Evidence-based, in-depth understanding - 5 hot issues around SGLT2i

On August 27~28, 2022, the "2nd Frontier Study Class on Research Progress in the Prevention and Treatment of Endocrinology and Metabolic Diseases in 2022" jointly organized by the Department of Endocrinology of Peking University People's Hospital and the China Diabetes Journal was officially opened
.
At this conference, Professor Cai Xiaoling, chief physician of the Department of Endocrinology, Peking University People's Hospital, delivered a wonderful academic report
entitled "In-depth understanding of SGLT2 inhibitors".

Based on evidence-based medical evidence, Professor Cai Xiaoling answered five hot questions around SGLT2i (such as "Is there a difference in efficacy and safety of SGLT2i in patients with different kidney function?").
"What is the risk of lower extremity complications of SGLT2i?" etc.
), which provides more evidence
for clinical in-depth understanding and standardized use of SGLT2i, a new star of hypoglycemia.

Cai Xiaoling

Department of Endocrinology, Peking University People's Hospital, Chief Physician, Associate Professor, Doctoral Supervisor
.
Visiting scholar
at the University of Melbourne and the Royal Melbourne Hospital.
He is also a youth committee member of the Diabetes Branch of the Chinese Medical Association, a member of the Education Group of the Diabetes Branch of the Chinese Medical Association, a member of the Diabetes Branch of the Beijing Medical Association, a member of the Diabetes Committee of the Chinese Association of Women Physicians, a vice chairman of the Diabetes Prevention and Rehabilitation Professional Committee of the Chinese Rehabilitation Medical Association, a vice chairman of the Endocrine and Metabolism Committee of the Smart Health Education Working Committee of the China Intelligent Engineering Research Association, a corresponding editorial board member of the Chinese Journal of Diabetes and a corresponding editorial board member of the Chinese Medical Journal (English version).

。

Question 1: Is the efficacy of SGLT2i consistent and safe in patients with different renal function?

The Peking University People's Hospital research team provided the latest evidence-based medical evidence to answer this question, and this study entitled "Meta-analysis of the efficacy and safety differences in the use of SGLT2i in patients with different renal function" systematically evaluated the differences
in efficacy and safety of SGLT2i treatment in patients with different renal function.

The researchers searched
the PubMed/Medline, Embase and Cochrane databases for studies published before December 2021.
Randomised controlled trials (RCTs) reporting baseline eGFR levels and at least one of the following absolute changes from baseline: glycosylated haemoglobin (HbA1c)
levels, body weight, blood pressure, and eGFR were included.
Eligible trials were analysed
by fixed-effect and random-effects models.

Efficacy results included changes in HbA1c, body weight, systolic and diastolic blood pressure, and eGFR; Safety outcomes included incidence
of urinary tract infections, genital infections, amputations, hypovolemia, orthostatic hypotension, fractures, diabetic ketoacidosis, and hypoglycaemia.
A total of 1382 studies were screened, 1296 studies were excluded and 86 studies
were included.

The study found that: 1.
The changes in HbA1c and body weight after SGLT2i treatment were roughly parallel to eGFR.
2.
The decrease in blood pressure caused by SGLT2i treatment was not related to baseline eGFR levels; 3.
The risk of hypovolemia in the subgroup with normal renal function and severe impairment of renal function is significantly increased, and the risk of hypoglycemia in patients with different renal functions is not increased; 4.
Compared with placebo, the incidence of hypoglycemia in patients with SGLT2i increases significantly only in patients with normal renal function, and the effect size gradually decreases
as renal function deteriorates.

Fig.
1 HbA1c and weight changes in SGLT2i treatment of patients with different renal function

Fig.
2 Changes in blood pressure and eGFR in patients with different renal functions treated with SGLT2i

Fig.
3 Safety of SGLT2i in patients with different renal functions

Table 1 Hypoglycemia in patients with different renal functions treated with SGLT2i compared with placebo

Key points:

➤ In patients treated with SGLT2i, HbA1c and weight loss are often parallel
to baseline eGFR levels.

➤ In patients treated with SGLT2i, the decrease in blood pressure was not related
to baseline eGFR levels.

