BRIEF REPORT

SGLT2 Inhibitors and the Clinical Implicationsof Associated Weight Loss in Type2 Diabetes:A Narrative Review

Andrej Janez . Paola Fioretto

Received: April 15, 2021 /Accepted: June 3, 2021 / Published online: July 9, 2021� The Author(s) 2021

ABSTRACT

Introduction: The obesity epidemic is closelylinked to the rising prevalence of type 2 diabetes(T2D). Body weight reduction remains animportant challenge in patients with T2D, as itrequires changing their overall metabolic con-trol. Of all glucose-lowering therapies, onlysodium–glucose cotransporter 2 inhibitors(SGLT2is) and glucagon-like peptide 1 receptoragonists (GLP-1 RAs) consistently result inweight improvement. Moreover, the same twoclasses have important cardiovascular and renalbenefits. We summarize the key availableinformation related to the weight loss effect ofSGLT2is in T2D, focusing on the unexploitedpotential of these drugs.

Methods: Data on weight change with SGLT2isin patients with T2D were extracted from pub-lished cardiovascular outcomes trials (CVOTs).A discussion on patient perspectives aboutweight change is based on key preclinical andclinical trials, meta-analyses, and reviews and issupplemented by the authors’ clinical judgmentand research experience in the field.Results: SGLT2is have a unique mode of actionresulting in caloric loss through glycosuria. Theanticipated weight loss with SGLT2is is notreflected in clinical trial results. There is a dis-crepancy between the magnitude of improve-ment in glycemic control and the weight loss,cardiovascular, and renal benefits obtained inlarge clinical trials.Conclusion: The relationships between themagnitude of weight loss, improvement in gly-cemic control, and cardiorenal benefits withSGLT2i are still unclear. Potential mechanismsother than simple glycemic efficacy should berevealed and explained. Better weight controlmay be achieved if adequately intensive lifestylechanges are implemented and monitored in theT2D population treated with SGLT2is.

Keywords: CVOT; SGLT2 inhibitors; Type 2diabetes; Weight loss

A. Janez (&)Department of Endocrinology, Diabetes andMetabolic Diseases, University Medical CentreLjubljana, Zaloska Cesta 7, 1000 Ljubljana, Sloveniae-mail: andrej.janez@kclj.si

P. FiorettoDepartment of Medicine, University of Padua,Padua, Italy

P. FiorettoUnit of Medical Clinic 3, Hospital of Padua, Padua,Italy

Diabetes Ther (2021) 12:2249–2261

https://doi.org/10.1007/s13300-021-01104-z

Key Summary Points

Why carry out this review?

Obesity is closely linked to type 2 diabetes,and it is often difficult to achieve andmaintain the control of these conditions.

SGLT2 inhibitors are among a fewtherapeutic options with clear benefits onweight management.

Accumulating evidence also demonstratesthe important cardiorenal risk reductionin this patient population.

What was learned from this review?

The mechanisms by which SGLT2inhibition leads to cardiorenal riskreduction are not fully elucidate, butreduction is an important component.

A structured approach to enhance SGLT2inhibitor effects on weight may beimplemented in clinical practice with thepotential to enhance healthy behaviors toyield optimal outcomes in patients withtype 2 diabetes.

DIGITAL FEATURES

This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.14718531.

INTRODUCTION

Type 2 diabetes (T2D) is a chronic disease with amajor impact on patients’ lives and health caresystems. Its prevalence ranges from 7% to 25%[1] in European Union countries, and it is clo-sely associated with overweight, obesity, andphysical inactivity. Current estimates project anincrease in T2D incidence of up to 20% in

Europe in the next 20 years [1, 2]. In recentyears, a new term has emerged, diabesity,reflecting the lack of weight control in patientswith T2D [3] and the urgent need to find effi-cient strategies to address both diabetes andobesity.

Lifestyle changes promoting a reduction incaloric intake and an increase in energyexpenditure represent the first-line action [4].Patients with diabetes are educated on how tointegrate a balanced, calorie-restricted diet andat least moderate physical activity in their rou-tine. However, the implementation of dailyhealthy behavior is out of the strict control ofthe medical team, relying mostly on patients’understanding, motivation, and commitmentto reaching realistic goals. Achievement andmaintenance of normal weight is one of themost important treatment objectives forpatients with T2D. Current therapeutic guide-lines for T2D favor the early use of pharma-cotherapies with demonstrated cardiovascular(CV) and renal benefits and a positive impact onweight control, irrespective of HbA1c value [4].

