Pharmacological Research 199 (2024) 107040

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Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Type 2 diabetes mellitus pharmacological remission with dapagliflozin plus

oral semaglutide☆
Maria Elena Lunati a, Vincenzo Cimino b, Davide Bernasconi c, Alessandra Gandolfi a,
Paola Silvia Morpurgo a, Camilla Tinari a, Elisa Lazzaroni a, Laura Baruffaldi a, Milena Muratori a,
Laura Montefusco a, Ida Pastore a, Antonio Rossi a, Ivano Giuseppe Franzetti e,
Fabrizio Muratori f, Roberto Manfrini g, Olga Eugenia Disoteo h, Rosa Terranova h,
Paolo Desenzani i, Angela Girelli i, Renata Ghelardi j, Francesca D’Addio k, Moufida Ben Nasr k,
Cesare Berra d, Franco Folli g, Loredana Bucciarelli d, Paolo Fiorina a, k, l, *
a
Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
b
Department of Biomedical and Clinical Sciences L. Sacco Endocrinology and Diabetology, Milan, Italy
c
University of Milan, Milan, Italy
d
IRCCS MultiMedica Sesto San Giovanni, Milano, Italy
e
ASST Valle Olona, Varese, Italy
f
Division of Endocrinology and Diabetology, Sant’Anna Hospital, Como, Italy
g
Endocrinology and Metabolism, Department of Health Science, Università di Milano, ASST Santi Paolo e Carlo, Milan, Italy
h
Division of Diabetology, Niguarda Hospital, Milan, Italy
i
ASST Spedali Civili Brescia, Milano, Italy
j
ASST Melegnano-Martesana, Milan, Italy
k
International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Italy
l
Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor and semaglutide, a glucagon-like peptide 1 receptor
GLP-1RA agonist, have both demonstrated efficacy in glycemic control, reducing blood pressure, body weight, risk of renal
SGLT2-I and heart failure in type 2 diabetes mellitus. In this observational, real-world, study we aimed to investigate the
T2D
efficacy of the combination therapy with those two agents over glycemic control. We thus obtained the data of
Dual treatment
1335 patients with type 2 diabetes followed by 11 Diabetes centers in Lombardia, Italy. A group of 443 patients
Combination therapy
was treated with dapagliflozin alone, the other group of 892 patients was treated with the combination therapy
of dapagliflozin plus oral semaglutide. We analyzed changes in glycated hemoglobin from baseline to 6 months of
follow-up, as well as changes in fasting glycemia, body weight, body mass index, systolic and diastolic pressure,
heart rate, creatinine, estimated glomerular filtration rate and albuminuria. Both groups of patients showed an
improvement of glycometabolic control after 6 months of treatment; indeed, the treatment with dapagliflozin
plus oral semaglutide showed a reduction of glycated hemoglobin of 1.2% as compared to the 0.5% reduction
observed in the dapagliflozin alone group. Significant changes were observed in body mass index, fasting
plasmatic glucose, blood pressure, total cholesterol, LDL and albumin to creatinine ratio, with a high rate (55%)
of near-normalization of glycated hemoglobin. Our real world data confirmed the potential of the oral combi­
nation therapy dapagliflozin with semaglutide in inducing pharmacological remission of type 2 diabetes mellitus.

This article is authored by a Consulting Editor. According to our policy the article has been handled by another editor independently, with the author being blind
☆

to the whole process.

