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Sodium Glucose Cotransporter-2 Inhibitors in ClinicalPractice: Impact beyond Glycemic Control
Sodium Glucose Cotransporter-2 Inhibitors in Clinical
Practice: Impact beyond Glycemic Control
1Karthik Rao N, 2KM Prasanna Kumar
1Assistant Professor, 2Consultant
1Department of Medicine, Kasturba Medical College, ManipalKarnataka, India
2Department of Endocrinology, CDEC and Bangalore DiabetesHospital, Bengaluru, Karnataka, India
Correspondence: Karthik Rao N, Assistant ProfessorDepartment of Medicine, Kasturba Medical College, ManipalKarnataka, India
Phone: +919886124423
mail: karthikrao85@gmail.com
Type 2 diabetes mellitus is a metabolic disorder that occursdue to an interplay of multiple perplexing pathophysiologicalmechanisms and leads to hyperglycemia. However, till datethere has been no single unique molecule that can by itselfeffectively address all the metabolic abnormalities occurringin type 2 diabetes. Furthermore, type 2 diabetes must bemanaged with agents that can combat hyperglycemia withoutcausing hypoglycemia and adverse cardiovascular outcomes.Thus, the need of the hour is for a unique molecule that candeliver beyond glycemic control and can in addition address thecardiovascular risk factors that arise in type 2 diabetes. Sodiumglucose cotransporter-2 (SGLT-2) inhibitors are the latest ofthe oral hypoglycemic agents that act by insulin-independentmechanisms and tackle several cardiovascular risk factorsthat occur in type 2 diabetes. The scope of this article will beto focus primarily on the cardiovascular benefits of SGLT-2inhibitors and its actions beyond glycemic control in providinga comprehensive care in the management of type 2 diabetes.
Keywords: Cardiovascular safety, Extra antihyperglycemicactions, Review, Sodium glucose cotransporter-2 inhibitors,Type 2 diabetes.
How to cite this article: Rao NK, Kumar KMP. SodiumGlucose Cotransporter-2 Inhibitors in Clinical Practice: Impactbeyond Glycemic Control. Hypertens J 2016;2(2):74-79.
Source of support: Nil
Conflict of interest: None

Sodium glucose transporter-2 (SGLT-2) inhibitors arethe latest of the oral hypoglycemic agents introducedin the management of type 2 diabetes. Unlike mostof the oral hypoglycemic agents, this novel group ofagents seems to be promising and encouraging dueto its insulin-independent action causing negligibleand imperceptible risk of hypoglycemia. Besides itsantihyperglycemic action, the SGLT-2 inhibitors havebeen consistently proven to promote weight loss, reduce blood pressure, and act complementary to the currenttreatment modalities.

  Sodium Glucose Cotransporter-2 Receptors in
Type 2 Diabetes

It is well known that uncontrolled type 2 diabetes leads toglycosuria owing to the saturation of the SGLT-2 receptorsinvolved in glucose reabsorption. Nevertheless, despitethe severe hyperglycemia, SGLT-2 receptors surprisinglycontinue to reabsorb glucose through an insulinindependentmechanism.1 Curiously, despite the highblood glucose levels, uncontrolled diabetes causes the upregulationof SGLT-2 leading to augmented renal tubularglucose reabsorption (Fig. 1). Thus, the threshold for glucosesaturation is altered with diabetes and increased glucosereabsorption occurs owing to the overexpression of theSGLT-2 molecules.2 Thus, SGLT-2 inhibitors cause glucoselowering effect in an insulin-independent mechanismby arresting the increased reabsorption of glucose acrossthe renal tubules (Figs 2 and 3). The drugs that arecurrently available for use in India include canagliflozin,dapagliflozin, and empagliflozin.

Sodium Glucose Cotransporter-2 Inhibitors in ClinicalPractice: Impact beyond Glycemic Control
Fig. 1: Complementary role of hyperglycemia and SGLT-2 inhibitors.(Hyperglycemia induces the overexpression of SGLT-2 receptorswhich by enhanced glucose reabsorption leads to exacerbation ofthe prevailing hyperglycemia.)