The development of sodium–glucosecotransporter 2 (SGLT2) inhibitors (SGLT2is)represents a major turning point in the man-agement of diabetes owing to their uniquemechanism of action and proven cardiovascularand renal benefits. One of the first reportedadditional benefits of SGLT2is was the weightloss effect, a result of caloric excretion and fatmass reduction.

Mechanism of Action and Effect on EnergyBalance

Glycosuria is one of the key characteristics ofpoorly controlled diabetes, along with hyper-glycemia and reduced insulin secretion and/orglucose utilization. Kidneys play a key role inmaintaining glucose homeostasis, participatingin steps along the whole metabolic chain ofglucose, including its production (gluconeoge-nesis), utilization, filtration, reabsorption, andexcretion.

SGLT2 is a high-capacity, low-affinity glu-cose transporter responsible for 90% of glucosereabsorption [5]. SGLT2 transporters are located

2250 Diabetes Ther (2021) 12:2249–2261

in kidneys, mainly in the S1 and S2 segments ofthe proximal convoluted tubules [6]. The rest ofthe glucose is further reabsorbed in the S3 seg-ment by SGLT1, a low-capacity, high-affinitytransporter. Tubular reabsorption reaches itsmaximum capacity at approximately 375 mgglucose/min, with a corresponding plasma glu-cose level of 200 mg/dL. Glycosuria occurswhen this threshold is exceeded. If the hyper-glycemic status is persistent, enhanced SGLT1/2expression leads to paradoxically higher rates ofglucose reabsorption [7].

The development of SGLT2is represents amajor paradigm shift in the treatment of dia-betes, turning a ‘‘defect’’ into a ‘‘mode ofaction’’. Four SGLT2is are currently approved inEurope for T2D treatment in combination withdiet, exercise, and lifestyle changes (canagli-flozin, dapagliflozin, empagliflozin, and ertu-gliflozin). They are not specifically approved byregulatory agencies for body weight reductionor treatment of obesity.

SGLT2 Inhibition: Effect on Body Weight

At therapeutic doses, urinary glucose excretion(UGE) is approximately 70–90 g/day, equivalentto 300 kcal/day, with additional diuresis of400 mL/day [8, 9]. On the basis of the measurednumber of calories lost per day due to UGE, theexpected weight loss would be approximately10 kg/year [7]. The actual loss in body weight ismuch less, as shown in clinical trials and inclinical practice [10]. The relationship betweenSGLT2 inhibition and the caloric effect turnedout to be much more complex and not a simplelinear function, as initially thought [11]. Clini-cal trials and observational data show thatweight reduction is lower than expected (ap-proximately 2–5 kg), with variations accordingto baseline weight and concomitant medica-tion. The body weight reduction during treat-ment with SGLT2is has been consideredmodest, though it provides large cardiovascularbenefits. The mechanisms of weight loss andtheir influence on cardiorenal effects seemcomplex and are not fully elucidated.

This short review explores how the weightloss achieved with SGLT2is might influence

multiple outcomes in T2D. Our aim is to brieflyreview the weight-related results reported in thecontext of cardiovascular outcomes trials(CVOTs) and discuss the possible implicationsfor clinical practice.

METHODS

This is a narrative review based on a literaturesearch in the PubMed database up to Febru-ary 26, 2021. The search algorithm coveredSGLT2 inhibitors or inhibition, canagliflozin,dapagliflozin, empagliflozin, ertugliflozin inconnection with weight loss, weight change,metabolic change, adipose tissue, body compo-sition, and CVOTs. Documentation was basedon information from full-text publications,including preclinical and clinical trials, meta-analyses, and reviews on this topic. The searchstrategy was limited to English-language arti-cles. Case reports on weight change withSGLT2is were not included. CVOTs in patientswith T2D only were selected. Data extractionwas conducted by one reviewer and revised byone coauthor. The selected references wereindividually searched to identify more infor-mation on the topic. The discussion is supple-mented by the authors’ research experience andclinical judgment.

