SGLT2 inhibitors in T2DM

• 1. Which of the Following Related to Genital Mycotic Infections (GMI) with

SGLT2 Inhibitors is True?
• Relative risk is increased by 20-30% compare to placebo.
• They only occur in women.
• SGLT2i should be discontinue when GMI occur.
• Occur equally in those with or without prior history of GMI
• None of above are true.
 • 2. Which of the Following Related to Urinary Tract Infections (UTI) with SGLT2
Inhibitors is True?
1. Large CVOTs do not show increase in UTI
2. Urosepsis has been a common complication
3. SGLT2i should be discontinue when UTI occurs
4. Most UTIS refractory to treatment
5. UTIS occur similar rate in male and female.

The safety data from the large cardiovascular outcome trials did not demonstrate an increase in UTIs in
Type 2 Diabetes patients on SGLT2i versus placebo. In EMPA-REG OUTCOME trial, the rate of UTIs was
18.0% vs 18.1% in placebo while in CANVAS program, the rate was 40 vs 37 (event rate per 1000
patient-year). Meanwhile in DECLARE-TIMI 58, there was also similarly no imbalance whereby the rate
of UTIs was 1.5% vs 1.6% in placebo.
• 3. Which of the Following Volume-Related Adverse Events with SGLT2 Inhibitors
is True?
1. More likely in the elderly and those treated with loops diuretics
2. More likely in the elderly
3. Avoid ACEi or ARB because increase risk of hypotension
4. All of above
5. More likely in those treated with loops diuretics
• Which of the Following Related to Acute Kidney Injury (AKI) with SGLT2
Inhibitors is True?
1. there has been no increased risk of AKI in large CVOTs
2. phase 3 data show a doubling of risk vs placebo for AKI
3. AKI was increase in the group allocated to empagliflozin in the EMPA-REG
OUTCOME trial
4. phase 3 data show a doubling of risk vs placebo and holding SGLT2i during sick
days can likely reduce AKI
5. all of above are true.
SGLT2i(MOA)
 SGLT2i(MOA)

EPO= erythropoietin;
SGLT2= sodium
glucose cotransporter
2;
T2DM=type 2
diabetes mellitus.
SGLT2i(MOA)

• SGLT2 inhibitors reduce the burden on the proximal renal tubules.

• SGLT2 inhibitors reduce central sympathetic overactivity, probably by
suppressing renal afferent signaling to the brain. A mild state of ketosis also
contributes to reduction of sympathetic tone.
• Decreased sympathetic outflow from the brain to the kidney alters the pressure–
natriuresis relationship so that the kidneys excrete more sodium and water at a
given pressure, thereby improving fluid retention.
• It may also suppress the renal renin–angiotensin system (RAS) and augment
circulating natriuretic peptide levels by attenuating renal neprilysin activity ,
thereby correcting the imbalance between the natriuretic peptide/soluble guanylate
cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway and the RAS
pathway, leading to cardiovascular and renal protection.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors
-glifloxin

• Brenzavvy™ (bexaglifloxin)
• Invokana® (canagliflozin)
• Farxiga® (dapagliflozin)
• Jardiance® (empagliflozin)
• Steglatro® (ertugliflozin)
Anti-inflammatory role of
SGLT2 inhibitors as part of
their anti-atherosclerotic
activity:

ox-LDL= oxidized-LDL;
Ils=interleukins;
TNF-α= tumor necrosis factor-α;
CCR2=C-C chemokine receptor
type 2;
NOS 2=nitric oxidase synthase 2;
TGF-β=transforming growth
factor beta;
M-CSF=macrophage colony-
stimulating factor
SGLT2i effects on inflammation in atherosclerosis

SGLT2i inhibit endothelial dysfunction reducing the expression of circulating

inflammatory molecules and LDL-oxidation.
Moreover, SGLT2i attenuate macrophages infiltration, M1 polarization and foam cell
formation.M1 macrophages express the main pro-inflammatory molecules playing role in
maintaining chronic inflammation, forming foam cells, and plaque initiation and
progression
Inversely, M2 macrophages are associated with an anti-inflammatory phenotype producing
anti-inflammatory factors.
The imbalance of these polarized macrophages may be responsible for plaque development
or regression.