Sodium Glucose Cotransporter-2 Inhibitors in ClinicalPractice: Impact beyond Glycemic Control
Fig. 2: Normal location and function ofSGLT-2 receptor


Sodium Glucose Cotransporter-2 Inhibitors in Clinical Practice: Impact beyond Glycemic Control

Sodium Glucose Cotransporter-2 Inhibitors in ClinicalPractice: Impact beyond Glycemic Control
Fig. 3: Mechanism of action of SGLT-2 inhibitors

The Unique Mode of Action of SGLT-2 Inhibitors

Till date, the oral hypoglycemic agents used in type 2diabetes have focused primarily on insulin-dependentmechanisms to counteract hyperglycemia, such asincreasing the secretion of endogenous insulin. However,the efficacy of the agents acting through insulin signalingand dependant pathways will be compromised overtime due to the deterioration of beta cell function thatensues with the progression of diabetes.3 Thus there is aneed for a drug that will address the multiple challengesinvolved in achieving sustained glycemic control byinsulin-independent mechanisms.

Familial renal glycosuria, a condition without anysinister clinical consequences occurs due to the geneticmutation in the SGLT-2 receptor that can lead to significantglycosuria (up to 134 g/day reported) but has normalrenal tubular structure and function. Thus, learning fromfamilial glycosuria, SGLT-2 inhibitors appear to be safemolecules and by their unique insulin-independent modeof action are promising in combating hyperglycemia ina dependable and sustained manner.


The phenotype of Indians with type 2 diabetes variessignificantly from their western counterparts in beingmore insulin-resistant due to increased abdominalobesity, having unfavorable lipid profiles with increasein atherogenic small dense LDL cholesterol, increase inC-reactive protein (CRP) levels, and low adiponectin,making them susceptible to cardiovascular events4,5("The thin fat Indian"). To make matters worse, theonset of diabetes is a decade earlier among Indians andgenerally associated with a poor and inadequate betacell reserve due to a delay in diagnosis.6,7 The prevailingtherapies in the management of type 2 diabeteshave several limitations and flaws like weight gain,risk of hypoglycemia, gastrointestinal side effects, andthe inability to maintain effective and persistent longtermglycemic control. However, with the advent of thisnovel class of SGLT-2 inhibitors, the shortcomings in the current pharmacological therapies will be addressedeffectively.
Sodium Glucose Cotransporter-2

Apart from its antihyperglycemic effect, SGLT-2 inhibitorshave been consistently shown to induce weight loss,reduce blood pressure, and act complementary to theprevailing treatment modalities.8-10 In addition, SGLT-2inhibitors can potentially target the numerous risk factorsfor atherosclerosis in type 2 diabetes, such as visceraladiposity, hyperinsulinemia, arterial stiffness, albuminuria,uric acid, and oxidative stress. The reduction inbody weight with SGLT-2 inhibitors was attributed to theloss of about 200 to 300 calories per day through glucoseexcretion in urine. In an intriguing study, the additionof dapagliflozin in patients uncontrolled on metforminmonotherapy resulted in increased oxidation of fattyacids compared to placebo, supporting the mechanism offat breakdown and catabolism as a fundamental cause ofweight loss. The reduction in body weight achieved waslargely due to the reduction in the total body fat massin the visceral and subcutaneous adipose tissue. Thishypothesis was supported with the use of dual-energyX-ray absorptiometry (DEXA), which revealed a significantlygreater reduction in adipose stores among patientsreceiving dapagliflozin in comparison with patients whoreceived placebo.11