Compliance with Ethics Guidelines

This article is based on previously conductedstudies and does not contain any new studieswith human participants or animals performedby any of the authors.

RESULTS

Difference Between Estimated Energy Lossand Actual Weight Reduction

Several years ago, Rajeev et al. [8] explored thediscrepancy between the anticipated effect ofSGLT2is and actual weight loss reported inclinical trials. They described several adaptivechanges, such as compensatory hyperphagia,

Diabetes Ther (2021) 12:2249–2261 2251

increased gluconeogenesis, and a shift towardfatty acid utilization as a metabolic substrate.

Evidence to support compensatory hyper-phagia is limited. In rodent models, lack ofSGLT2 expression or chronic administration ofdapagliflozin or canagliflozin led to weightreduction and increased caloric intake, consid-ered to be compensatory to energy loss [12–14].Similar predictions come from mathematicalmodels with canagliflozin [15] or empagliflozin[16], showing several-fold increases in calorieintake compared to the adaptation in energyexpenditure. However, this theory was notsupported by a 12-week randomized controlledtrial with dapagliflozin vs. placebo, whereweight loss obtained with SGLT2 inhibition wasnot associated with a significant increase infood intake (p = 0.659) [17]. Another clinicaltrial in patients with T2D [18] showed similarresults, with no significant association of dapa-gliflozin with compensatory carbohydrateintake.

Another possible explanation for the limitedbody weight decrease is an increase in glucagoneffects, with promotion of renal and hepaticgluconeogenesis and a consequent increase inendogenous glucose production. However, therole of SGLT2 inhibition in endocrine regula-tion remains unclear.

Compensatory metabolic and endocrineprocesses do not totally counteract the weightloss effect. Clinical trials with SGLT2is haveshown a biphasic pattern of weight loss: aninitial large effect, probably resulting fromenhanced fluid elimination, followed by a slowincrease, with mean weights lower than base-line at any assessment [19, 20]. The gradualeffect is maintained for up to 4 weeks withdapagliflozin [21] and has been explained bythe reduction in visceral and subcutaneous fatmass [21–23].

A Closer Look into Weight ChangesReported in CVOTs

Developed for T2D treatment and currentlyused as antihyperglycemic drugs, SGLT2is haveproven cardiovascular and renal benefits inlarge CVOTs. Since the primary and key

secondary objectives have focused on thereduction of CV and renal events, weightchanges were only briefly reported in the pri-mary manuscripts (Table 1) [24–28].

CANVAS Program

A post hoc analysis [29] showed similar car-diorenal results between different baseline bodymass index (BMI) groups. The authorsacknowledged a substantial variation in weightchange over time. The weight decrease withcanagliflozin vs. placebo was larger at the12-month follow-up (- 2.77%; 95% CI - 2.95,- 2.59) than at the 3-month follow-up (-1.72%; 95% CI - 1.83, - 1.62). The mostplausible explanation resides in the time-addi-tive effects of the dual mechanisms of weightloss with SGLT2is. A dose-dependent effect wasobserved at both time points. Early effects werepositively associated with coadministration ofinsulin or glucagon-like peptide 1 receptoragonists (GLP-1 RA), as well as the absence of ahistory of heart failure or arterial hypertension(all p for trend\0.05); however, a possibleexplanation was not apparent. A contradictoryresult was the larger weight reduction at3 months in people with lower initial HbA1c.Nevertheless, the baseline weight did notinfluence the prevention of CV events bycanagliflozin.

CREDENCE Trial

The CREDENCE trial was designed to primarilyassess the renal outcomes with canagliflozin100 mg/day vs. placebo in patients with T2Dand reduced kidney function [25]. The averagechange in weight with canagliflozin vs. placebo(- 0.8 kg; 95% CI 0.69, 0.92) [25] was main-tained irrespective of the initial glomerular fil-tration rate [30].

