Article Type : Case Report
Authors : Mikhail N
Keywords : Sodium-glucose cotransporters type 2 inhibitors; Calcium; Hypercalcemia; Parathyroid hormone; Diabetes
Background:
Few data suggest that the use of sodium-glucose cotransporter’s type 2
inhibitors (SGLT2is) might be associated with hypercalcemia.
Objective:
To review investigations of calcium status in subjects using SGLT2is.
Methods:
Pubmed search until November 10, 2022. Search terms included SGLT2is, calcium,
hypercalcemia, adverse effects. Pertinent case reports, clinical trials,
reviews and meta-analyses were included.
Results:
Seven case reports described hypercalcemia (serum calcium 10.6-17.4 mg/dl)
among patients using 3 SGLT2is (canagliflozin n=3), dapagliflozin (n=2), and
empagliflozin (n=2). The highest calcium level recorded of 17.4 mg/dl was
likely due to calcium toxicity in a man who was taking 1600-4000 mg of calcium
carbonate daily. In 5 of the 6 remaining cases, there were other factors
causing hypercalcemia, namely intake of hydrochlorothiazide (2 patients),
undiagnosed primary hyperparathyroidism (2 patients) and possible familial
hypocalciuric hypercalcemia (1 patient). Four investigations designed to
examine electrolyte abnormalities in patients using SGLT2is did not found any
significant changes in serum calcium levels after 5 days to 3 months of
follow-up. Large clinical trials of
SGLT2is including thousands of patients with different pathologies did not
report hypercalcemia as adverse effect of SGLT2is. One meta-analysis showed
that SGLT2is might be associated with minimal increase in mean serum calcium
levels of 0.04 mg/dl.
Conclusions:
The balance of evidence suggests that use of SGLT2is does not cause clinically
meaningful hypercalcemia. Therefore, for users of SGLT2is, monitoring of serum
calcium values more frequently than in standard care is not indicated. Yet,
close follow-up of circulating calcium levels may be required among SGLT2is
users having other risk factors for hypercalcemia such as thiazide use or
untreated primary hyperparathyroidism.
SGLT2is are widely
used drugs for multiple indications: treatment of type 2 diabetes, heart
failure and chronic kidney disease (CKD) due to their favorable impact on
cardiorenal outcomes and mortality [1-5]. Several studies have shown that use
of SGLT2is was associated with mild increase in serum magnesium and phosphates
[6]. Meanwhile, few data are available regarding the effects of SGLT2is on
calcium homeostasis. The first reported case of hypercalcemia related to SGLT2i
was published in 2015 by Kaur and Winters [7]. They described a patient with
high oral calcium intake, severe volume depletion, and diabetic
ketoacidosis. Since then, few case
reports described patients with mild hypercalcemia possibly related to different
SGLT2is [8-11]. However, elevation in serum calcium concentrations is not
listed among adverse effects of SGLT2is approved by the Federal Drug
Administration (FDA) [12-15].The purpose of this review is to clarify the
effects of SGLT2is on serum calcium concentrations based on case reports, short-term
mechanistic studies, and large clinical trials.
Review of literature revealed 7 patients (49 to 75-year-old, 3 women) presenting with hypercalcemia in relation to intake of SGLT2is, 3 cases with canagliflozin, 2 with empagliflozin and 2 with dapagliflozin (Table 1).
Table
1: Case
reports of hypercalcemia related to use of SGLT2is.
