharmacological blood concentrations [12].

SGLT-2 inhibitor is a type of glycoside similar to phlorizin. It inhibits SGLT-2 from the tubular side in a competitive manner. Due to the structural formula and high SGLT-2 selectivity, SGLT-2i can only act at the proximal tubule at clinical pharmacological concentrations [13]. From various studies, SGLT-2i can cause not only urinary glucose excretion but also several suppressive actions on the cardiovascular event including the effect of lowering blood pressure.

There have been four well-known studies concerning SGLT-2i, which were EMPA-REG OUTCOME, CANVAS, CREDENCE, and DECLARE-TIMI 58 (Table-1) [14-17]. The antihypertensive effects of them are summarized. Among them, T2DM patients for secondary prevention are mostly provided by antihypertensive agents (AHA) together. Average BP before studies were 135-140 mmHg during systole and 77-78 mmHg during diastole. With adding SGLT-2 inhibitors, BP was changed -4 mmHg for systole and -1 mmHg in diastole.

Possible Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors for Reducing Effects of Blood Glucose and also Blood Pressure

Table-1

Lowering effect for blood pressure in trials of SGLT2 inihibitors

The precise mechanism of reducing BP remains unclear. However, this antihypertensive effect may be obtained from some osmotic diuresis associated with urinary glucose excretion, suppression of sodium reabsorption. As a result, ATP consumption in the proximal tubule may be suppressed, and then sympathetic nerve excitation may be suppressed. The degree of urinary glucose excretion is known to depend on the renal function and blood glucose level of the subject. There were two studies using canagliflozin, which were CREDENCE and CANVAS. In the former, renal protective effect was examined in cases of renal function deterioration, where the degree of blood pressure reduction was lower compared with that of CANVAS.

From these results, the usefulness of SGLT-2i for BP control would be considered [10,18]. The degree of BP-lowering effect was not so large. The goal of SGLT-2i was not the achievement of reducing effect, but the suppression of cardiovascular event. Consequently, diabetic patients on SGLT-2i seem to have clinical benefits in the light of decreased blood glucose, blood pressure, and the possibility of a cardiovascular event.

There was The Yokohama Add-On Inhibitory Efficacy of Dapagliflozin on Albuminuria in Japanese Patients with Type 2 Diabetes Study (Y-AIDA Study) [10]. As the results of 85 patients for home blood pressure on 24 weeks later, changes in the morning, evening, and nocturnal home BP showed – 8.3/- 4.2 mmHg, – 9.6 /- 4.5 mmHg, – 2.4/- 1.2 mmHg (all p>0.05). In addition, the reduction in urine albumin-to-creatinine ratio (UACR) has a significant correlation with the BP improvement profile [10].

A close relationship was found between BP changes and proteinuria. In T2DM, BP variability was associated with urinary albumin elevation, which is independent of other factors [18]. Consequently, control of home BP may lead to a potential therapeutic method for T2DM patients.

Similar to this article, Kluger had compared the clinical effect on a cardiovascular event for 4 main studies, in which data of CREDENCE study are from Berkovic et al. [19,20]. Four studies are DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE. As the result of drug and placebo in each study, relative risk reduction of renal outcome event was 47%, 40%, 46%, 30%, and of major adverse cardiovascular (CV) event was 7%, 14%, 14%, 20%, respectively [19]. Consequently, glomerular filtration function and albuminuria value have been the most important indicators of clinical risk for renal and cardiovascular events. SGLT2i may give the greatest beneficial influence to these two factors.

SGLT2 inhibitor empagliflozin was given to 2286 T2DM for 24 weeks and changes of BP were analyzed [21]. In cases with lower eGFR, reduced systolic blood pressure (SBP) was maintained. Compared with placebo, change in SBP was -3.2 mmHg, -4.0 mmHg, -5.5 mmHg, -6.6mmHg in cases with 4 group of eGFR as >90, 60-89, 30-59, 30> ml/ min/1.73m², respectively.

In summary, the important points from the mentioned above are summarized below:

SGLT-2i have excellent cardiovascular event inhibitory action. Due to its structural characteristics, it has no action points in vivo other than SGLT-2 of the proximal tubule.
Various studies have reported multifaceted effects on human beings associated with urinary glucose excretion. Although the blood pressure-lowering effect was limited in the cardiovascular outcome studies, SGLT-2i seems to have beneficial clinical efficacy.
The ultimate goal of antihypertensive and hypoglycemic agents is not the achievement of target values, but the suppression of cardiovascular events. The administration of SGLT-2i would be also an excellent strategy for event suppression and as an adjunct to antihypertensive treatment.
Trials of SGLT-2i for heart failure, renal failure, NASH, etc. in non-diabetic patients are also in progress at present.

