Chapter 16
Cardiovascular Benefits of SGLT2
Inhibitors
JAMSHED J. DALAL
INTRODUCTION
Despite the fact that type-2 diabetes mellitus
(T2DM) ingrains a high cardiovascular (CV) risk,
glycaemia control has failed to demonstrate clear
macrovascular benefits1. Consequently, the specific
antidiabetic agents have garnered lesser interest in
therapeutic CV protection, except possibly metfor-
min. Paradoxically, for the antidiabetic agents, the
CV safety aspects have assumed greater clinical rel-
evance. Following the worsening of CV outcomes
noted with rosiglitazone, any newer agent for T2DM
is required to demonstrate a safe CV profile for
clinical use2. The subsequently marketed antidia-
betic agents, including sitagliptin, exenatide and
lixisenatide had demonstrated CV safety3–5. The
more essential aspect of possible CV protection
with an antidiabetic agent had remained conspicu-
ously elusive and understated.
Since late 2015, the promising results observed in
EMPA-REG OUTCOME study have prompted a re-
surgence of interest, in possible CV protection with
antidiabetic therapies6. In this study, empagliflozin
therapy for 3 years, in merely 36 patients of CV
disease with T2DM, would prevent one additional
heart failure event (hospitalization or CV death)
beyond the existing standard of care. Moreover, in
patients with heart failure burden, treating merely
21 such patients with empagliflozin for 3 years,
would prevent one additional CV death. With these
developments, the cardiology fraternity has been
blessed with additional options, to address the con-
siderable residual CV risk in patients of T2DM.
WHAT IS AN SGLT2 INHIBITOR?
SGLT2 inhibitors represent a novel class of therapeu-
tic agents, originally developed for the management
of hyperglycaemia in T2DM. These agents facilitate
excretion of glucose through the urine, thus acting
as proximal tubular diuretics, as well as metabolic
modulators. As a consequence of urinary glucose
excretion, these agents improve the preload, after-
load and possibly the cardiac efficiency7.
In healthy individuals, around 180 g of glucose is
filtered by the renal glomeruli every-day. The fil-
tered glucose is almost completely reabsorbed in
the proximal tubules, through the glucose trans-
porters (Fig. 16-1). Sodium- glucose cotransporters
(SGLT) are the predominant glucose transporters in
the proximal renal tubules. The SGLT type-2 trans-
porter (SGLT2) is more specifically located in the
kidneys, and accounts for nearly 90% of the renal
glucose reabsorption. The activity of SGLT2 trans-
porter is further upregulated in T2DM, which con-
tributes to hyperglycaemia, and also to altered renal
haemodynamics. The SGLT type-1 transporter
(SGLT1) acts as a minor transporter in the renal
proximal tubules, although it is more ubiquitously
present in the body, including the gut, skeletal
muscles and myocardium. The nonspecific inhibi-
tion of SGLT1 transporter, in various tissues of the
body, may have possible unintended effects. Hence,
the selective inhibition of the SGLT2 transporter
has succeeded as a clinically acceptable therapy8.
The use of selective SGLT2-inhibitors results in an
average urinary glucose excretion of about 60–80 g
per day (Fig. 16-1). The efficacy of SGLT2-inhibitors
depends on the existing glycaemia levels; higher
levels of glycaemia are associated with greater uri-
nary glucose excretion. Glucose excretion is associ-
ated with about 400–500 mL of fluid loss for the
initial few weeks. Transient natriuresis is also ob-
served following SGLT2-inhibitor therapy. This
could be of particular relevance to patients with
insufficient natriuresis. However, these agents do
125
126 SECTION II Preventive Cardiology
Filtered glucose
load > 180g/day
SGLT2
inhibitor
SGLT1
SGLT, sodium glucose cotransporter.
*Loss of ~ 80 g of glucose per day = 240 cal/day.
Figure 16-1. SGLT2 inhibition: fundamental mechanism.
not increase the plasma renin activity or serum al-
dosterone levels, except in a volume deficient
state9,10. These agents also restore the altered tubu-
loglomerular feedback (TGF) in T2DM, which helps
preserve the renal function in long term11.
The metabolic and haemodynamic effects of
SGLT2-inhibitor are summarized in Fig. 16-2.
SGLT2 INHIBITORS AND
CARDIOVASCULAR MECHANISMS
The proof of mechanism has been studied for the
following effects with SGLT2 inhibitors.
IMPROVED ARTERIAL STIFFNESS
In a small 8-week mechanistic study in patients of
type-1 diabetes, empagliflozin 25 mg OD demon-
strated an improvement in arterial stiffness param-
eters, including the augmentation index and
carotid-radial pulse wave velocity12. The improve-
ment in arterial stiffness is not explained by renin–
angiotensin–aldosterone pathway, sympathetic ac-
tivity or nitric oxide pathway. The possible beneficial
mechanisms could be weight loss, attenuation of
hyperinsulinaemia, anti-inflammatory effect, vas-
cular smooth muscle relaxation following negative
sodium balance, etc. However, these need to be
studied in detail.
SGLT2 inhibitors
reduce glucose
re-absorption
in the proximal
tubule, leading to
urinary glucose
excretion* and
osmotic diuresis
SYSTOLIC AND DIASTOLIC BLOOD
PRESSURE (BP) REDUCTION
The SGLT2 inhibitors reduce 24-h ambulatory sys-
tolic BP by 3–4 mm Hg, and diastolic BP by 1–2 mm
Hg. Systolic and diastolic BP reductions were also
observed, in daytime as well as night-time read-
ings13. Both glucuresis as well as natriuresis may
contribute to modest volume contraction, and con-
sequent reduction in BP14. Greater reductions in BP
are observed with the SGLT2-inhibitors, in patients
with higher BP values at baseline. BP reduction is
not associated with an increase in heart rate. In a
post hoc assessment of EMPA-REG blood pressure
study, the circadian rhythm of BP was not altered
with empagliflozin either in the dippers or in non-
dippers15.
Some cases of difficult hypertension in T2DM
may particularly respond to an SGLT2-inhibitor16.
In T2DM, hyperinsulinaemia, fluid and sodium re-
tention could result in resistant hypertension.
SGLT2-inhibitors lower hyperinsulinaemia by an
improvement in metabolic profile; these agents also
facilitate natriuresis through a direct effect on the
SGLT2 transporters. Thus, although the average BP
reduction facilitated by SGLT2-inhibitor therapy is
modest, certain patients with uncontrolled hyper-
tension, volume overload or inadequate natriuresis
may be particularly benefitted.
 Chapter 16 — Cardiovascular Benefits of SGLT2 Inhibitors 127