In a study conducted with the use of canagliflozin atdoses of 100 and 300 mg resulted in a significant decreasein the blood pressure and a reduction in the body weight.In the overall population, least-square (LS) mean percentreductions in body weight with canagliflozin 100 and300 mg were -2.9 and -3.6% respectively. In the Indiansubgroup of patients, mean percent decrease in bodyweight with canagliflozin 100 and 300 mg were -2.5 and-3.2% respectively. The LS mean reduction in systolicblood pressure (SBP) with canagliflozin 100 and 300 mgwere -3.4 and -4.1 mm Hg respectively. In the Indiansubgroup, canagliflozin 100 and 300 mg were associatedwith -3.4 and -4.4 mm Hg decrease in the BP. In the overallpopulation, canagliflozin 100 and 300 mg were associatedwith a diastolic BP reduction of -1.9 and -1.9 mm Hgrespectively, and a reduction of -0.5 and -0.7 mm Hgin the diastolic BP in the Indian subgroup. The studydemonstrated that despite the relatively lower baselinebody weight and BMI of the patients in the Indian subgroupin comparison to the overall population, canagliflozinwas associated with convincing reductions in the bodyweight.12 Comparable outcomes of weight loss rangingfrom -2.7 to -3.2 kg at 24 weeks of therapy were obtained with 10 mg dapagliflozin.13 In patients with inadequateglycemic control with potentially weight-gainingoral hypoglycemic agents, addition of dapagliflozinresulted in a significantly greater loss of weight incomparison to glimepiride (dapagliflozin, -2.26 kgvs placebo, -0.72 kg) and also blunted the increase inweight associated with the use of pioglitazone up toweek 48 (dapagliflozin, + 0.69 kg vs placebo, + 2.99 kg).14,15Dapagliflozin when introduced as an add-on to insulintherapy maintained weight near baseline, and escalatingdoses of insulin resulted in a steady weight gain in theplacebo group (dapagliflozin, -1.5 kg vs placebo, + 0.9 kg).16
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Karthik Rao N, KM Prasanna Kumar

Owing to SGLT-2 inhibitor's insulin-independentmechanism for glycemic control, reductions in bodyweight and BP will be the ideal pharmacological agent toinitiate treatment in the Asian population who typicallyare severely insulin-resistant and having a poor beta-cellreserve.17 The weight loss achieved with SGLT-2 inhibitorswould enhance the insulin sensitivity and arrest theprogression of beta cell failure that ensues over timewith diabetes.18 This revival in the beta-cell function andenhanced insulin sensitivity has been shown to last evenon sustained therapy with SGLT-2 inhibitors.19


Apart from hyperglycemia, the pathogenesis of cardiovascularcomplications in diabetes is multifactorial andthus mandates a comprehensive approach in the management.Hence, it would be phenomenal if an oral hypoglycemicagent could provide benefits over and aboveglycemic control alone. Among the oral hypoglycemicagents currently available, SGLT-2 inhibitors appear tobe the prime molecule that can provide additional cardiovascularbenefits. The proposed mechanisms of extraglycemic effects and cardiovascular risk factor modulationwith SGLT-2 inhibitors are elaborated below.

Reduced Risk of Hypoglycemia

The sympathetic nervous system stimulation that occursin response to hypoglycemia causes a decline in theglomerular filtration rate (GFR) by blunting the action ofSGLT-2 inhibitors.20 In addition, the ability to counteractpostprandial glycemic excursions and reduced glycemicvariability and enhanced insulin sensitivity withSGLT-2 inhibitors could perhaps translate into favorablecardiovascular outcomes.21

Reduction in BP and Arterial Stiffness

Sodium glucose cotransporter-2 inhibitors have consistentlyshown to decrease BP even without a compensatory increase in the heart rate. The antihypertensive action ismultifactorial and involves diuretic-like action, loss ofsodium, decrease in weight, and reduction in the arterialtone.22

Improvement in Endothelial Function or the
Vascular Architecture

Sodium glucose cotransporter-2 inhibitors alter thestructural proteins present in the connective tissue of thevessel wall like collagen, elastin, and abnormal glycationof proteins, which occur due to hyperglycemia andimprove endothelial dysfunction.23
Reduction in Visceral Adiposity

This action is unique to SGLT-2 inhibitors in comparisonto other oral hypoglycemic agents and may translate inreducing the cardiovascular outcomes.24

Effects on Proteinuria and Kidney Function

Sodium glucose cotransporter-2 inhibitors reduce urinaryalbumin excretion and the intra-glomerular hypertensionby altering the tubuloglomerular feedback due toincreased distal sodium delivery.25

Reduction in Levels of Uric Acid

In addition, the glycosuria that ensues with the use ofSGLT-2 inhibitors will alter the transport activity of uricacid in the renal tubules and reduce the serum uric acidlevels that are generally elevated in metabolic syndrome.26

