Background. After their introduction to clinical use, several reports related the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors to certain cancer. In this review, we will discuss whether the use SGLT2 inhibitors can increase cancer or, surprisingly, reduce the risk of certain cancers. We will also discuss the proposed mechanisms of inducing or inhibiting cancer by SGLT2 inhibitors with special attention to immunity as a point that needs further consideration. Summary. While some SLGT2 inhibitors might induce cancer in human, others might protect against cancer. Animal results showed some contradiction. None of the clinical studies considered the effect of SLGT2 inhibitors on immunity during assessment of the relationship between SLGT2 inhibitors and cancer. Key messages. It seems that the relationship between SLGT2 inhibitors and cancer is not a class. Further studies should focus whether the interaction between SLGT2 inhibitors and immune system could affect cancer growth.
The risk of cancer is elevated in patients with type 2 diabetes . Although the actual mechanisms are yet to be revealed, many factors related to diabetes may play a role in increasing the risk of cancer. Obesity that usually associates type 2 diabetes mellitus is an example . Some anti-diabetic medications by themselves can increase the risk of certain cancers. One example is pioglitazone which was linked to bladder cancer . Another example is sodium–glucose cotransporter 2 (SGLT2) inhibitors .
In the kidney, the filtered glucose is reabsorbed again in the proximal tubules via SGLT1 and SGLT2 . SGLT2 accounts for 90% of the glucose reabsorbed from the kidneys while SGLT1 accounts for only 10% [6,7]. SGLT2 inhibitors are a new class of anti-diabetic drugs that reduce plasma glucose levels by inhibiting SGLT2 in the renal tubules. Recently, these drugs are gaining popularity because they can also reduce blood pressure and body weight . Common examples of SGLT2 inhibitors include dapagliflozin, canagliflozin, and empagliflozin. In this review, we will focus on the relation between SGLT2 inhibitors and cancer.
The first report that linked the use of SGLT2 inhibitors to induction of cancer was in 2011 . It was reported that dapagliflozin was associated with higher incidents of male bladder cancer and female breast cancer in comparison to control diabetic patients of the same age. For either cancer types, 9 cases were reported in comparison to one case in the control arm . The 9 cases of bladder cancer were reported on dapagliflozin out of 5,478 patients while the only reported case in the control arm was out of 3,156 patients . However, these results were not replicated in animals. An experimental study that exposed mice and rat to a high dose (100-fold human dose) of dapagliflozin for up to 2 years found no increase tumor incidence or urinary bladder preneoplastic lesions . On the contrary to dapagliflozin, canagliflozin did not increase the overall incidence of bladder, breast and renal cancers in a pooled analysis of eight clinical trials . However, experimental settings gave variable results. Long-term exposure to canagliflozin at doses up to 14-fold human dose did not increase the incidence of neoplasms or preneoplastic lesions in mice . Clinical trials on empagliflozin reported an increase in the risk of bladder cancer . Away from individual SGLT2 inhibitors, a study on SGLT2 knockout mice compared with wild-type mice did not find increased hyperplasia or neoplasia in the urinary bladder mucosa, urogenital tract or kidney although mice had significant glucosuria .
Focusing on the clinical aspect, several studies and clinical trials since 2011 have been conducted to clarify whether SGLT2 inhibitors are associated with increase cancer risk [10,13]. One meta-analysis suggested that lack of proper diagnosis prior to
randomization might explain the increased risk of cancers rather
than a causal relationship . Another recent meta-analysis
reported 580 incidences of cancer among 34,569 people with
type 2 diabetes. The study found that, SGLT2 inhibitors were not
significantly associated with an increased risk of overall cancer.
However, they found that SGLT2 inhibitors might increase the
cancer risk in obese participants (BMI ≥30 kg/ m2) while age
and sex were irrelevant. In addition, SGLT2 inhibitors, especially
empagliflozin, was found to increase the risk of bladder cancer
. Most incidences of bladder cancer were identified from
one trial.12 Interestingly, the originally accused SGT2 inhibitor,
dapagliflozin, in addition to canagliflozin did not significantly
increased risk of bladder cancer. Moreover, canagliflozin might
be associated with reduction of gastrointestinal cancers .
The study did not detect any increase in breast cancer risk with
the use of SGLT2 inhibitors. Nevertheless, the authors warned
that the results of their meta-analysis are not conclusive since
the duration of most of the clinical trials was not long enough.
The low number of incidences was another point to consider
before reaching final conclusion .
The mechanisms underlying the probable elevated risk of
bladder cancer associated with SGLT2 inhibitors remain unclear.
It was suggested that diabetes and obesity are, by themselves,
risk factors for bladder cancer [1,2]. The inflammatory
cytokines, inflammation and generation of free oxygen species
by hypertrophied adipose tissue can enhance cancer cells
proliferation . Another proposed mechanism is inhibition
of SGLT2 function with or without the resultant glucosuria or
urinary tract infections . However, it was found that SGLT2
knockout mice did not show any increase in hyperplasia or
neoplasia in the urinary bladder mucosa, urogenital tract or
kidney over the 15 months of observation although glucosuria
was significant.9 This indicates that neither glucosuria nor
loss of SGLT2 function could explain the increased cancer risk.