Funding

There was no funding received for this paper.

Conflict of Interest

The author has no conflicts of interest to declare.

References

[1] Association AD. 1. Improving Care and Promoting Health in Populations: Standards of Medical Care in Diabetes–2020. Diabetes Care. 2020 Jan;43(Suppl 1):S7-13. [PMID: 31862744]

[2] Mauricio D, Alonso N, Gratacòs M. Chronic Diabetes Complications: The Need to Move beyond Classical Concepts. Trends Endocrinol Metab. 2020 Apr;31(4):287-95. [PMID: 32033865]

[3] Atkins RC. Dr. Atkins’ New Carbohydrate Gram Counter. M. Evans and Company; 1996.

[4] Bernstein RK. Dr. Bernstein’s Diabetes Solution. New York: Little, Brown and company; 1997.

[5] Ebe K, Ebe Y, Yokota S, Matsumoto T, Hashimoto M, Sakai Y. Low Carbohydrate diet (LCD) treated for three cases as diabetic diet therapy. Kyoto Medical Association Journal. 2004;51:125-29.

[6] Nakamura T, Kawashima T, Dobashi M, Narita A, Bando H. Effective Nutritional Guidance for Obesity by Low Carbohydrate Diet (LCD). Asp Biomed Clin Case Rep. 2019 Jan 27;2(s1):16-21.

[7] Bando H, Ebe K, Muneta T, Bando M, Yonei Y. Clinical effect of low carbohydrate diet (LCD): Case report. Diabetes Case Rep. 2017 Jun 10;2(2):124.

[8] Toyama T, Neuen BL, Jun M, Ohkuma T, Neal B, Jardine MJ, Heerspink HL, Wong MG, Ninomiya T, Wada T, Perkovic V. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis. Diabetes Obes Metab. 2019 May;21(5):1237-50. [PMID: 30697905]

[9] Bando H. Clinical Influence of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors for Cardiovascular and Renal Points of View. Diab Res Open Access. 2020 Jan 30;2(S1):9-13.

[10] Kinguchi S, Wakui H, Ito Y, Kondo Y, Azushima K, Osada U, Yamakawa T, Iwamoto T, Yutoh J, Misumi T, Aoki K, Yasuda G, Yoshii T, Yamada T, Ono S, Shibasaki-Kurita T, Hosokawa S, Orime K, Hanaoka M, Sasaki H, Inazumi K, Yamada T, Kobayashi R, Ohki K, Haruhara K, Kobayashi Y, Yamanaka T, Terauchi Y, Tamura K. 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). Cardiovasc Diabetol. 2019 Aug 27;18(1):110. [PMID: 31455298]

[11] Marshall SM. The bark giving diabetes therapy some bite: the SGLT inhibitors. Diabetologia. 2018 Oct;61(10):2075-78. [PMID: 30132029]

[12] Danne T, Biester T, Kordonouri O. Combined SGLT1 and SGLT2 Inhibitors and Their Role in Diabetes Care. Diabetes Technol Ther. 2018 Jun;20(S2):S269-77. [PMID: 29916741]

[13] Takasu T, Yokono M, Tahara A, Takakura S. In Vitro Pharmacological Profile of Ipragliflozin, a Sodium Glucose Co-transporter 2 Inhibitor. Biol Pharm Bull. 2019;42(3):507-11. [PMID: 30828082]

[14] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. [PMID: 26378978]

[15] Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-57. [PMID: 28605608]

[16] Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Capuano G, de Zeeuw D, Greene T, Levin A, Pollock C, Sun T, Wheeler DC, Yavin Y, Zhang H, Zinman B, Rosenthal N, Brenner BM, Perkovic V. Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups. Circulation. 2019 Aug 27;140(9):739-50. [PMID: 31291786]

[17] Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE–TIMI 58 Investigators. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-57. [PMID: 30415602]

[18] Ushigome E, Matsumoto S, Oyabu C, Kitagawa N, Tanaka T, Hasegawa G, Ohnishi M, Tsunoda S, Ushigome H, Yokota I, Nakamura N, Oda Y, Asano M, Tanaka M, Yamazaki M, Fukui M. Prognostic significance of day-by-day variability of home blood pressure on progression to macroalbuminuria in patients with diabetes. J Hypertens. 2018 May;36(5):1068-75. [PMID: 29283972]