➤ Patients with good renal function and decreased HbA1c are more likely to develop hypoglycemia
than placebo.

Question 2: Cardiovascular benefits other than urinary glucose excretion of SGLT2i?

In 2022, the research team of Peking University People's Hospital published in the journal Diabetes Obes Metab "Cardiovascular benefits other than urinary glucose excretion: hypotheses from two meta-analyses" explored this question, and Professor Cai Xiaoling interpreted the literature
.

This review systematically evaluated the association
between SGLT2i treatment for urinary glucose excretion (UGE) and cardiorenal outcomes.
Researchers searched PubMed/Medline, Embase and Cochrane, Clinicaltrial.
gov, Scopus, and Web of Science databases for relevant studies (up to September 2021).

Eligible trials were analysed
accordingly by fixed-effect models, random-effects models, and ANOVA trend tests.
Outcome measures included cardiorenal endpoints [major adverse cardiovascular events (MACEs) including non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death], combined heart failure (HF) outcomes (including hospitalisation for HF, emergency visit for HF, or cardiovascular death); Renal composite outcomes (including deterioration of renal function, end-stage renal disease, or death from nephropathy).

A total of 661 UGE studies were screened, of which 653 were excluded and eight were included; A total of 2067 studies were screened for cardiorenal outcomes, of which 2057 studies were excluded and 10 studies
were included.
The study found that the cardiorenal benefit of SGLT2i therapy in patients with severe renal insufficiency was preserved, even with significantly weakened UGE (Figure 4).

Fig.
4 Comparison of the benefits of SGLT2i under different renal functions

Note: A, UGE changes in patients with different renal functions; B.
occurrence of MACE in patients with different renal functions (major adverse cardiovascular events, including non-fatal myocardial infarction, non-fatal stroke or cardiovascular death); C, HF-related outcomes by renal function, including hospitalisation for HF, emergency visit for HF, or cardiovascular death; D, renal composite outcomes with different renal functions, including deterioration of renal function, end-stage renal disease, or death
due to renal disease.

Key points:

➤ Even with significant weakening of UGE, the cardiorenal benefit of SGLT2i therapy in patients with severe renal insufficiency is preserved;

➤ The risk reduction of the composite outcome MACE and HF in patients with severe renal insufficiency was significantly preserved, and the risk reduction of MACE and HF was more significant in people with low eGFR;

Conversely, the renal benefits of SGLT2i appear to be dependent on eGFR, as a greater
risk reduction has been observed in patients with good renal function.
Therefore, the renal and cardiovascular protection mechanisms of SGLT2is may be different
.

Question 3: Does SGLT2i cause changes in "plasma fasting glucagon levels"?

In 2021, the research team of Peking University People's Hospital published a research report in the journal Eur J Pharmacol "SGLT2i increases plasma fasting glucagon levels in diabetic patients: a meta-analysis" to explore this problem, and Professor Cai Xiaoling interpreted the literature
.

This study systematically evaluated the overall effect
of SGLT2i therapy on fasting plasma glucagon levels in people with diabetes.
We searched the PubMed/Medline, Embase and Cochrane databases for studies
published before August 2020.
To include clinical trials
of pre- and post-glucagon changes in SGLT2i interventions in patients with type 1 and type 2 diabetes.
Eligible trials were analysed accordingly by fixed-effect models, random-effects models, and meta-regression analyses
.
A total of 430 studies were screened, of which 410 were excluded and 10 studies
were included.

The primary endpoint was changes in plasma fasting glucagon levels before and after SGLT2i use; Secondary endpoints were changes
in fasting blood glucose levels, fasting insulin levels, and fasting plasma ketone levels before and after SGLT2i use.

The study found that:

1.
Compared with the non-SGLT2i control group, the fasting plasma glucagon level in the SGLT2i treatment group was significantly increased (WMD, 8.
35pg/ml; 95% Cl, 2.
17-14.
54pg/ml, P<0.
01).