SGLT2-inhibition

Metabolism Volume Sodium

Reduced HbA1c Reduced preload Restored TGF

Metabolic switch, Reduced afterload Reduced intra-

Reduced Weight (BP reduction) glomerular pressure

Attenuated
Hyperinsulinemia

Ketogenesis,
Efficient energetics

Reduced
Oxidative stress

Figure 16-2. Summary of metabolic and haemodynamic effects of SGLT2-inhibitor.

SGLT2-inhibitors is mediated at the level of afferent

PRESERVATION OF RENAL FUNCTION
The SGLT2-inhibitors have demonstrated a slowing
in decline of renal function in patients of T2DM.
The development of diabetic kidney disease is influ-
enced by alterations in intrarenal haemodynamics.
Increased activity of the SGLT2 transporter in prox-
imal tubules leads to increased proximal sodium
reabsorption; as a result, lesser quantity of sodium
reaches the macula densa. This activates a TGF
mechanism, resulting in dilatation of the afferent
arterioles and increase in the intraglomerular pres-
sure. Hyperfiltration is an early development in
diabetic kidney disease, and the single-nephron
glomerular filtration rate (GFR) remains elevated in
such patients, even as the overall renal function
declines progressively.
SGLT2-inhibitors increase the flux of sodium at
the macula densa, by blocking the proximal sodium
reabsorption. As a result, the TGF is normalized,
and the abnormal dilatation of the afferent arteriole
is restored. This effect results in a small initial dip in
the estimated GFR (eGFR), reflecting as a marginal
rise in serum creatinine levels11. A similar mecha-
nism is also evident with the renin–angiotensin
system (RAS) inhibitors. However, the RAS-inhibi-
tors act at the level of efferent arteriole, resulting in
relaxation of the efferent arteriole. The effect of
arteriole.
In long-term studies, empagliflozin and cana-
gliflozin have demonstrated preservation of the
eGFR, as compared to glimepiride or placebo17,18
(Fig. 16-3). In the EMPA-REG OUTCOME study,
empagliflozin decreased ‘new-onset or worsening
of nephropathy’ by 39% as compared to placebo,
on the top of RAS-blocker therapy17. In terms of
absolute risk reduction, treating 17 patients with
empagliflozin for 3 years prevented one additional
event of incident or worsening nephropathy. Re-
duction in albuminuria is consistently observed
with these agents. The confirmatory evidence of
long-term renal protection is expected from the
ongoing studies.
IMPROVEMENT IN LEFT VENTRICULAR
FUNCTION
In the EMPA-REG OUTCOME study, empagliflozin
demonstrated a 35% reduction in hospitalizations
for heart failure, as compared to placebo19. This was
achieved on the top of standard of care heart failure
therapies, including RAS-blockers, diuretics, and
beta blockers. Although EMPA-REG OUTCOME
study was not designed to assess the effect of empa-
gliflozin on the heart failure outcomes, the findings
128 SECTION II Preventive Cardiology

