SGLT 2 inhibitors

1. Sodium-glucose cotransporters 2 inhibiors:
Novel therapeutics for Reno- and
Cardioprotrction in Diabetes Mellitus

2. History
• 1835: “Phlorizin”, a bitter white glycoside isolated
by French chemist from the bark of an apple tree
• 1886: Joseph Vas Mering first described
pharmacological role of SGLT 2 inhibitor causing
glycosuria.
• 1997: phlorizin administered to mice blocked
increase in blood glucose after ingestion of glucose
• 2003: SGLT2i first tested in humans
• 2012: 1st SGLT2i approved for use in humans

3. 2013 2017 2019 2020
EMPAREG
OUTCOME
N =7020
3p - MACE
CANVAS
program
N- 10,142
3-P MACE
CVD REAL
N - 309056
•N=17276
•MACE,CV death, HHF
DECLARE
TIMI 58
•N=4500
•CV death, HHF
DAPA-HF
•N=4464
•ESRD, doubling of sr.
Creat, CV/Renal death
CREDENCE
VERTIS CV
N= 8000
MACE
DAPA-CKD N=4000
>50%
sustained
decline in
eGFR or
reaching
ESRD or CV
death or
renal death
EMPEROR-
Reduced
N=2850
CV death,
HHF
EMPEROR-
PRESERVED
N=4126
CV death or
HHF
SOLOIST
WHF
N=4000
CV death, HF

4. Sodium Glucose Linked Transporter
• In people without diabetes, about 180 g of glucose is
filtered daily by the renal glomeruli, and is then
reabsorbed in the proximal convoluted tubule (PCT).
• This is achieved by passive transporters, namely,
facilitated glucose transporters (GLUTs), and active
cotransporters, namely, sodium-glucose cotransporters
(SGLTs).
• There are six identified SGLTs, of which two (SGLT1 and
SGLT2) are considered most important

5. Comparison of SGLT1 and SGLT2
Characteristic SGLT1 SGLT2
Location Small intestine; later part of PCT
(segment 3)
Early PCT (segment 1,
2)
Capacity Low High
Affinity High Low
Contribution to glucose
reabsorption
10% 90%
Disease state if
mutation/deficiency occurs
Glucose-galactose malabsorption Familial renal
glucosuria
Inhibitors Phlorizin SGLT 2 inhibitors

6. The sodium-glucose cotransporter-2 (SGLT2) mechanism in the
proximal tubule

7. SGLT 2 inhibitors
• Empagliflozin
• Dapagliflozin
• Canagliflozin
• Ertugliflozin
• Sotagliflozin
• Ipragliflozin
• Tofogliflozin

8. MECHANISM OF ACTION
• SGLT2 is a
– low affinity but high capacity sodium-glucose
cotransporter in the proximal tubule of the nephron
– responsible for approximately 90% of urinary glucose
reabsorption.
• Inhibition of SGLT2 results in glucose lowering
through induction of glucosuria.
• This effect is more pronounced in the setting of
hyperglycemia, where significant amounts of
glucose are filtered into the urine.
• Glucosuria diminishes significantly as blood glucose
normalizes.

9. • As shown in figure, with the
increase in plasma glucose
concentration, the reabsorption
of glucose also increases
gradually. When the plasma
glucose level is < 180 mg/dl,
there is no excretion of glucose
in the urine.
• The maximum ability of the
renal tubule to reabsorb
glucose or the transport
maximum for glucose is
exceeded as the plasma glucose
level reaches a threshold of
around 180–250 mg/dl.
• When it passes this threshold,
excretion of glucose in the urine
ensues.

10. • With the reduction in the renal threshold for glucose
excretion, SGLT-2 inhibitors
– prevent the renal reabsorption of glucose and thereby,
increase the UGE and
– improve glycemic control.
• The inhibition of SGLT-2 leads to the hindrance of only
~30%–50% renal reabsorption of the glucose.
• They act independent of insulin secretion and thus are
less likely to be associated with risk of hypoglycemia.
• Based on the agent and dosage used, SGLT-2 inhibitors
reduce glycosylated hemoglobin by 0.5%–1% and
fasting plasma glucose (FPG) by 15–35 mg/dL.