2.
In the subgroup analysis, when analyzed by the non-SGLT2i control group, the plasma fasting glucagon level in the SGLT2i treatment group was significantly higher than that in the placebo control subgroup (WMD, 3.
00pg/ml; 95% Cl, 2.
21-3.
80 pg/ml, P<0.
01) and active drug control subgroup (12.
18 pg/ml; 95%Cl，0.
66-23.
69pg/ml，P=0.
04）
。

Fig.
5 Forest plot of fasting plasma glucagon levels in SGLT2i treatment group and control group

3.
In subgroup analysis, when analyzed by disease type, SGLT2i treatment significantly increased plasma fasting glucagon levels (WMD, 35.
00 pg/ml; 95% CI, 23.
61–46.
39 pg/ml, P<0.
01), while plasma fasting glucagon levels did not increase<b10> significantly in patients with T2DM.

Fig.
6 Forest plot of subgroup analysis stratified by disease type, and comparing plasma fasting glucagon changes between SGLT2i treatment group and control group

4.
Analysis of trials without control group, plasma absolute fasting glucagon level after SGLT2i treatment was significantly higher than baseline (WMD, 15.
38 pg/ml; 95%CI，0.
78–29.
99 pg/ml，P=0.
04）

Overall, it was significantly elevated in patients with T1DM (WMD, 53.
00 pg/ml; 95% CI, 45.
63–60.
37 pg/ml, P<0.
01), was not significantly increased<b10> in T2DM.

Fig.
7 Forest plot was analyzed by subgroups stratified by disease type, and fasting glucagon changes were compared at baseline and endpoint

5.
Meta-regression analysis showed that baseline characteristics, including age, proportion of male patients, course of diabetes, baseline HbA1c level, and baseline fasting glucagon level, were not related to changes in fasting glucagon after SGLT2i treatment; In addition, changes in FPG or changes in fasting insulin levels after SGLT2i treatment were not associated
with changes in glucagon.

Key points:

➤SGLT2i intervention treatment increased plasma fasting glucagon levels in diabetic patients;

➤ An increase in fasting glucagon may be associated with a decrease in fasting insulin, which may increase the glucagon/insulin ratio, making patients prone to ketosis;

➤ When using SGLT2i to reduce glucase, possible concomitant changes
in glucagon and insulin should be taken into account.
Individualized evaluation of patients with diabetes may help to better use SGLT2i therapy
.

Question 4: Is the use of SGLT2i related to the occurrence of "diabetic retinopathy"?

In 2022, the Peking University People's Hospital research team published in the journal Expert Rev Clin Pharmacol "Association between SGLT2i Use and Risk of Diabetic Retinopathy and Other Ocular Diseases: A Systematic Review and Meta-analysis" to explore this issue, and Professor Cai Xiaoling interpreted the literature
.

This study systematically evaluated the association
of SGLT2i treatment with the development of diabetic retinopathy.
Researchers searched
the PubMed/Medline, Embase, and Cochrane databases for studies published before October 2021.
Randomised controlled trials
reporting on the occurrence of diabetic retinopathy and other eye diseases in both SGLT2i users and non-users were included.
Eligible trials were analysed accordingly by fixed-effect models, random-effects models, and meta-regression analyses
.

The primary endpoint was the relationship between SGLT2i use and the incidence of sugar webs; Secondary endpoints were the relationship between SGLT2i use and the incidence of sugar webs during the proliferative phase; The exploratory endpoint was the association between SGLT2i use and the
incidence of other eye diseases (cataracts, glaucoma, macular degeneration, and vascular lesions).
A total of 3013 studies were screened, of which 2965 were excluded and 48 studies
were included.

The study found that:

1.
The use of SGLT2i was not significantly associated with the occurrence of diabetic retinopathy (OR=0.
80, 95% CI, 0.
61-1.
06, P=0.
12).

Fig.
8 Risk of diabetic retinopathy in SGLT2i treatment patients

2.
The use of SGLT2i was not significantly associated with the occurrence of sugar webs during the proliferation phase (OR=0.
83, 95%Cl, 0.
58-1.
17, P=0.
28).

Fig.
9 Risk of proliferative sugar webs in SGLT2i treated patients

3.
The use of SGLT2i is not significantly related
to the occurrence of hemorrhage and retinal detachment.

Fig.
10 Risk of bleeding in SGLT2i treated patients

4.
Subgroup analysis: In patients with a disease course of < 10 years, the use of SGLT2i was associated with a reduced risk of sugar webs (Figure 11).