93
Glimepiride 1–4 mg Empagliflozin 25 mg

Mean (SE) eGFR (mL/min/1.73m2)

91
Difference 5.1;
(95% CI 3.5 to 6.8)
89 p<0.0001

87

85

83

81
0 12 28 52 78 104 130 156 182 208 LVOT FU*
Week

Glimepiride 757 751 726 707 677 657 503 492 478 459 588 573

Empagliflozin 742 740 713 690 679 651 537 525 520 510 579 570

Baseline: mean (SE) in the treated set; weeks 12–208: adjusted mean (SE) from MMRM in the treated set; LVOT and FU:
adjusted mean (SE) from ANCOVA in patients from the FAS who had a measurement at follow-up. *FU was 4 weeks after
termination of study medication. FU, follow up; LVOT, last value on treatment.

Figure 16-3. Preservation of eGFR over 4 years: empagliflozin versus glimepiride18.

suggest a pertinent aspect of clinical interest. Fur- and renal metabolism. Ketone bodies are known to
thermore, in patients with heart failure burden at be more efficient energy substrates, yielding more
baseline or during the study, empagliflozin offered ATP per oxygen atom consumed, as compared to
a considerable absolute risk reduction for CV fatty acids (Table 16-1).
death20. The benefits were observed early, and sus- The myocardium is an omnivore, which mainly
tained throughout the trial. In a small mechanistic depends on fatty acids as a substrate, but may also
study, short-term empagliflozin therapy demon- derive energy from glucose, ketone bodies and
strated significant improvements in left-ventricular amino acids. Diabetic cardiomyopathy is character-
mass index, and in early lateral annular tissue Dop- ized by the accumulation of fatty acids within the
pler velocity21. Apart from the reduction in preload myocardium. This pathological development results
and afterload, metabolic modulation is also in lipotoxicity, characterized by reduced myocardial
believed to contribute towards improved cardiac glucose uptake, inefficient metabolism, apoptosis
outcomes. and accelerated pump failure. The background of
mild ketosis generated with SGLT2-inhibitor ther-
apy, could have a favourable effect on the myocar-
METABOLIC EFFICIENCY HYPOTHESIS dial metabolism23,24. This hypothesis is presently
An interesting hypothesis suggests a possible im- under evaluation in various studies. The reduced
provement in myocardial metabolism, with the use workload on the heart (preload and afterload),
of SGLT2 inhibitors. Therapy with SGLT2-inhibitors combined with improved myocardial efficiency,
prompts various physiological metabolic adapta-
tions, as a result of the ongoing glucose loss. Over a
few weeks of therapy, the peripheral tissues start us- TABLE 16-1 ENERGETICS OF DIFFERENT
ing fat as an alternate energy substrate. This results SUBSTRATES
in weight loss with these agents, which plateaus over
ATP Yield per Oxygen
4–6 months of therapy. Furthermore, the insulin
Atom Consumed
requirement is lowered as a result of clearance of
Substrate (P/O Ratio)
glucotoxicity, and improved peripheral insulin sensi-
tivity. This engenders a glucagon-dominated milieu Glucose 2.58
Ketone (beta-hydroxybutyrate) 2.50
in the liver, facilitating ketogenesis22. Thus, a back-
Fatty acid (palmitate) 2.33
ground of mild ketosis is engendered, which may
have a favourable metabolic effect on myocardial
 Chapter 16 — Cardiovascular Benefits of SGLT2 Inhibitors 129