DECLARE-TIMI 58 Trial

The DECLARE-TIMI 58 trial outcomes (com-posite risk of CV disease and hospitalization forheart failure and its components, including CVand renal events) were analyzed according to

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Table 1 Summary of weight change results with SGLT2is in CVOTs including patients with T2D only

CVOT nameand SGLT2i

CVOT study population Meanfollow-up(SD), years

Baselineweight(SD), kg

Weightreduction(SD) with theSGLT2i, kg

Risk reduction for theprimary objective

CANVAS

[24]:

canagliflozin

T2D and either symptomatic

ASCVD or multiple CV

risk factors

N = 10,142

Mean age (BL) = 63.3 years

Mean HbA1c (BL) = 8.2%

3.6 (2.0) 90.2

(NR)

- 1.6 (2.42) 3P-MACE

HR = 0.86; 95% CI

0.75–0.97

P\ 0.001 (non-

inferiority)

P = 0.02 (superiority) vs.

placebo

CREDENCE

[25]:

canagliflozin

T2D and CKD and

albuminuria

N = 4401

Mean age (BL) = 63 years

Mean HbA1c (BL) = 8.3%

2.6

(0.02–4.53)

87.1

(NR)

- 0.8 (1.95) Composite of

ESRD/doubling of

serum creatinine vs.

baseline/CV or renal

death

HR = 0.70; 95% CI

0.59–0.82

P = 0.00001 vs. placebo

DECLARE-

TIMI 58

[26]:

dapagliflozin

T2D and either symptomatic

atherosclerotic CV disease

or multiple CV risk factors

N = 17,160

Mean age (BL) = 64.0 years

Mean HbA1c (BL) = 8.3%

4.2 (3.9–4.4) 91.0

(NR)

- 1.8 (5.0) 3P-MACE

HR = 0.93; 95% CI

0.84–1.03

P = 0.17 vs. placebo

CV death/hHF

HR = 0.83; 95% CI

0.73–0.95

P = 0.005 vs. placebo

EMPA-REG

[27]:

empagliflozin

T2D and established ASCVD

N = 7020

Mean age (BL) = 63.1 years

Mean HbA1c (BL) = 8.1%

3 (2.2–3.6) 86.3

(19.0)

- 2.00 (NR) 3P-MACE

HR = 0.86; 95% CI

0.74–0.99

P = 0.04 (superiority)

Diabetes Ther (2021) 12:2249–2261 2253

baseline BMI categories (normal to very obese)[31]. A similar reduction in body weight (ap-proximately 2% vs. placebo) and similar relativerisk for the composite event were observedacross the BMI categories.

EMPA-REG Outcomes Trial

A post hoc analysis of EMPA-REG OUTCOMESdata [32] evaluating the early benefits showed asignificant weight reduction with empagliflozinvs. placebo (p\ 0.0001) at 12 weeks, 6 months,and 1 year. The clinical and metabolic benefitswere apparent in patients with T2D with orwithout heart failure at baseline and were con-sidered largely independent of HbA1creduction.

VERTIS CV Trial

The weight change observed with ertugliflozin5 mg or 15 mg in the VERTIS CV trial [28] wasslightly lower than that previously reported.The results from another trial, although not aCVOT, showed that weight loss at 26 weeks was

maintained for a longer period of time, up to104 weeks [33]. No specific results from VERTISCV on weight change with ertugliflozin bybaseline BMI or HbA1c group have been pub-lished, but another clinical trial with ertugli-flozin in overweight and obese patientsconcluded that achievement of glycemic con-trol at 26 weeks (HbA1c reduction) was similarirrespective of baseline BMI, and so was thepercentage of weight loss (approximately 3–4%)[34].

The impressive cardiorenal outcomes areonly partially explained by the SGLT2is’ effectson the heart, kidneys, blood vessels, and thewhole body [35]. Potential mechanisms includestructural (reduction of ventricular mass andwall stress, improvement of fibrosis markers andendothelial function), dynamic (direct inhibi-tion of myocardial Na?/H? pump, reduction ofblood pressure, and improvement of the ven-tricular loading conditions and tubu-loglomerular feedback), and energetic changes(improvement of cardiac metabolism).