|
Reference |
Patient |
SGLT2i |
Serum calcium (albumin-corrected) |
PTH (pg/ml) |
urine calcium (mg/24 h) |
Contributing factors |
|
1.Kaur and Winters [7] |
60-year-old man |
Canagliflozin, dose NR |
17.4 mg/dl (8.9-10.3) |
11 (12-88) |
NR |
Calcium toxicity 8-10
*tums tablets/day |
|
2.Marques Vidas et al [8] |
63-year-old woman |
Dapagliflozin 5 mg q12h |
11.0 mg/d dropped to 10.4
mg/dl after stopping hydrochlorothiazide |
40 |
NR |
Hydrochlorothiazide 12.5
mg/d |
|
3.Akhanli et al, [9] |
49-year-old man |
Dapagliflozin 10 mg/d for
6 months |
11.28 mg/dl (8.8-10.6) |
70.8 (15-65) |
492 (100-300) |
Underlying
hyperparathyroidism |
|
4.El Masri et al [10]
Lebanon |
66- year-old woman |
Canagliflozin 300 mg/d |
12.2 mg/dl (N 8.3-10.2) |
79.6 pg/ml |
56 mg (100-300) |
Possible familial
hypocalciuric hypercalcemia |
|
5.El Masri et al [10] |
75-year-old man |
Canagliflozin 300 mg/d |
10.8 mg/dl |
57 pg/ml |
NR |
Hydrochlorothiazide 12.5
mg/d |
|
6.El Masri et al [10] |
64-year-old woman |
Empagliflozin 25 mg/d |
10.6 mg/dl (8.3-10.4) |
82 |
205 mg |
None |
|
7.Awada et al [11] |
57-year old man |
Empagliflozin for 2 years |
10.9 (8.8-10.6) |
21 (9-39), repeat PTH 13.8
(15-76) |
415 (100-300) done 4 weeks
after stopping empagliflozin |
Underlying primary
hyperparathyroidism |
|
Number between brackets
represent the normal reference range In many patients, reference
range was not reported. *Each tums tablet contains
200-400 mg of calcium carbonate. Abbreviations: SGLT2is:
sodium-glucose co-transporter 2 inhibitors, PTH: parathyroid hormone, NR: not
reported |
||||||
Serum calcium on presentation ranged from 10.6 to 17.4 mg/dl. Circulating
calcium values before starting SGLT2is were not reported except in one case [8].
In 6 of the 7 cases, there were other factors causing hypercalcemia. The most
obvious example was the first reported patient by Kaur and Winters who
presented with hypercalcemic emergency (serum Ca 17.4 mg/dl (normal reference
8.9-10.3 mg/dl) and diabetic ketoacidosis (DKA). This 60-year-old man was
taking large amounts of calcium carbonate in the form of 8-10 tums tablets
daily for 1 week for treatment of heart burn. Since each tablet of tums
contains 200-400 mg of calcium carbonate, his daily intake ranged from 1600 to
4000 mg of calcium carbonate daily, i.e. his hypercalcemia was largely
attributed to calcium toxicity. In addition, severe dehydration as result of
DKA exacerbated hypercalcemia. Thus, the contribution of canagliflozin in
inducing hypercalcemia in this case is minimal if any. Two other patients had
underlying primary hyperparathyroidism, 2 patients were taking hydrochlorothiazide,
and 1 patient had possible undiagnosed familial hypocalciuric hypercalcemia
(Table 1). Another observation arguing against a major role of SGLT2is in
causing hypercalcemia was the fact that in 2 patients, the SGLT2i was not
discontinued without recurrence of hypercalcemia . Thus, in general, the
evidence derived from the above case reports is considered weak and does not
support a direct causative role of SGLT2is in the development of hypercalcemia.
To the best of the author’s knowledge, there are 4 clinical studies that examined electrolyte status, including calcium, and pertinent hormones in subjects starting 3 different SGLT2is (Table 2). As depicted in table 2, these studies had different designs, follow-up durations, and included healthy subjects as well as patients with type 2 diabetes with and without various degrees of kidney function.
Table
2:
Mechanistic studies to examine serum calcium and pertinent markers in subjects
using SGLT-2is.