* Correspondence to: Nephrology Division, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave. Enders Building, Boston MA 02115, USA.
E-mail address: paolo.fiorina@childrens.harvard.edu (P. Fiorina).

https://doi.org/10.1016/j.phrs.2023.107040
Received 9 November 2023; Received in revised form 10 December 2023; Accepted 11 December 2023
Available online 20 December 2023
1043-6618/© 2023 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
M.E. Lunati et al. Pharmacological Research 199 (2024) 107040

1. Introduction by his/her height (meters) squared. BMI classifications was defined as

underweight (under 18.5 kg/m2), normal weight (18.5 to 24.9 kg/m2),
In the last 15 years or so, several novel therapeutic agents have been overweight (25 to 29.9 kg/m2), class 1 obesity (30 to 34.9 kg/m2), class
discovered for type 2 diabetes mellitus treatment. Particularly, the 2 obesity (35 to 39.4 kg/m2) and class 3 obesity (40 or more). All data
sodium-glucose contransporter-2 inhibitors (SGLT2i) and the Glucagon- were analyzed by the Coordinating Center. Quantitative data are
like peptide-1 receptor agonists (GLP-1RA) [1] have demonstrated described as mean ± standard deviation and range, whereas qualitative
effectiveness. SGLT2i are a class of drugs acting on proximal convoluted variables have been expressed as absolute number of cases and as per­
tubule inhibiting the reabsorption of glucose, which is then excreted in centage of the cohort of evaluated patients. Normal distribution of all
the urine. SGLT2i were shown to reduce the progression of diabetic parameters was assessed by means of the Shapiro Wilk test. Statistical
kidney disease, liver fibrosis, heart failure and cardiovascular in patients differences were determined by Mann–Whitney U and Student’s t tests
with type 2 diabetes [2–5]. GLP-1RA are a class of drugs which increase for nonparametric and parametric continuous variables, respectively.
glucose-dependent insulin release, reduce glucagon secretion and Discrete variables were compared by the χ2 Test or the Fisher’s Exact
decelerate gastric emptying, the latter inducing post-prandial fullness Test. The p value for statistical significance was defined as < 0.05.
and weight loss [2,6–8]. Among SGLT2i, Dapagliflozin is a selective Differences between groups were determined by ANOVA for normally
inhibitor which has a demonstrated strong efficacy in achieving optimal distributed variables, and by Mann-Whitney test for those not normally
glycemic control, in combination with all other benefits of SGLT2i class distributed. Levels of significance was set at p < 0.05. Binary logistic
described above [9,10]. Oral semaglutide is a GLP-1RA that has shown regression with a stepwise selection approach was employed to deter­
effectiveness in ameliorating both glycometabolic and is the first mine the major contributors to achieve HbA1c< 6.5%. Dichotomic
GLP-1RA developed as an oral medication, allowing an earlier initiation dependent variable was HbA1c < 6.5% (1/0), while independent vari­
of GLP-1RA therapy [11,12]. Combining agents from those two classes ables taken in account were sex, age, years of disease, BMI (Kg/m2), FPG
of drugs has shown to ameliorate glycemic profile and blood pressure (mg/dl) and HbA1c (%) values at baseline, type of treatment and eGFR
control [13–17]. Some studies have also shown that this combination (mL/min/1.73 m2) values at baseline. All statistical analyses have been
determines a reduction in systolic blood pressure and triglycerides levels performed using statistical package SPSS for Windows version 20.0
[13]. The combination therapy of dapagliflozin and oral semaglutide has (SPPS Inc. Chicago, IL). In cases of drop-out, only the data available up
not been previously investigated, on glycometabolic control in patients to the time of drop-out have be considered for the analysis. No source
with type 2 diabetes mellitus. The aim of this study was to evaluate the data verification has been performed. Data collection and analysis were
efficacy of the combination therapy with dapagliflozin together with approved by the Institutional Review Board (Protocol ID 2022002; Luigi
oral semaglutide on glycemic control in patients with type 2 diabetes Sacco Hospital, University of Milan). The trial is registered in Trialgov.