11. • Beyond their effect on blood glucose, SGLT2
inhibitors also cause diuretic and natriuretic
effects, weight loss, and lowering of systolic
blood pressure.
• Moreover, SGLT-2 inhibitors are also associated
with modest reductions in weight (−1.5–−3.5
kg) and systolic blood pressure (SBP) (−3–−5
mm Hg).
• Because their mode of action relies upon
normal renal glomerular-tubular function,
SGLT2i efficacy is reduced in persons with renal
impairment.

12. • In addition, several studies, demonstrated that it
improved β cell function and insulin sensitivity.
• SGLT2 inhibition is associated with increased glucagon
(possibly via direct pancreatic α-cell effects) and
reduced insulin concentrations, thereby promoting the
production of ketones such as β-hydroxybutyrate.
• Ketones are freely taken up by the heart and can act as
an efficient substrate for myocardial energy generation.
• This metabolic substrate shift leads to improved energy
use, potentially contributing to improved cardiac
efficiency, contractility, and cardiovascular protection.

13. • SGLT2 inhibition leads to increase in
hematocrit.
• In conjunction with increases in hematocrit
leading to improved oxygen delivery to the
heart, SGLT2 inhibition may both increase
oxygen supply to the heart and reduce cardiac
oxygen demand, thereby improving cardiac
function.

14. Clinical pharmacology
• DAPAGLIFLOZIN:
– Dapagliflozin is rapidly absorbed after oral
administration, reaching peak plasma
concentration in 2 h
– oral bioavailability of 78%.
– Dapagliflozin is metabolized by uridine
diphosphate glucuronosyl transferase (UGT)1A9 in
both the liver and kidneys
– Should not be initiated in patients with eGFR <60
ml/mt/1.73 m2

15. • CANAGLIFLOZIN:
– Canagliflozin achieve maximal plasma
concentration 1–2 h after oral
– administration and steady state after 4–5 days.
– oral bioavailability 65%
– It is metabolized by glucuronidation by UGT1A9
and UGT2B4
– dosing reductions are required for patients with
eGFR of <60 and >45 mL・min-1・1.73 m–2.
– contraindicated in patients with eGFR of <45 mL
・min–1・1.73 m–2

16. • Empagliflozin
– Empagliflozin reaches peak plasma concentration
1.33–3.0 h after oral administration, before
declining in a biphasic manner.
– The terminal half-life has been calculated to be
10.3–18.8 h in multiple dose studies, with steady
state being achieved by day 6.
– No dosage adjustments are required in renal or
hepatic impairment

17. Effect of SGLT2i on Glycemic Parameters
• In treatment-naïve T2DM patients, SGLT-2
inhibitors including canagliflozin, dapagliflozin
and empagliflozin as monotherapy reduced
HbA1c by 0.6%–1.0% as compared with the
placebo and also associated with the decreased
risk of hypoglycemia ranging from 0% to 3%.
• In addition, considerable improvements in the
FPG levels were also observed.

18. • In patients with T2DM and inadequately
controlled with metformin monotherapy, as
compared with sulfonylurea glipizide,
dapagliflozin demonstrated
– comparable efficacy and
– it was associated with the significant weight loss
of-3.2 kg versus 1.2 kg with glipizide and
– decreased risk of hypoglycemia (3.5%) versus glipizide
(40.8%; P < 0.0001).
» Nauck MA, Del Prato S, Meier JJ, Durán-García S, Rohwedder
K, Elze M, et al. Dapagliflozin versus glipizide as add-on
therapy in patients with type 2 diabetes who have
inadequate glycemic control with metformin: A randomized,
52-week, double-blind, active-controlled noninferiority trial.
Diabetes Care 2011;34:2015-22.

19. • A randomized trial, which assessed the efficacy and safety of
canagliflozin, showed that at 52 weeks,
– canagliflozin 100mg was noninferior and 300 mg was
superior in reducing HbA1c by 0.93% as compared with
glimepiride (0.81%) in patients with T2DM who were
inadequately controlled with metformin.
– The incidence of hypoglycemic risk was significantly
lesser with canagliflozin 100 mg (6%) and 300 mg (5%)
than with glimepiride (34%) with a P < 0·0001 for both
parameters.
» Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, et al. Efficacy and safety of
canagliflozin versus glimepiride in patients with type 2 diabetes inadequately
controlled with metformin (CANTATA-SU): 52 week results from a randomised,
double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50

