The SA Journal Diabetes & Vascular Disease Vol 15 No 2 (November 2018)

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72 VOLUME 15 NUMBER 2 • NOVEMBER 2018
REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE
as described above is the primary mechanism for renal protection,
with reduction in BP having a lesser role.
The CANVAS programme using canagliflozin compared to
placebo reported similar reductions in CV and kidney events.22
More recently a dedicated trial (CREDENCE) using canagliflozin
vs placebo in patients with DKD was stopped prematurely due to
the superior effects of canagliflozin on kidney end-points (https://
). This study is not published and further details
are awaited. Outcomes studies with dapagliflozin have not been
reported to date.
Although the place of SGLT-2 inhibitors in the treatment of type
2 diabetes is not formally established, they should undoubtedly
be used in overweight patients with established CV or at high risk
of CV disease based on the EMPA-REG OUTCOME study and the
CANVAS programme, provided there are no contra-indications,
and taking into account the side-effect profile of the SGLT-2
inhibitors.
In addition, they should be considered in patients with signs of
CKD (albuminuria and/or reduced eGFR but not below 30 ml/min),
although this not a registered indication in South Africa. There is
also no reason, except for immediate drug costs, why these drugs
should not also be considered as second line after metformin in
the diabetic algorithm of care; they can also be combined with
most other antidiabetic medications, including insulin.
The future of these drugs looks very exciting as further CV
and kidney outcome studies are nearing completion. Additionally,
studies are being extended to CV and kidney protection in
non-diabetic subjects. In patients with CKD, there is increased
single-nephron GFR due to increased glomerular pressure and
hyperfiltration to compensate for loss of GFR, which in the long
term is deleterious to the kidney. SGLT-2 inhibitors may indeed
benefit patients with non-diabetic CKD by reducing glomerular
pressure and hyperfiltration.
Cautions and side effects of SGLT-2 inhibitors
The prescriber should refer to the full package insert before
selecting a SGLT-2 inhibitor for treatment of type 2 diabetes, but
there are a few important contra-indications and cautions to be
considered.23 Firstly it should not be given to type 1 diabetics due to
risk of ‘normoglycaemic’ ketoacidosis and used with caution in thin
type 2 diabetics as they may potentially be mislabelled and have
type 1 diabetes. Normoglycaemic ketoacidosis can occur very rarely
in type 2 diabetics, usually during periods of prolonged fasting.
The SGLT-2 inhibitor should be stopped in these circumstances or
carefully monitored. They should also be avoided in patient > 75
years, where risks of dehydration may outweigh benefits.
The most common side effect is genital candidiasis due to
glycosuria, and is mainly seen in females. This is easily treated
with local antifungal creams and seldom recurs. There may be
a slight increase in urinary tract infection, but this is seldom
severe.
Initial reports suggested a possible increase in fracture risk
with SGLT-2 inhibitors, but this was not borne out by a recent
meta-analysis.24 Initial reports suggested an association between
bladder cancer and dapagliflozin, but further analysis suggested
these cases were pre-existing.25 Canagliflozin was linked to
increased risk of amputation in the CANVAS programme,22 and
further study is required to establish if this is a causal link.
Conclusions
The publication of the EMPA-REG OUTCOME study in 2015 was a
major milestone in development of safer and more effective drugs
for type 2 diabetes. It broke the nihilism expressed by many in
relation to prevention of CV disease in type 2 diabetics. For the
first time in decades an antidiabetic drug was found to safely lower
blood glucose and show unequivocal evidence for prevention
of CV and renal disease that can be explained by the underlying
mechanism of action. It is important that a pharmaco-economic
analysis be undertaken with regard to these drugs, especially in
relation to prevention and the prohibitive costs of treatment of
end-stage CKD.
Acknowledgement
This report was made possible by an unrestricted educational
grant from Boehringer Ingelheim. The content of the report is
independent of the sponsor.
References
1. Palatini P. Glomerular hyperfiltration: a marker of early renal damage in pre-
diabetes and pre-hypertension. Nephrology, Dialysis, Transplantation 2012; 27(5):
1708–1714.
2. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and
progression of nephropathy in type 2 diabetes: the United Kingdom Prospective
Diabetes Study (UKPDS 64). Kidney International 2003; 63(1): 225–232.
3. Ritz E, Schmieder RE, Pollock CA. Renal protection in diabetes: lessons from
ONTARGET. Cardiovascular Diabetology 2010; 9: 60.
4. Wen CP, Chang CH, Tsai MK, Lee JH, Lu PJ, Tsai SP, et al. Diabetes with early
kidney involvement may shorten life expectancy by 16 years. Kidney Int 2017;
92(2): 388–396.
5. South African Renal Registry. Annual Report, 2015.
DYNA INDAPAMIDE SR. Each tablet contains 1,5 mg indapamide. S3 A42/7.1/0790. NAM NS2 12/7.1/0138.
For full prescribing information, refer to the professional information approved by SAHPRA, 25 November
2011. 1) Weidmann P. Metabolic profile of indapamide sustained-release in patients with hypertension.
Drug Safety 2001;24(15):1155-1165. 2) Database of Medicine Prices (11 April 2018). Department of Health
website. - Accessed on 11 April 2018. DINF477/06/2018.
only generic 1,5 mg
sustained release
formulation
R37,162
CUSTOMER CARE LINE 0860 PHARMA (742 762) / +27 21 707 7000