In this context, the associated weight losshas been investigated as a potential distinctivemediator of CV risk reduction in diabetes. A

Table 1 continued

CVOT nameand SGLT2i

CVOT study population Meanfollow-up(SD), years

Baselineweight(SD), kg

Weightreduction(SD) with theSGLT2i, kg

Risk reduction for theprimary objective

VERTIS CV

[28]:

ertugliflozin

Established ASCVD involving

the coronary,

cerebrovascular, and/or

peripheral arterial system

N = 8246

Mean age (BL) = 64.4 years

Mean HbA1c (BL) = 8.2%

3.5 NR

Baseline

BMI:

31.9

(5.4)

kg/m2

At 1 year:

- 2.4 (3.9) kg

with 5 mg

- 2.8 (4.0) kg

with 15 mg

3P-MACE

HR = 0.97; 95% CI

0.85–1.11

P\ 0.001 vs. placebo

3P MACE 3-point major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction or nonfatalstroke, ASCVD atherosclerotic cardiovascular disease, BL baseline, BMI body mass index, CKD chronic kidney disease, CIconfidence interval, CV cardiovascular, CVOT cardiovascular outcome trial, ESRD end-stage renal disease, HbA1c glycatedhemoglobin, HR hazard ratio, NR not reported, T2D type 2 diabetes, SD standard deviation, SGLT2i sodium–glucosecotransporter 2 inhibitor

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recent systematic review and meta-analysis [36]of large CVOTs with different glucose-loweringdrugs showed a significant relative reduction inthe risk of heart failure of 5.9% (3.9–8.0%) forevery difference of 1 kg between treatmentgroups (p\ 0.0001). Another meta-analysiswith meta-regression [37] concluded that GLP-1RAs and SGLT2is reduce the risk of cardiovas-cular and mortality endpoints regardless of thereductions in systolic blood pressure and bodyweight. In patients with T2D with renalimpairment, previous research showed thatdapagliflozin 10 mg improved weight and sys-tolic pressure, while the benefit on glycemiccontrol was small [38]. When published, weightchange results from the DAPA-CKD trial [39]will probably enable further correlationsbetween weight loss and renal outcomes.

The CV advantages obtained with SGLT2inhibitors in large CVOTs have been only par-tially clarified by their mechanism of action andrelated glycemic control. Different approacheshave been taken to explain cardiac and renalimprovements, which place this class on a dif-ferent treatment path than the rest of the oralantihyperglycemic agents [4].

DISCUSSION

Potential Protective Mechanisms of SGLT2Inhibition Associated with Weight Loss

Intensive lifestyle measures may result in clini-cally significant weight reduction (at least 5%)that can be maintained in the long term [40],and a minimum 3% reduction in weight isadvantageous for metabolic control [41]. In real-life practice, rebound weight gain is common.

The initial decrease in body weight is theresult of two major effects of SGLT2 inhibition:caloric loss due to glucose excretion (a processalso called calorie restriction mimicry) and lossof body water due to osmotic diuresis. Bothmechanisms appear to become effective earlyafter treatment initiation, with glycosuria con-tinuing in the long term without any significantfluid change. We are confident that upcomingstudies will clarify whether the weight loss

effect is a key component or only an add-on tothe impressive cardiorenal outcomes.

The fat loss associated with SGLT2 inhibitionis the result of a complex metabolic processdescribed by Ferrannini et al. [16, 42] as agradual shift to fatty acid utilization. Theincrease in glucagon concentration in responseto reduced blood glucose and insulin levelstriggers a cascade of metabolic events leading tolipolysis and lipid oxidation. Increased produc-tion of ketone bodies, a more efficient source ofenergy for the heart that require less oxygen fortheir metabolism, would allow more efficientcardiac contractility, thereby improving thebenefits on heart failure. This explanation isoffset by the fact that patients with heart failurepresent high ketone body levels, even in theabsence of SGLT2 inhibition. Moreover,ketoacidosis is a trigger of inflammatory condi-tions, whereas the use of SGLT2is has beenproven to reduce inflammation.

Considering the improvement of cardiacfunction and the associated body fat reduction,the effect of SGLT2 inhibition on epicardialadipose tissue (EAT) was investigated. A smallrandomized controlled trial (N = 40) showedthat 6-month dapagliflozin treatment wasassociated with a significant reduction in EATvolume compared to baseline, with no changesin the control group [43]. This observation isimportant since arterial stiffness has been cor-related with diabetes, obesity, and hyperten-sion. Despite the limited available information,it is likely that SGLT2 inhibitors act by modu-lating the risk factors, giving them a synergisticlarger effect than initially estimated.