20. • Both empagliflozin doses of 10 and 25 mg as an
add-on therapy to metformin also significantly
improved of glycemic control ,with adjusted mean
changes from baseline in HbA1c were
• −0.70% with empagliflozin 10 mg,
• −0.77% with empagliflozin 25 mg and
• −0.13% with placebo (both P < 0.001).
• Empagliflozin 10 mg and 25 mg as add-on to basal
insulin for 78 weeks also improved glycemic
control.
» Rosenstock J, Jelaska A, Kim G, Broedl UC, Woerle HJ.
Empagliflozin as add-on to basal insulin for 78 weeks improves
glycemic control with weight loss in insulin-treated (T2DM).
Can J Diabetes 2013;37:S13-84

21. • A 104-week study of empagliflozin versus glimepiride
revealed that,
– Glimepiride was associated with greater short term HbA1c
reduction at 12 weeks,
– But by the end of the trial, there was a significant (0.11%)
advantage in favor of empagliflozin.
– Beyond this small-magnitude difference in HbA1c, in
comparison with the sulfonylurea, there was a substantial
mean 4.5-kg reduction in body weight and a 90% lower risk
of hypoglycemia with the SGLT2 inhibitor.
» Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC;
EMPA-REG H2H-SU trial investigators. Comparison of empagliflozin
and glimepiride as add-on to metformin in patients with type 2
diabetes: a 104-week randomised, active-controlled, double-blind,
phase 3 trial. Lancet Diabetes Endocrinol. 2014;2:691–700. doi:
10.1016/S2213-8587(14)70120-2

22. • A head-to-head trial which evaluated the efficacy and
safety of canagliflozin compared with sitagliptin in
patients with T2DM and uncontrolled with the dual
therapy of metformin and sulfonylurea have
demonstrated that
– canagliflozin 300 mg was superior in reducing the HbA1c
(−1.03%) as compared to sitagliptin 100 mg (−0.66%) at 52
weeks.
– Statistically significant decrease in FPG was also observed
in patients treated canagliflozin as compared to
sitagliptin-treated patients.
– The occurrence of hypoglycemia was comparable between
both the treatment groups.
» Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, et al.
Canagliflozin compared with sitagliptin for patients with type 2 diabetes
who do not have adequate glycemic control with metformin plus
sulfonylurea: A 52-week randomized trial. Diabetes Care
2013;36:2508-15

23. Effect on Body Weight
• Several clinical trials have shown that the use of SGLT-2 inhibitors is
associated with the weight loss ranging from −1.6 to −5 kg versus
placebo.
• Furthermore, the reduction in body weight was maintained over 104
weeks as demonstrated by the clinical trials which evaluated the
long-term efficacy of SGLT-2 inhibitors.
• Numerous studies have shown that the weight loss associated with
the SGLT-2 inhibitors therapy was owing to the reduced fat mass
which accounts for 60%–90% and fluid loss following osmotic
diuresis.
• Although the urinary energy loss caused by SGLT-2 inhibitor is ~200
kcal/day, chronic glycosuria causes an adaptive increase in energy
intake. Therefore, combining SGLT-2 inhibition with dietary restriction
potentially can lead to augmented weight loss.

24. Effect on Blood Pressure
• Consistent systolic ~5 mm Hg and diastolic ˜2 mm Hg
BP-lowering effects of SGLT2 inhibitors have been
reported in patients with T2DM.
• In patients with T2DM, 24-hour ambulatory BP-
monitoring studies have suggested that empagliflozin
successfully reduces systolic BP at night, including in
patients with nocturnal nondipping.
• Furthermore, when 24-h ambulatory BP monitoring
was used, the modest reductions in blood pressure
were not associated with increased heart rate.

25. • Although the exact mechanism by which SGLT-2
inhibitors reduces BP is still not known, it has
been assumed that it is related to their effects on
osmotic diuresis and mild natriuresis.
• Besides these, the local inhibition of the
renin-angiotensin-aldosterone system that occurs
following an increased delivery of sodium to the
juxtaglomerular apparatus is an additional
mechanism by which SGLT-2 inhibitor potentially
induced reduction in BP

26. Interactions with antihypertensive
• No additive BP-lowering effect of combining
the canagliflozin with a thiazide, nor does the
combination produce a greater natriuretic
effect in comparison with either drug alone.
» Devineni D, Vaccaro N, Polidori D, Rusch S, Wajs E. Effects
of hydrochlorothiazide on the pharmacokinetics,
pharmacodynamics, and tolerability of canagliflozin, a
sodium glucose co-transporter 2 inhibitor, in healthy
participants. Clin Ther. 2014;36:698–710.