could stimulate multifactorial benefits in diabetic TABLE 16-2 KEY CV OUTCOMES FROM
cardiomyopathy. EMPA-REG OUTCOME
Empagliflozin vs. Placebo
CLINICAL EVIDENCE: EMPA-REG OUT-
Absolute Risk
COME STUDY Relative Risk Reduction
EMPA-REG OUTCOME is the first cardiovascular out- Reduction (Number
come trial (CVOT) in the SGLT2-inhibitor class as (Hazard Ra- Needed to
well as in the history of T2DM, which demonstrated Outcome tio, P-Value) Treatb)
conclusive CV benefits with an antidiabetic agent. In 3-Point MACE 14% (0.86, 1.6% (63
patients of T2DM with CVD, empagliflozin demon- P  .04) patients)
strated a significant 14% reduction in the major CV mortality 38% (0.62, 2.2% (46
P  .001) patients)
adverse CV events, as compared to placebo. The CV
Hospitalizations for 35% (0.65, 1.4% (72
protection was evident despite most patients receiv- heart failure P  .002) patients)
ing the optimum cardioprotective therapies in the Hospitalizations for 34% (0.66, 2.8% (36
background, including RAS inhibitors, antiplatelet heart failure or P  .001) patients)
agents, antihypertensives, statins and antidiabetic CV mortality
agents. CV protection was driven by a 38% reduction CV death in patients 33% (0.67, 4.9% (21
in CV mortality with empagliflozin, compared to with heart-failure P  .05) patients)
burdena
placebo. Apart from these, over 30% reductions were
Incident or worsen- 39% (0.61, 6.1% (17
observed in the heart failure, and nephropathy- ing of nephropathy P  .001) patients)
related end points. The overall mortality reduced by 40% sustained 45% (0.55, 1.4% (72
32%, as compared to placebo6. The key prespecified decline in eGFR P  .001) patients)
and post hoc assessments from the EMPA-REG Incident macroal- 38% (0.62, 5.0% (20
OUTCOME study are summarized in Table 16-2. buminuria P  .001) patients)
Regarding the cerebrovascular outcomes, a bene- All-cause mortality 32% (0.68, 2.6% (39
fit was not evident with empagliflozin. Rather, a P  .001) patients)
numerical imbalance was evident for nonfatal Source: Adapted from references 6, 17, 19, 20, 25
a
stroke, most of such excess events happening more Heart failure burden: Heart failure at baseline, hospitalization
than a month after the discontinuation of empa- for heart failure or heart failure as an investigator-reported
gliflozin. When stroke and transient ischaemic adverse event.
b
Number needed to treat: Number of patients to be treated
attacks are considered together, the numerical im-
with empagliflozin for 3 years, to prevent one additional
balance disappeared. Moreover, the imbalance was event.
mainly observed in the participants of European
origin, rather than the Asians or other participants.
Based on the elaborate assessments of the study
evidence, the imbalance in stroke events with em- in patients with T2DM, for preventing or delaying
pagliflozin was adjudicated as a chance finding by the onset of heart failure or prolonging life (class
the USFDA, and unlikely to be causally associated IIA, Level B recommendation)29. Empagliflozin is
with empagliflozin26,27. also the first antidiabetic agent to have been
The number needed to treat gives a good clinical approved by the USFDA and other countries, to
inference of the research evidence. If empagliflozin is reduce CV death in patients of CVD and T2DM30.
administered to 39 patients of CVD and T2DM, one
additional death maybe prevented over 3 years. This PRESENTLY AVAILABLE SGLT2
benefit is in addition to the existing cardioprotective INHIBITORS
therapies. In PARADIGM-HF study, treating 32
patients with sacubitril– valsartan over 2.2 years pre- Three selective SGLT2-inhibitors are marketed for
vented one additional CV death28. Albeit different in T2DM, including canagliflozin, dapagliflozin and
context, the analogy of these two studies impresses empagliflozin. All these SGLT2-inhibitors are more
the clinical relevance of empagliflozin to the existing selective for the SGLT2 transporter, as compared to
options of cardioprotective therapies. SGLT1. These agents have differences in their phar-
The European Society of Cardiology guidelines macological and clinical characteristics. All these
(2016), for the management of acute and chronic agents may be used in once-daily administration
heart failure, recommend the use of empagliflozin in the recommended doses, regardless of meals.
130 SECTION II Preventive Cardiology