Fig.
11 Forest plot for subgroup analysis grouped by disease course

5.
Subgroup analysis: SGLT2i use was associated
with a reduced risk of sugar webs compared to the active control group.

Fig.
12 Subgroup analysis forest plot grouped by control type

Key points:

➤SGLT2i use was not significantly associated with the occurrence of diabetic retinopathy;

➤ In patients with a disease course of less than 10 years, the use of SGLT2i was associated with a reduced risk of sugar webs;

➤ Early use of SGLT2i may bring greater eye benefits
.

Q5: Is there a correlation between SGLT2i use and "lower limb complications"?

In 2021, the research team of Peking University People's Hospital published in the academic journal Cardiovasc Diabetol "SGLT2i and Lower Limb Complications: An Updated Meta-analysis" to explore this problem, and Professor Cai Xiaoling interpreted the literature
.

This study systematically evaluated the relationship between SGLT2i treatment and the risk of lower extremity complications and analysed
the associated factors.
Using PubMed, Medline, Embase, Cochrane and clinicaltrial.
go, the researchers searched for studies
published between the inception of the database and November 2020.
Randomised controlled studies of SGLT2i that reported on amputation, peripheral arterial disease, and diabetic foot events
.
Fixed-effect models, random-effects models, and meta-regression analyses were analysed
accordingly.
The outcome indicators were the correlation of SGLT2i treatment with the risk of amputation, peripheral arterial disease and diabetic foot and related factors
.
A total of 1223 studies were screened through the search, of which 1184 studies were excluded and 39 randomized controlled studies were included,

The study found that:

1.
Compared with the non-SGLT2i control group, patients in the SGLT2i treatment group had a slight increase in the risk of amputation (OR=1.
23, 95% CI: 1.
08-1.
40, P=0.
002).

2.
By study type (cardiovascular and renal outcome trials and efficacy and safety assessment trials), the increased risk of amputation was mainly caused by cardiovascular and renal outcome trials (amputation risk: OR=1.
23, 95%C: 1.
07-1.
40, P=0.
003).

Fig.
13 Risk of amputation in SGLT2i treatment patients

3.
Compared with the non-SGLT2i control group, patients in the SGLT2i treatment group had a slightly increased risk of peripheral arterial disease (OR=1.
21, 95% CI, 1.
03-1.
42, P=0.
02).

4.
By study type (cardiovascular and renal outcome trials and efficacy and safety evaluation trials), the increased risk of peripheral arterial disease was mainly caused by cardiovascular and renal outcome trials (OR=1.
24, 95% Cl: 1.
05-1.
46, P=0.
01).

Fig.
14 Risk of peripheral arterial disease in patients treated with SGLT2i

5.
Subgroup analysis showed that patients with diabetes alone, placebo-controlled studies, and follow-up period > 52 weeks were associated
with a significantly increased risk of amputation.

Table 2 Risk of amputation events in SGLT2i treatment patients

Table 3 Risk of amputation, peripheral arterial disease and diabetic foot events in patients treated with SGLT2i

6.
The greater the degree of weight loss in the SGLT2i treatment group, the higher the
risk of amputation, peripheral arterial disease and diabetic foot.

Table 4 Factors and risks of lower limb complications in patients treated with SGLT2i

7.
The lower the baseline diastolic blood pressure and the more decreased systolic and diastolic blood pressure in the SGLT2i treatment group, which were associated
with an increased risk of amputation, peripheral artery disease and diabetic foot, respectively.

Table 5 Factors and risks of lower limb complications in patients treated with SGLT2i

Key points:

➤ Patients treated with SGLT2i had a slightly increased risk of amputation and peripheral arterial disease compared to patients not treated with SGLT2i;

➤ In patients treated with SGLT2i, the more weight and blood pressure decreased, the greater the possible risk of developing lower limb complications;

➤ For patients at high risk of lower extremity complications, monitoring reduced body weight and blood pressure may be an important risk prevention when
using SGLT2i.