27. • The addition of a thiazide diuretic to dapagliflozin does
not yield additional antihypertensive effect,
• Whereas ß-blocker and calcium channel blocker
combinations with dapagliflozin did accentuate the
degree of BP lowering.
• Similarly, the addition of dapagliflozin to a background
of a renin angiotensin-aldosterone system (RAAS)
inhibitor in patients with T2DM lowers systolic BP by an
additional 3 to 4 mm.
» Kojima N, Williams JM, Slaughter TN, Kato S, Takahashi T, Miyata N,
Roman RJ. Renoprotective effects of combined SGLT2 and ACE
inhibitor therapy in diabetic Dahl S rats. Physiol Rep. 2015;3.

28. • A second mechanism that may play some part in the
BP-lowering effect observed with SGLT2 inhibitors
relates to
– a reduction in arterial stiffness, demonstrated by pulse
wave velocity and augmentation index in young patients
with uncomplicated T1DM.
• In patients with T2D, markers of arterial stiffness such
as pulse pressure also improve with SGLT2 inhibition in
conjunction with improvements in markers of
myocardial oxygen consumption (ie, rate pressure
product).
» Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE.
Effects of empagliflozin on blood pressure and markers of arterial stiffness and
vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab.
2015;17:1180–1193

29. • In patients with CKD, HbA1c and weight-
lowering effects of SGLT2 inhibition are
consistently attenuated, probably because of
the attenuation of glycosuria in the setting of
CKD.
• In such patients with CKD, the magnitude of
BP lowering is preserved and possibly
augmented.

30. Renal Hemodynamic Function & Albuminuria
• In patients with T2D, eGFR changes are characterized
by acute, dose-dependent reductions of 5 mL·min–
1·1.73 m–2 over several weeks.
• After this initial dip, eGFR subsequently tends to
return toward baseline and remains stable over time.
• In the kidney, SGLT2 inhibition–mediated proximal
tubular natriuresis increases sodium delivery to the
macula densa, which activates tubuloglomerular feed
back, afferent vasoconstriction, and reduces
glomerular pressure.

31. • These intra renal hemodynamic effects may
account for the 30% to 40% reduction in
albuminuria observed with SGLT2 inhibitor
agents.
• Natriuresis mediated by SGLT2 inhibition is
likely a major factor leading to cardiovascular
and renoprotective effects observed with
empagliflozin and canagliflozin, which appears
to extend across CKD stages

32. • In patients with type 2 DM and kidney disease,
the risk of kidney failure and cardiovascular
events was lower in canagliflozin group than in
placebo at median follow up of 2.62 years.

33. CREDENCE trial, 4401 participants

35. Effect on uric acid levels
• Plasma uric acid levels have been associated with
hypertension, cardiovascular disease, and renal
disease.
• The SGLT2 inhibitor class of drugs has been
associated with a 10% to 15% reduction in
plasma uric acid levels as a result of increased
glycosuria, leading to secretion of uric acid in
exchange for glucose reabsorption via the GLUT9
transporter.

37. Cardiovascular effects of SGLT2i

38. Cardiovascular outcome trials
Name Treatment Duration Sample size Published
in
EMPA-REG
OUTCOME
Empagliflozin 10 mg
or 25 mg daily vs
placebo
4.6 y 7020 patients with
established cardiovascular
Complications
2015
CANVAS
Program
Canagliflozin 100 mg
or 300 mg daily vs
placebo
3.6 y 10 142 patients with
established vascular
complications or ≥2
cardiovascular risk Factors
2017
CREDENCE Canagliflozin 100 mg
daily vs placebo
4 y 3627 patients with stage 2 or
3 CKD and macroalbuminuria
and on ACEi/ARB
2019
DECLARE-
TIMI 58
Dapagliflozin 10 mg
vs placebo
6 y 17 276 patients with high risk
for cardiovascular events
2019
VERTIS Ertugliflozin vs
placebo
Upto 6.1
y
8000 patients with
established vascular
Complications
Anticipated
2019

40. The primary 3-point major adverse cardiovascular event end point
(cardiovascular death, nonfatal myocardial infarction,nonfatal stroke)
was reduced by 14%, driven by a 38% reduction in cardiovascular
death, without significant reductions in either nonfatal myocardial
infarction or stroke.