SGLT2 Inhibitors, Obesity,and Inflammation

Obesity is linked to a chronic inflammatoryresponse, with abnormal cytokine and chemo-kine production. Associated insulin signalingpathways include mitogen-activated proteinkinases (MAPKs), IjB-kinase b (IjKb)/nuclearfactor jB (NF-jB), and mammalian target ofrapamycin (mTOR)/S6 kinase [44]. SGLT2 inhi-bition leads to activation of lysosomal degra-dation and inhibition of mTOR, with possible

Diabetes Ther (2021) 12:2249–2261 2255

changes in mitochondrial status followed by a‘‘switch’’ in inflammatory events. The idea ofimproving the response to a toxic environmentthrough profound changes in ‘‘cellular life his-tory programs’’ has recently been advanced [45].This would include the induction of a fasting-like state [46] by SGLT2 inhibition. Such ideasencourage scientists to accept how majorimprovements are the result of subtle changes.

A Possible Change in Patients’ Perspective

Current guidelines in diabetes are very clearabout placing the patient at the center of diseasemanagement. Lifestyle changes, including diet-ary restrictions and an increase in physicalactivity, form the basis of the treatment andshould be adapted to individual needs, andpatient preferences should be considered whendiscussing the overall treatment approach. Met-formin remains the first-line pharmacologicaltherapy owing to its effectiveness in bothmonotherapy and combination therapy, and onthe basis of extensive experience [4]. With aneutral overall effect on weight, metformin doesnot provide cardiorenal protection in patientswith diabetes. The paradigm shift from glycemiccontrol to cardiorenal risk control in diabetesplaces SGLT2is high on the list of pharmacologicagents to be used early in treatment. Addition-ally, SGLT2is can be used in various therapeuticassociations considering their overall efficacyand safety profile and the unique insulin-inde-pendent mechanism of action. In clinical prac-tice, the time of intensification with an SGLT2idoes not seem to influence the proportion ofweight lost [47], but a change of 3–4% is stilllower than anticipated on the basis of the calorieexcretion mechanism.

With the development of new and moreefficacious treatments for diabetes, the choice ofantihyperglycemic agent has become impor-tant. In patients with high CV risk requiringadditional disease control, the association of anSGLT2i with GLP-1 RA seems a rational choice.The DURATION 8 study [48, 49] showed thatdapagliflozin plus exenatide once weeklyimproved glycemic control and resulted in alarger weight loss than either drug alone.

Similar results were seen in more recent trials,AWARD-10 [50] and SUSTAIN-9 [51], with otherGLP-1 RAs added to a background treatmentwith an SGLT2i. On the basis of the overallevidence, it seems that sequential or concomi-tant use of SGLT2is and GLP-1 RA provides themost favorable approach based on their CVprotection (heart failure and major adversecardiovascular events), glycemic control (HbA1clowering), and metabolic effects (attenuation ofcompensatory hyperphagia, weight loss, andminimal risk of hypoglycemia).

For patients and medical staff, T2D man-agement requires an ongoing effort to controlthe disease. We strongly believe that novelagents associated with weight loss—SGLT2isand GLP-1 RAs—should be exploited at a higherrate. Updated guidelines and current treatmentrecommendations are a solid basis for thisopinion. Although many elements of SGLT2is’potential are still not elucidated, it is likely thatphysicians go through a clear decision-makingprocess when prescribing them in daily clinicalpractice.

Interviews conducted with patients withT2D under treatment with one SGLT2i providea new perspective on patient-reported outcomes[52]. Such qualitative research may representthe starting point for developing a differentcommunication framework with patients whoare adherent to SGLT2is that will allow them topursue other positive behaviors to control dia-betes. In the overall perception of their healthstatus, patients with T2D ascribe a moreimportant role to observed weight changes [53]than to HbA1c and blood pressure control.From this point of view, the weight loss effect ofSGLT2is, although considered modest andbelow the clinical significance of 5% overall, hasthe potential to become the anchor for ourefforts to shift the perspective of patientstoward healthy behaviors and adherence totreatment. The structured clinical approachsuggested in Fig. 1 has the potential to addressboth obesity and T2D, aiming to lower the BMIcategory and promote the cardiorenal benefitsof novel therapies.