Effect on Lipid Parameters

Sodium glucose cotransporter-2 inhibitors increasethe levels of both high-density lipoprotein-cholesterol(HDL-C) and low-density lipoprotein-cholesterol(LDL-C) with no change in HDL-C/LDL-C ratio. Thisincrease in LDL-C levels may negate some of the potentialbenefits of SGLT-2 inhibitors.27

Effects on Other Cardiovascular Risk Pathways

Animal studies have shown that SGLT-2 inhibitorsreduce oxidative stress and leukocytosis induced byhyperglycemia that are fundamental in the pathogenesisof atherosclerosis.28 With reductions in the bloodpressure, weight, and diuresis, SGLT-2 inhibitors canpotentially benefit treatment of patients with cardiacfailure. Studies done in rats with heart failure have showndecrease in left ventricular mass and left ventricular enddiastolic diameter with SGLT-2 inhibitors.29

The HbA1C Paradox

Most of the oral hypoglycemic agents as well as insulincause reduction in HbA1C at the cost of weight gain i.e., associated with adverse outcomes. Patients whogained weight during treatment for type 2 diabetes had1.8- to 2.3-fold increase in risk of cardiovascular diseasecompared with those who gained less weight or who lostweight.30 Every 3 kg gain in weight offsets the benefitsof HbA1C reduction by 1%.31 In an article published inLANCET endocrinology, an increase in weight by 1 kgdue to treatment with antidiabetic medications leadsto a relative increase in risk of heart failure.32 Thus,conventional antihyperglycemic agents, despite causingsatisfactory reduction in HbA1C, will cause collateraldamage due to weight gain. Hence, minimizing risk ofweight gain is of utmost priority that can be effectivelyachieved with the novel class of SGLT-2 inhibitors.


Sodium Glucose Cotransporter-2 Inhibitors in Clinical Practice: Impact beyond Glycemic Control

The "EMPA-REG" study is a landmark study thatdemonstrated cardiovascular safety of SGLT-2 inhibitorempagliflozin.33 Notably, the benefits observed withempagliflozin were seen in high-risk cardiovascular type 2diabetes patients on treatment with statins, aspirin, anddrugs blocking the renin-angiotensin-aldosterone axis.The study involved 7,020 patients randomized to receiveonce daily empagliflozin 10 or 25 mg against placebo. Theprimary endpoint was death from cardiovascular causes,non-fatal myocardial infarction, or non-fatal stroke amongthe pooled empagliflozin group vs the placebo group. Themajor secondary composite outcome was the primaryoutcome and hospitalization for unstable angina. Theprimary outcome occurred in 490 of 4,687 patients (10.5%)in the pooled empagliflozin group and in 282 of 2,333patients (12.1%) in the placebo group (hazard ratio in theempagliflozin group, 0.86; 95.02% confidence interval,0.74 to 0.99; p = 0.04 for superiority). Remarkably, thedecrease in the risks of death from cardiovascular causesand from any cause occurred early in the trial persistedall through the study. There were no significant betweengroupdifferences in the rates of myocardial infarctionor stroke, but in the empagliflozin group there weresignificantly lower rates of death from cardiovascularcauses (3.7% vs 5.9% in the placebo group; 38% relativerisk reduction), hospitalization for heart failure (2.7 and4.1% respectively; 35% relative risk reduction) and deathfrom any cause (5.7 and 8.3% respectively; 32% relativerisk reduction). There was no significant between-groupdifference in the key secondary outcome (p = 0.08 forsuperiority). For the first time, the EMA-REG study hasdemonstrated that an antihyperglycemic agent to benot just non-inferior but rather superior over placeboin high-risk type 2 DM patients. Does this translate toother SGLT2 inhibitors or not? Is this a molecular effectof empagliflozin or class effect of SGLT-2 inhibitorsthat can only be substantiated with ongoing studieslike Canagliflozin Cardiovascular Assessment Study(CANVAS)?