43. • There were no significant differences in the rates of
MI or stroke between two groups. But in the
empagliflozin group, there were
– significantly lower rates of death from CV causes (3.7%, vs.
5.9% in the placebo group; 38% relative risk reduction),
– hospitalization for heart failure (2.7% and 4.1%, respectively; 35%
relative risk reduction), and
– Death from any cause (5.7% and 8.3%, respectively; 32% relative risk
reduction).
• Reduction of cardiovascular mortality and heart
failure hospitalization was observed within 3
months of starting treatment, and was observed in
a wide range of subgroups, including those with
CKD

44. • Mycotic genital infections occurred in 4.5%
more patients on empagliflozin than placebo,
yet <0.6% had to discontinue treatment.
• Rates of serious adverse events leading to
drug discontinuation, acute renal failure,
acute kidney injury were lower in
empagliflozin-treated patients, whereas rates
of DKA, volume depletion, and
thromboembolic events were not increased by
empagliflozin.

45. • In patients with type 2 DM and high CV risk,
empagliflozin, given in addition to standard of
care, reduced heart failure hospitalization or CV
death with consistent benefits observed in both
those with or without heart failure at baseline.
• Empagliflozin reduced the end point of “new
onset or worsening nephropathy” (new-onset
macroalbuminuria, doubling of creatinine, and initiation of renal
replacement therapy, death due to renal disease) and also
reduced the composite of doubling of creatinine
initiation, of renal replacement therapy, and
death due to renal disease.

46. Canagliflozin in CANVAS Program
• The CANVAS program integrated data from 2
trials (CANVAS and CANVAS-R [Canagliflozin
Cardiovascular Assessment Study-Renal])
involving a total of 10,142 participants with
T2DM and high CV risk.
• Participants were randomly assigned to
receive canagliflozin (100–300 mg) or placebo
and were followed for a mean of 3.6 years.

47. • The combined analysis of the 2 CANVAS trials
demonstrated a 14% relative reduction in the
primary endpoint of triple MACE (a composite
of nonfatal MI, nonfatal stroke, and CV death).

49. • From a renal perspective, the progression of
albuminuria was reduced by 27%, and the
composite outcome (sustained 40% reduction
in eGFR, the need for renal-replacement
therapy, or death from renal causes) was
reduced by 40%.

56. Conclusion

57. International Observational Studies of CV
Benefits of SGLT2 Inhibitors

58. Randomized controlled clinical trials in
patients with HF
Name Treatment Duration Sample size Published in
DEFINE-HF Dapagliflozin
10 mg daily vs
placebo
12 weeks 250 patients
with HF
(≥19 y)
2019
PRESERVED HF Dapagliflozin
10 mg daily vs
placebo
12 weeks 320 patients
with HF
(≥19 y)
Ongoing
DAPA-HF Dapagliflozin
10 mg daily vs
placebo
36 months 4500 patients
with HFrEF
(≥18 y)
2019
EMPEROR-
Preserved
Empagliflozin
10 mg daily
vs placebo
38 months 4126 patients
with
HFpEF (≥18 y)
Ongoing
EMPEROR-
Reduced
Empagliflozin
10 mg daily vs
placebo
38 months 2850 patients
with
HFrEF (≥18 y)
Ongoing

64. SUMMARY of DAPA-HF trial
• Dapagliflozin reduced the risk of worsening heart
failure events and cardiovascular death and improved
symptoms, in patients with HFrEF, when added to
standard therapy.
• The relative and absolute risk reductions in death and
hospitalization were substantial, clinically important
and consistent across important subgroups, including
patients without T2DM.
• Dapagliflozin was well tolerated and rate of treatment
discontinuation was low.
• Dapagliflozin offers a new approach to the treatment
of HFrEF.

66. IMPACT OF SGLT2 INHIBITION ON
CARDIAC STRUCTURE AND FUNCTION

67. • Results of this trial indicate that empagliflozin
results in beneficial effects on LV remodelling at 6
months among patients with T2DM and stable
CAD but normal EF and without clear history of
HF.

68. Potential Mechanisms by Which SGLT2
Inhibition Decreases CV Events

69. SGLT2 INHIBITION AND POTENTIAL
SIDE EFFECTS
• Although SGLT2 inhibition has emerged as a promising
new cardiorenal protective therapy, it is important to
recognize the potential adverse effects related to drugs in
this class.
• The most commonly reported side effect attributable to
glycosuria is genitourinary infections, mostly genital
mycotic infections, but in some studies bacterial urinary
tract infections as well.
• These infections are not usually serious, tend to resolve
with a brief course of antifungal agents, and rarely recur.