However, it is advisable to administer these agents
at the same time every day.
The characteristics of these three agents are sum-
marized in Table 16-3.
Recently, the results of CV outcome trials of
canagliflozin, another SGLT2-inhibitor, were pub-
lished40. CANVAS programme was a pooled analysis
of two trials of canagliflozin in patients of T2DM,
who were at high risk for CV disease. The study in-
cluded patients with either a symptomatic presen-
tation of CVD, or those having multiple CV risk
factors. In the CANVAS programme, some of the CV
outcomes observed with canagliflozin were similar
to empagliflozin. Canagliflozin demonstrated a
14% reduction in the relative risk for 3P-MACE
events, and a 33% reduction for heart failure–
related hospitalizations, as compared to placebo, on
top of standard of care. However, unlike empa-
gliflozin, there was no evident benefit for CV mor-
tality or all-cause mortality with canagliflozin, in
the CANVAS programme. CANVAS included both
high- and low-CV risk patients and this may ac-
count for this difference. Moreover, an increased
risk of lower limb amputations and bone fractures
was observed with canagliflozin, as compared to
placebo. Although the relative risk for lower limb
amputations was twofold higher with canagliflozin
as compared to placebo, these were rare adverse
events. Treatment of 115 patients with canagliflozin
over 3 years resulted in one additional event of
lower limb amputation. Also important is to note
that lower limb amputations were actively looked
for as per protocol in CANVAS. Similarly, treatment
of 96 patients with canagliflozin over 3 years re-
sulted in one additional event of bone fracture40.
Another real-world study, CVD-REAL, evaluated the
new users of SGLT2-inhibitors versus the new users
of other antidiabetic therapies42,43. This retrospec-
tive observational study, which had most patients
receiving dapagliflozin as the SGLT2-inhibitor, also
suggested a benefit of SGLT2-inhibitor based ther-
apy on CV mortality, and 3P-MACE in patients with
established CVD. However, in patients without a
history of CVD, only a benefit in 3P-MACE was
demonstrated. However, this study had several lim-
itations, including the inherent limitations of an
observational design, shorter duration of 0.9 years
and discordant results of CV mortality benefit in a
CVD-REAL cohort which predominantly received
canagliflozin, with that observed in the CANVAS
programme42,43. Overall, the results of EMPA-REG
OUTCOME and CANVAS programme suggest a pos-
sible class benefit for SGLT2-inhibitors for certain
CV outcomes like 3P-MACE and hospitalizations
for heart failure, in patients of T2DM with estab-
lished CVD. However, a CV mortality benefit is
conclusively demonstrated only with empagliflozin,
and is approved as an additional indication for this
agent. Furthermore, there are certain differences in
safety outcomes, as observed with the three SGLT2-
inhibitors. The ongoing studies will enhance our
understanding on the finer aspects of CV protection
and risk–benefit profiles of the available SGLT2-
inhibitors, across a broader profile of patients.

