14 / 44
148
VOLUME 11 NUMBER 4 • NOVEMBER 2014
REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
SGLT inhibitors increase urinary glucose elimination and reduce
HbA
1c
levels by approximately 0.7–0.8% in type 2 diabetes patients
with an initial baseline HbA
1c
level of 8%.
16
Fig. 2 shows placebo-
corrected change in HbA
1c
levels for members of the SGLT2 inhibitor
class. Importantly, data is not directly comparable because these
were not head-to-head studies and patient characteristics were
variable.
The incidence of hypoglycaemia is comparable to placebo
26,27
The
mechanism for low incidence of hypoglycaemia is unknown but
postulations include activation of counter-regulatory mechanisms
and reduced renal perfusion and associated reduced renal glucose
clearance. However, there is an increase in hypoglycaemic episodes
when combined with agents that commonly cause hypoglycaemia,
specifically insulin and sulphonylureas.
23,28
Mycotic genital infections are increased in patients exposed
to SGLT inhibitors. Causative organisms include
Candida albicans
and
Candida glabrata.
Reported incidence for one member of the
class ranged from 3 to 13% versus 0 to 5% in the placebo group.
29
Genital infections rarely resulted in discontinuation of therapy and
responded to standard topical therapy.
29
In general, urinary tract infections (UTIs) are higher in patients
receiving the SGLT inhibitors.
29
Urinary tract infections with one
SGLT inhibitor ranged between one and 12.9% versus 6.2% in
controls and 9% on metformin monotherapy. Most urinary tract
infections were mild to moderate in intensity, non-recurrent, and
responded to standard management.
29
Risk factors for developing
urinary tract infections in patients treated with SGLT2 inhibitors
included female gender and history of urinary tract infections. It
is advised to avoid this class of drugs in patients with recurrent
urinary and genital infections.
Bladder cancer was diagnosed in nine out of 5 478 (0.16%)
patients treated with a SGLT inhibitor versus one in 3 156 patients
on placebo (0.03%,
p
= 0.15).
20
Of these nine cases of bladder
cancer, five patients initially had haematuria, suggesting that
bladder cancer may have been present at the start of the study.
20
Nine of 2 223 women developed breast cancer in the SGLT
inhibitor-treated group (0.4%) versus one of 1 053 patients on
placebo (0.09%,
p
= 0.27).
20
It was suggested that because of
aggressive screening for UTIs, the identification of haematuria
was higher and subsequent investigations for bladder cancer
were entertained when no microbial cause for the haematuria
was identified.
20,30
Furthermore, breast cancer may have been easy
to diagnose because of the weight loss.
20,30
This explanation is
limited since it is highly debatable that a mean weight loss of 2
to 3 kg would increase the ability of the patient or clinician to
notice a breast mass. The short duration of the studies suggests
that a causal relationship between dapagliflozin and breast cancer
is unlikely. The difference between these cancers and the placebo
was not statistically significant. However, careful monitoring and
long-term studies are required.
There was no clinically significant increase in mean urine
volume when compared to placebo.
31
The increase in mean urine
volume translated to one extra void per day and did not result in
volume depletion.
27
Clinical studies have shown a mean reduction in weight of
approximately 2 to 3 kg.
13
Bolinder
et al
.
32
studied the effects of
dapagliflozin on body weight, total fat mass and regional adipose
tissue distribution, and concluded that the weight loss is largely
due to loss of body fat. One would have expected a greater weight
loss but this did not occur. Study subjects probably compensated
by eating more. Nevertheless, weight loss of 2 to 3 kg in an
overweight/obese patient is significant and at least weight gain is
not a problem, unlike other anti-diabetic drugs.
SGLT inhibitors reduce systolic/diastolic blood pressure by 4–5
/2–3 mmHg.
33
The exact mechanism remains to be determined, but
may be related to the mild diuretic effect, weight loss or effects
on the renin–aldosterone–angiotensin system. Further studies are
required to elucidate the mechanism of blood pressure reduction.
Table 4 provides a summary of this discussion.
Conclusion
SGLT inhibitors are a novel class of oral anti-diabetic drugs with a
mode of action that is independent of beta-cell function and insulin
resistance. Beneficial effects of this class of drugs on measures of
glycaemia, blood pressure and weight will be gauged by its ability
to mitigate long-term complications of type 2 diabetes mellitus,
including adverse cardiovascular events, e.g. myocardial infarction
and cerebrovascular accidents.
Declaration:
Dr P Naidoo and Dr K Ho are employees of Boehringer-
Ingelheim, South Africa
Table 4.
Linking extrapolated effects to actual effects demonstrated in clinical studies
Effect extrapolated from mode of action
Data from clinical studies
Reference
Weight reduction
Mean reduction 2–3 kg
13
Blood pressure reduction
Reduces systolic/diastolic blood pressure by 4–5/2–3 mmHg
33
Urinary tract infections
Lower urinary tract infections increased. Responds to standard therapy. Mild to
moderate severity.
29
Genital tract infections
Mycotic infections increased. Responds to standard therapy. Mild to moderate
severity.
29
Increased urinary volume with volume depletion
Equates to one increased void per day. Does not cause volume depletion
31
Hypoglycaemia
Monotherapy as safe as placebo; hypoglycaemia only increased when concomitant
drugs causing hypoglycaemia added, e.g. sulphonyureas and insulin
21, 27
Bladder cancer*
Not significantly increased when compared to placebo
20, 30
Breast cancer*
Not significantly increased when compared to placebo
20, 30
*Not extrapolated from mode of action but relevant to discussion of SGLT inhibitor class