70. • Less common but perhaps more important in the HF
population in the context of concomitant diuretic use is
the potential for volume depletion.
• Whether this hemodynamic effect will prove a serious
risk for ill and elderly patients with comorbid medical
conditions is unclear.
• Although the EMPA-REG OUTCOME trial did not report
a specific approach to adjusting baseline diuretic
agents, it is reasonable to be cautious when combining
SGLT2 inhibitors with other diuretics, especially in
patients with severe systolic dysfunction.

71. • Although acute kidney injury has been reported with SGLT2
inhibition, rates of acute kidney injury were less common in
empagliflozin versus placebo-treated patients in the
EMPAREG OUTCOME trial, and similar trends were
observed in the CANVAS Program.
• This is reassuring, because 80% of patients in EMPA-REG
OUTCOME were taking concomitant RAAS inhibitors, which
also decrease intraglomerular pressure.
• From a safety point of view, SGLT2 inhibitors
– should be part of sick-day T2DM management strategies,
and
– may need to be held in the context of nonsteroidal anti-
inflammatory drug use or radiocontrast administration
because of the potential for volume depletion and
hemodynamic side effects.

72. • There is also an increased risk of diabetic ketoacidosis
with SGLT2 inhibitors in the absence of significant
hyperglycemia, often called “euglycemic diabetic
ketoacidosis,” although moderate hyperglycemia is
common.
• This risk has been shown to be very low in the large
randomized controlled trials of patients with T2DM,
particularly in those not requiring insulin therapy.
• Patients with signs or symptoms of ketoacidosis, such
as dyspnea, nausea, vomiting, and abdominal pain,
should be instructed to discontinue SGLT2 inhibitors
and seek immediate medical attention.

73. • In the CANVAS Program, patients treated with
canagliflozin had a significantly higher risk of
lower extremity amputations in comparison
with the placebo group.
• The increased risk of lower extremity
amputations observed in CANVAS with
canagliflozin has not been reported with
dapagliflozin, empagliflozin, or other SGLT2
inhibitors.

74. • The CANVAS Program also reported an increased risk for bone
fracture, an observation not yet reported with other agents in
this drug class.
• Mechanistically, SGLT2 inhibition may exert adverse effects on
bone physiology through increased concentrations of
parathyroid hormone and fibroblast growth factor-23.
• The impact on bone fracture risk does not appear to exist
across this drug class, because a recent meta-analysis by Tang
et al failed to broadly demonstrate bone fracture risk with
SGLT2 inhibitor use.
• Nevertheless, these agents should be used with caution in frail
individuals who are at risk of falling, including those with
hypotension.

75. SGLT2i conclusions
• Decreased risk of MACE
– Primarily CV death and HF
– Appears to be confined to patients with
established ASCVD
• Decreased risk of hospitalization for heart
failure
– Seen in both patients with or without h/o HF
• Decreased risk of progression of Kidney
disease

77. Considerations for Drug Initiation and Monitoring
in Patients Starting on SGLT2 Inhibitor
• If HbA1C well-controlled at baseline, or known history of
frequent hypoglycemic events, reduce dose of
sulfonylurea by 50% or basal insulin dose by 20% when
starting therapy.
• Avoid hypovolemia. May need to reduce thiazide or loop
diuretic dose.
• Educate patients regarding symptoms of low blood
pressure (light headedness, orthostasis, weakness)
• Instruct patients to more closely monitor glucose at home
for the first 4 weeks of therapy

78. Considerations for Drug Initiation and Monitoring
in Patients Starting on SGLT2 Inhibitor
• Educate patients regarding symptoms of diabetic
ketoacidosis (nausea, vomiting, weakness) and that
diabetic ketoacidosis can occur even if blood glucose
readings are in the 150–250 mg/dL range. If patient
experiences diabetic ketoacidosis-like symptoms, he or she
should be instructed to seek medical attention.
• Educate patients regarding foot care and follow-up foot
pulse examination (particularly canagliflozin)
• Monitor kidney function
• Educate patients regarding potential for genital mycotic
infections

80. Cardiovascular risk categories in patients
with diabetes

82. Recommendations for glucose-lowering
treatment for patients with diabetes