TABLE 16-3 CURRENTLY AVAILABLE SGLT2 INHIBITORS

Empagliflozin Dapagliflozin Canagliflozin
SGLT2:SGLT1 selectivitya 250031 120031 25031
Nonspecificb tissue Lowest32 Intermediate32 Highest32
distribution
Risk of hyperkalaemia No imbalancec (see ref 33) No imbalancec (see ref 34) h In moderate renal impairmentc
(see ref 35)
Risk of bone fractures No imbalance33,36 No imbalance34,37 Increased risk35,38
Risk of malignancy No imbalance33,36 Imbalance for bladder No imbalance35,38
cancerd (see refs 34,37)
CV mortality reduction Demonstrated (EMPA-REG Study ongoing Not demonstrated (CANVAS
OUTCOME)6 (DECLARE- TIMI 58)39 programme)40
Risk of leg and foot No imbalance33,36 No imbalance34,37 Twofold h in risk with
amputations canagliflozin (both doses)41
a
The clinical relevance of SGLT-transporter selectivity is incompletely understood at present.
b
Nonspecific: Organs other than target organ (kidney), or the organs of absorption and elimination (gut and liver). This is an
extrapolation from the observed preclinical data, based on the respective Cmax and area-under-the-curve values observed at
clinically used doses of the three agents.
c
In case of conditions that may lead to fluid loss, careful monitoring of volume status and electrolytes is recommended.
d
An imbalance in bladder cancers was observed in clinical trials. Dapagliflozin should not be used in patients with active blad-
der cancer and should be used with caution in patients with a prior history of bladder cancer.
 Chapter 16 — Cardiovascular Benefits of SGLT2 Inhibitors
SAFETY CONSIDERATIONS
Certain clinical considerations are essential for ap-
propriate clinical use of SGLT2-inhibitors44,45. The
use of SGLT2-inhibitors may cause genital fungal
infections in about 5% of the patients. These infec-
tions are mild and easily manageable. The risk of
urinary tract infections is not increased, except in
predisposing conditions like patients with history
of recurrent infections. The SGLT2-inhibitors should
not be considered as substitutes for insulin, in pa-
tients with known severe insulinopenia. In patients
receiving insulin therapy, concomitant use of SGLT2
inhibitor may accompany gradual down-titration
of insulin, but not abrupt withdrawal or substitu-
tion. A small increase in serum LDL-C and HDL-C
levels are also observed with SGLT2-inhibitors. The
ratio of LDL-C to HDL-C does not get altered. These
effects are of minor clinical relevance, considering
the overall CV benefits demonstrated in the EMPA-
REG OUTCOME study.
The use of SGLT2-inhibitors may result in an ini-
tial rise in the serum creatinine levels (similar to
RAS inhibitors), due to a haemodynamic adaptation
in the nephrons. This is a protective mechanism,
secondary to the lowering of intraglomerular pres-
sure. However, the risk of acute renal impairment
should be considered, if these agents are concomi-
tantly used with other nephrotoxic agents, or in a
state of dehydration. In a state of volume depletion,
the rise in serum creatinine level may exceed 20%–
30% of its baseline value. This should prompt dis-
continuation of the SGLT2-inhibitor. Nephrotoxic
drugs, including NSAIDs and radiocontrast agents,
should not be used concomitantly. The safety as-
pects are summarized in Table 16-4.
The key recommendations should include:
• Maintenance of adequate hydration by consum-
ing adequate amount of fluid
• Consumption of adequate carbohydrates, and
avoiding fasting
• Maintaining perineal hygiene to avoid the risk of
urogenital infections
• Temporary discontinuation if the patient has
severe stress
• Discontinuation at least 2–3 days before planned
surgery or consumption of radiocontrast agents
• Avoid use in frail elderly patients, or any such
patient who may not tolerate fluid loss
• If serum creatinine acutely increases by 20%–30% or
more, discontinue treatment with SGLT2-inhibitor
• Avoid use with concomitant nephrotoxic drugs
like NSAIDs or radiocontrast agents
131
TABLE 16-4 CLINICAL CONSIDERATIONS FOR
APPROPRIATE USE OF SGLT2-
INHIBITORS
SGLT2-inhibitors should be avoided in:
• Known hypersensitivity to the medicine
• Chronic kidney disease stage 3b and beyond (eGFR
 45 mL/min/1.73 m2)
• Conditions of severe stress (medical or surgical illness,
severe trauma, fasting, hyperthyroidism or other cata-
bolic states)
• As substitutes for insulin, in patients with insulinopenia
needing replacement
Precaution must be observed in:
• Predisposition to volume depletion (frail older adults,
concomitant use of loop diuretics, predisposition to
dehydration): monitor the pulse and BP
• Avoid use in hypotension and hypovolaemia
• In normotension/normovolaemia, ensure maintenance of
hydration and adjust the dose of concomitant diuretics
• Complicated UTIs: temporarily discontinue SGLT2-inhibitor;
do not use if risk remains high
• History of recurrent UTIs: consider risk of UTI vs. possi-
ble benefit for the patient
• Existing elevation in haematocrit: avoid use, if in range
of high CV risk
• Risk of lower limb amputations (specifically with cana-
gliflozin): avoid canagliflozin in patients with neuropa-
thy, foot ulcer, amputation, peripheral vascular disease
• Risk of bone fractures (specifically with canagliflozin):
consider risk with this agent
CONCLUSION
The noteworthy CV outcomes demonstrated with
SGLT2-inhibitor, represent a novel, promising oppor-
tunity for addressing the huge residual CV risk in
patients of CVD, who have T2DM. The maximum
benefits were seen with empagliflozin, but evidence
suggests CV protection with canagliflozin, as well as
dapagliflozin, albeit with certain differences in CV
and safety outcomes. SGLT2 inhibitors influence the
vascular pathology in multiple ways, pertinent to the
patients of T2DM. We must, however, remember that
EMPA-REG was a high-risk population with majority
being White; the results must be interpreted and used
with caution assessing the need of each patient.
Based on the considerations of appropriate patient
selection, the agents with proven CV benefit should
be considered as a standard of care to optimize CV
protection in patients of CVD who have T2DM.
ACKNOWLEDGEMENT
I thank Dr Jignesh Ved, senior manager, medical af-
fairs, Boehringer Ingelheim, for his scientific sup-
port in the development of this manuscript.
132 SECTION II Preventive Cardiology
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