|
|
Blau
et al [16] |
Rau
et al [17] |
de
Jong et al [18] |
Masajtis-Zagajewska et al [19] |
|
Design |
Randomized,
placebo-controlled, single-blind, crossover in hospital |
Randomized,
double-blind, placebo-controlled |
Post-hoc
analysis of a randomized double-blind, cross-over trial |
Prospective,
uncontrolled |
|
SGLT2i |
Canagliflozin
300 mg/d |
Empagliflozin
10 mg/d |
Dapagliflozin
10 mg/d |
Empagliflozin
10 mg/d |
|
Subjects |
25 healthy
volunteers, age 38, 36% women |
42 patients
with type 2 diabetes, age 62, 19% women |
31 patients
with type 2 diabetes, age 62, 22% women, with early CKD (eGFR 72 ml/min/1.73
m2) |
42 patients
with CKD (eGFR 38.6 m/min/1.73 m2), age 56, 40% women |
|
Follow-up |
5 days, with
?1week wash-out |
At day 3, and
at 3 months |
6 weeks and 6
weeks wash-out |
7 days |
|
Serum Ca |
No change |
No change |
No change |
No change |
|
Urine Ca |
Decreased vs
placebo at day 4 |
No change |
NR |
No change |
|
Serum P |
16% increase
vs placebo |
Transient
increase vs baseline by 11% at day 3 |
Increase 11%
vs baseline |
Increased in
subgroup of patients with diabetes |
|
PTH |
25% increase
vs placebo |
Transient
increase by 22% vs baseline at day 3 |
Increase 15%
vs baseline |
No change |
|
FGF-23 |
20% increase
vs placebo |
Transient
increase vs baseline by 40% at day 3 |
Increase 20%
vs baseline |
Increased in subgroup
of patients with diabetes |
|
1,25 di-OH
vitamin D |
9.4% decrease
vs placebo |
Transient
decrease vs baseline by 37% at day 3 |
Decrease 19%
vs baseline |
No change |
|
Age is
expressed as means in years Abbreviations:
SGLT2is: sodium-glucose co-transporter 2 inhibitors, Ca: calcium, P:
phosphorus or phosphate, F; females, CKD: chronic kidney disease, eGFR:
estimated glomerular filtration rate |
||||
Despite these differences, the 4 studies did not demonstrate any
significant changes in serum calcium levels. It is noteworthy that in one study
of healthy subjects,found significant decrease in urinary calcium excretion on
day 4 of canagliflozin therapy versus placebo (1.44 versus 1.66
mmol/creatinine, P = 0.04). Yet, in 2 other studies, urinary calcium excretion
was unchanged at day 3, day 7 and 3 months after treatment with empagliflozin
10 mg/d [16-19]. Parathyroid hormone (PTH) and 1,25 di-hydroxy Vitamin D are
the 2 main regulators of circulating calcium levels that may lead to
hypercalcemia if their levels are increased [20]. Interestingly, 3 of the 4
studies recorded an increase in PTH concentrations by 15-25% and a decline by
9-37% in 1,25 di-hydroxy vitamin D few days after starting SGLT2is The increase
in PTH did not result in hypercalcemia presumably due to the concomitant
decrease in 1,25 di-hydroxy vitamin D levels. The most consistent finding in
the 4 studies was the increase in serum fibroblast growth factor-23 (FGF-23),
the main regulator of serum phosphorus [21]. This increase in FGF-23 is likely
a compensatory response to the rise in serum phosphorus.
Randomized trials of
several years of follow-up and including thousands of patients with or without
type 2 diabetes, heart failure, and CKD did not show any evidence of
hypercalcemia among adverse effects of various SGLT2is [1-5]. Recently, Zhang
et al [6] conducted a meta-analysis of 19 clinical trials that reported calcium
data in patients with type 2 diabetes using SGLT2is. Overall, they found that SGLT2is were
associated with significant elevation of serum calcium levels by 0.04 mg/dl
(0.01 mmol/L) [95% CI 0.0 to 0.04 mg/dl (0.0-0.01 mmol/L)]. However, this
minimal increase although statistically significant is unlikely to be
clinically meaningful.
Available data derived from mechanistic studies and
large clinical trials do not support the concept that SGLT2is cause hypercalcemia.
Despite the widespread use of SGLT2is, only 7 cases of hypercalcemia were
reported. In the majority of cases, baseline calcium levels were not reported,
and patients proved to have other causes of hypercalcemia. Accordingly, in
patients starting SGLT2is, monitoring of serum calcium levels more frequently
than in routine practice is not required. However, until further data become
available, it may be wise to get a baseline serum calcium value before starting
SGLT2i to rule out underlying primary hyperparathyroidism or other calcium
disorders. In addition, more frequent monitoring of serum calcium
concentrations (e.g. every 3-4 months) is recommended in SGLT2is users taking
thiazides and those with known untreated primary hyperparathyroidism.
The author has no conflict of interest to declare.