The enhanced glycosuria that ensues with the use ofSGLT-2 inhibitors leads to an increased risk of urinarytract infections, pyelonephritis, and candidiasis.34-36In addition, SGLT-2 inhibitors cause osmotic diuresisand polyuria that can lead to volume depletion andelectrolyte abnormalities. This risk is markedly enhancedwith combination of SGLT-2 inhibitors with diuretics.Accordingly, SGLT-2 inhibitors must be avoided inindividuals presenting with the classical hyperglycemicsymptoms of polyuria, polydipsia, polyphagia, andunintentional weight loss. The actions of SGLT-2inhibitors are blunted with renal impairment obligatingdose modifications and are not advocated for use withmoderate-to-severe renal disease.
Of late, the US FDA has issued a warning on therisk of developing euglycemic ketoacidosis with SGLT-2inhibitors. This is a matter of concern as the diagnosismay be unseen and missed due to lack of awarenessamong the treating clinicians and the absence ofsevere hyperglycemia that is typically associated withdiabetic ketoacidosis. It is hypothesized that the euglycemicketoacidosis is due to the hyperglucagonemia,non-insulin-dependent glucose clearance, and volumedepletion that occur with SGLT-2 inhibitors.37 Hence,euglycemic ketoacidosis must be strongly suspected inpatients on SGLT-2 inhibitors developing nausea, vomiting,or metabolic acidosis. Thus, SGLT-2 inhibitors arenot approved for treatment in individuals with type 1diabetes and must be used with utmost caution in individualshaving an increased risk of developing diabeticketoacidosis. In April 2016, the European MedicinesAgency (EMA) has initiated a review on canagliflozinin the ongoing Canagliflozin Cardiovascular AssessmentStudy after an increase in risk in amputations,mostly of the great toe was observed. The CanagliflozinCardiovascular Assessment Study is a randomizedstudy of about 4,000 type 2 diabetes patients with highcardiovascular risks to canagliflozin 100 or 300 mgdaily or to placebo and will be completed by 2017. TheEMA Pharmacovigilance Risk Assessment Committee(PRAC) has appealed to the pharmaceutical companyto assess for the increased risk in toe amputations withcanagliflozin.


Metformin unless contraindicated is the first and thebest drug to commence pharmacological therapy intype 2 diabetes.38 However, the dilemma has beenon the molecule to complement metformin therapy.Sulfonylureas, DPP-IV inhibitors, and pioglitazone have always been the preferred choice of second-lineantidiabetic therapy till lately. Nevertheless, thesedrugs are associated with adverse effects like weightgain, hypoglycemia, edema, increased risk of fractures,and cardiovascular safety concerns. Certainly, SGLT-2inhibitors with its unique mode of action and safetyprofile are an ideal add-on therapy to metformin.Various international and national guidelines, such asthe Research Society for the Study of Diabetes in India(RSSDI) guidelines and algorithm for management oftype 2 diabetes have accepted SGLT-2 inhibitors as theadd-on therapy after metformin.39 In a study publishedby Davidson et al,40 canagliflozin produced comparableoutcomes among different ethnic populations. Thestudy demonstrated identical reductions in HbA1c,body weight, and SBP among the Hispanic/Latino andnon-Hispanic/Latino patients with type 2 diabetes. In asubset analysis of canagliflozin global studies that wasperformed on Indian type 2 diabetic patients has beenpromising and has shown that SGLT-2 inhibitors areequally effective and safe in the Indian type 2 diabeticpopulation.41 Our experience with SGLT-2 inhibitors inthe last 1 year has been encouraging and satisfactory asmonotherapy and as add-on to other oral and injectableantidiabetic agents.
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With its unique mode of action, safety profile, andinnumerable benefits beyond glycemic control, the SGLT-2 inhibitors appear to be "the blockbuster molecule"that will assist the physician in achieving optimal andsustained glycemic control. The EMPA-REG studyhas demonstrated that SGLT-2 inhibitors are cardiacfriendlyoral hypoglycemic agents. Does this mean thatcardiologists should prescribe SGLT-2 inhibitors amongall cases of diabetes having high cardiovascular risk andespecially among those with cardiac failure? Will SGLT-2inhibitors be equally effective in patients of diabetes withlow cardiovascular risk in preventing all-cause mortality,cardiovascular mortality, and morbidity? Only time willanswer these unanswered questions.

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