This short narrative has focused on weightloss attributed to SGLT2is in CVOTs withexclusive T2D populations. The limitations of a

2256 Diabetes Ther (2021) 12:2249–2261

brief narrative review are inherent. Details onthe chemical and molecular pathways influ-encing the cardiorenal effects are only margin-ally introduced. An important topic, such as theeffect of SGLT2 inhibition on body weight insubjects without diabetes, is left unexplored.We also did not review in detail the relationshipbetween body weight and renal function indiabetes. Results from clinical practice from acombination of an SGLT2i with GLP-1 RA arenot included. The accumulating body of evi-dence highlights the need to explore weightreduction with SGLT2is in more depth in trialswith pragmatic designs to provide more valu-able insights that will support individualizedtreatment approaches.

Despite extensive research, the full implica-tions of weight loss associated with SGLT2inhibition are largely unknown. The cascade ofevents triggered by glucose excretion seems verycomplex, interlacing with inflammation, lipol-ysis, and deeper intracellular changes, so it

might take a long time to solve it completely.The effect on abdominal fat is clearly linked tothe obesity reduction, and the increased lipol-ysis and ketone body formation are linked tothe improvement in cardiac metabolism. Futurestudies and assessments could bring us closer tothe clinical predictors of better responses toSGLT2is, with a greater metabolic benefit andBMI improvement.

CONCLUSION

The mechanisms by which SGLT2 inhibitionleads to cardiorenal risk reduction are not fullyelucidated but include improved glycemic con-trol, reduced body weight, lower blood pressure,and osmotic diuresis. CV benefits and weightloss are consistently reported with SGLT2isacross different patient population groups,irrespective of baseline BMI, moderate chronicdisease, and glycemic control.

Fig. 1 Suggested practical algorithm to monitor weight loss in patients with T2D treated with an SGLT2i

Diabetes Ther (2021) 12:2249–2261 2257

Weight reduction remains a crucial goal inthe prevention and treatment of diabetes. Alongwith clinical trials, large real-world studieswould allow a better understanding of theappetite patterns and caloric behavior ofpatients with T2D treated with an SGLT2i toallow this versatile therapeutic class to reach itsfull potential.

ACKNOWLEDGEMENTS

Funding. This publication was supported byAstraZeneca UK Limited, Branch Office inSlovenia, Ljubljana, Slovenia (AstraZenecaSlovenia). The Rapid Service Fee was funded byAstraZeneca Slovenia.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Authors’ Contributions. The authors hadfull editorial control of the manuscript, con-tributed equally to its development, reviewedand edited various drafts, and provided theirfinal approval of all content.

Medical Writing, Editorial, and OtherAssistance. Medical writing assistance wasprovided by Raluca Voicu, MD of MedInteractivPlus (Bucharest, Romania) and was funded byAstraZeneca Slovenia.

Disclosures. The authors declare that thecurrent research was conducted in the absenceof any commercial or financial relationshipsthat could be construed as a potential conflict ofinterest. Andrej Janez has served as a consultantand is on speakers’ bureaus for AstraZeneca,Boehringer Ingelheim, Eli Lilly, MSD, NovoNordisk, and Sanofi. Paola Fioretto receivedpersonal fees for advisory boards or scientificpresentations from AstraZeneca, Mundipharma,Boehringer-Ingelheim, Eli Lilly & Co, andNovartis.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any new studies withhuman participants or animals performed byany of the authors.

Data Availability. Data sharing is notapplicable to this article, as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-Non-Commercial 4.0 International License, whichpermits any non-commercial use, sharing,adaptation, distribution and reproduction inany medium or format, as long as you giveappropriate credit to the original author(s) andthe source, provide a link to the CreativeCommons licence, and indicate if changes weremade. The images or other third party materialin this article are included in the article’sCreative Commons licence, unless indicatedotherwise in a credit line to the material. Ifmaterial is not included in the article’s CreativeCommons licence and your intended use is notpermitted by statutory regulation or exceeds thepermitted use, you will need to obtain permis-sion directly from the copyright holder. To viewa copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

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