Using glucose-free diet in another study, it was concluded that
malabsorption of glucose could be accused as a mechanism
to explain the ability of canagliflozin to induce tumors in rats
[16,17]. The authors suggested that such mechanism do not take
place in human. Nevertheless, it seems that the relation between
some SGLT2 inhibitors and cancer is not “class effect”. Individual
drugs might act indirectly to affect cancer development in
In the meta-analysis conducted by Tang et al. . they
reported that canagliflozin might be associated with reduction
of gastrointestinal cancers. In one experimental study using
mouse model of human non-alcoholic steatohepatitis, it was
found that canagliflozin attenuated hepatic steatosis and
significantly reduced the number of liver tumors after one
year of treatment.17 Similarly, canagliflozin inhibited cellular
proliferation and survival of lung and prostate cancer cells. It also enhanced the ability of chemotherapy and ionizing radiation
to inhibit clonogenic survival .
The mechanisms by which canagliflozin can inhibit
cancer cell growth remain unclear. In the study conducted
by Villani . authors found that canagliflozin, but not
dapagliflozin, successfully inhibited cancer cell growth because
only canagliflozin was capable of inhibiting mitochondrial
respiration. By inhibiting complex-I supported respiration,
canagliflozin inhibited mitochondrial respiration, which is
critical for antiproliferative actions. In a different way, Shiba .
suggested that canagliflozin reduced the number of liver tumors
by attenuating the development of nonalcoholic steatohepatitis,
reducing oxidative stress and expanding healthy adipose tissue.
Another proposed mechanism explaining the cancersuppressing
effect of canagliflozin depends on its affinity to
glucose transporter GLUT1. Canagliflozin can effectively inhibit
GLUT1 . GLUT1 is expressed in prostate cancer cells . It
would be expected that, by inhibiting GLUT1, depriving cancer
cells from glucose can play a crucial role in cancer cell survival.
However, inhibition of glucose uptake in prostate cancer cells
was found to be insufficient for inhibition of cellular proliferation
. In a different way, the cancer-suppressing effect of
canagliflozin could be attributed to its affinity to both SGLT1 and
SGLT2. In comparison to dapagliflozin, canagliflozin has a higher
affinity for inhibiting SGLT1 . SGLT1 is mainly expressed in
the gastrointestinal tract and SGLT2 is highly expressed in the
kidneys and, to a lesser extent, in the gastrointestinal tract .
In humans, SGLT1 is overexpressed in many cancers [24,25].
Inhibition of SGLT1 sensitizes prostate cancer cells to treatment
with EGFR (epidermal growth factor receptor) tyrosine kinase
inhibitor . However, such theory needs validation.
The ability of SGLT2 inhibitors to interact with the different
components of the immune system and, hence, affect cancer
development is a possibility yet to be discovered. Unfortunately,
most of the conducted clinical trials did not consider the effect
of SGLT2 inhibitors on immunity. Most of the data comes from
animal models and suggested a significant anti‐inflammatory
effect of SGLT2 inhibitors [26-28]. However, most of these
studies did not explain whether the anti-inflammatory effects
are the result of the specific activity of SGLT2 inhibitors or just
a secondary effect to correction of hyperglycemia. Immune
cells rely on glucose consumption in order to sustain their
pro‐inflammatory program . In non-diabetic models,
empagliflozin and dapagliflozin still exhibit anti-inflammatory
effects under normal blood glucose level [30,31]. It might be
possible that SGLT2 inhibitors inhibit inflammation by both
glycemia‐dependent and glycemia‐independent mechanisms.
SGLT2 inhibitors may indirectly exert their anti-inflammatory
effect via affecting oxidative balance, hemodynamics, the
renin–angiotensin system (RAS) activation and obesity‐related
inflammation; as reviewed by Yaribeygi . Whether this antiinflammatory
effect of SGLT2 inhibitors could induce, prevent
or repress cancer is yet to be determined. Initially, it could be
expected that inhibiting inflammation might indicate negative
affection on immunological response to cancer cells. However,
SGLT2 inhibitors reduce inflammation and oxidative stress in
adipose tissue . Hypertrophy of adipose tissue increases
M1 macrophages. These cells secrete inflammatory cytokines,
enhance low-grade inflammation and generate free oxygen
species, therefore, lead to genetic instability and cancer cells
proliferation.15 By reducing inflammation and oxidative stress
and enabling “healthy adipose tissue”, SGLT2 inhibitors may
have a potential to reduce cancer risk [17,33]. On the other
side, Xu . found that canagliflozin exerts anti-inflammatory
effects by promoting autophagy in immune cells. Further studies
are required to specifically determine what kind of immune cells
are affected by canagliflozin. Thus, we could expect the overall
effect of this drug on cancer growth. For example, autophagy in
myeloid-derived suppressor cells has been linked to suppression
of antitumor immunity . Promoting autophagy in such cells
is expected to enhance tumor growth.
Further studies are required to confirm whether SLGT2
inhibitors can affect tumor growth in human. Focusing on the
interaction between SLGT2 inhibitors and immune system might
clarify the current conflict. Nevertheless, it seems that, whether
induction or inhibition of cancer, SLGT2 inhibitors effects won’t
be a class effect and each drug in the class should be evaluated
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De Jonghe S, Johnson MD, Mamidi RNVS, Vinken P, Feyen B, et al. (2017) Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study. Chem Biol Inter 277: 85-90.