and potentially in inducing the remission of type 2 diabetes in the real com (NCT0518946).
clinical practice.
3. Results
2. Materials and methods
3.1. Baseline data
The PRECARE2 study is an observational, observational, real world,
multicenter study, aimed at evaluating the effects of the combination We analyzed data from 1335 patients with type 2 diabetes, 443 of
therapy with dapagliflozin plus oral semaglutide on glycometabolic which were on dapagliflozin alone treatment and 892 were treated with
control and in inducing remission of type 2 diabetes. Data were collected dapagliflozin plus oral semaglutide combination therapy. Complete
from 11 Diabetes Centers in Lombardia, Italy. The participant centers baseline characteristics, including mean age, sex, mean duration of
were: Sacco and Fatebenefratelli Hospitals (Milan) (coordinating cen­ disease and antidiabetic treatment are shown in Table 1 Suppl. online.
ters), Monzino Hospital (Milan), San Paolo Hospital (Milan), San Carlo Median HbA1c and median BMI at study entry were 7.6 ± 0.9% and
Hospital (Milan), Multimedica Sesto San Giovanni Hospital, Papa Gio­ 28.9 ± 4.4 kg/m2, respectively. Obesity was present in 431 of subjects,
vanni Hospital (Bergamo), San Matteo Hospital (Vigevano), San Giu­ with a prevalence of class I obesity and overweight patients (Table 1
liano Milanese Hospital, Ospedali Civili Hospital (Brescia). The Suppl. online). The majority of patients were affected by arterial hy­
inclusion criteria were: (a) age > 18 years old; (b) diagnosis of type 2 pertension (70%) and dyslipidemia (60%). Nearly one third of subjects
diabetes, according to the American Diabetes Association indications for had heart failure, mainly NYHA I (15.1%). A history of myocardial
at least 3 months; (c) therapy with dapagliflozin (dapa) or dapagliflozin infarction was present in 227 of patients, 157 were affected by diabetic
plus oral semaglutide (dapa+sema). The following data were collected at retinopathy and one fifth of the patients had detectable albuminuria,
the baseline visit and after 6 months of treatment: duration of the dis­ classified as micro-albuminuria, while only 23 had macro-albuminuria.
ease, weight, height, body mass index, estimated glomerular filtration More than half of patients had some degree of chronic kidney disease
rate (according to CKD-EPI), blood pressure, glycated hemoglobin (Table 1 Suppl. online).
(HbA1c), fasting blood sugar, total cholesterol, HDL cholesterol, tri­
glycerides, calculated LDL cholesterol, creatinine, urinary albumin to 3.2. Follow-up
creatinine ratio (ACR) (mg/g), presence of diabetic retinopathy, history
of ischemic heart disease, heart failure, cerebral vascular disease Of the 1335 baseline subjects considered at baseline, 959 were re-
(transient ischemic attack or stroke), peripheral vascular disease as well evaluated after 6 months of treatment, while 28% of patients were lost
as PRE-visit hypoglycemic therapy. In the follow-up visit some addi­ at follow up or suspended the treatment due to adverse events. Patients
tional data were collected, including side effects and drug suspension. who completed the follow up were divided according to the assumption
Changes in HbA1c from baseline to 6 months of follow-up, as well as in of therapy in two subgroups: group 1 (“dapa”) on dapagliflozin (10 mg/
fasting glycemia, body weight, BMI, systolic and diastolic pressure, day), group 2 (“dapa+sema”) dapagliflozin (10 mg/day) plus oral
heart rate, creatinine, eGFR and albuminuria were also analyzed. Nor­ semaglutide (mean dosage 12.76 mg/day) (Fig. 1 Suppl. online). Dapa
moalbuminuria was defined as an albumin to creatinine ratio (ACR) < group consisted in 415 subjects, 155 (37.3%) female, 260 (62.7%) male,
30 mg/g or with an albumin excretion rate (AER) < 30 mg/24 h; mean age 67.1 ± 10.1 years. Dapa+sema group consisted in 544 pa­
microalbuminuria was defined in the presence of an ACR between 30 tients, 260 (47.8%) female, 284 (52.2%) male, mean age 62.8 ± 7.7
and 299 mg/g or with an AER of 30–299 mg/24 h while macro­ years. In the group of patients treated with dapagliflozin, basal insulin
albuminuria was defined with ACR> 300 mg/g or AER> 300 mg/24 h. was suspended in 22% of subjects, rapid insulin in 32.4% and there was
Body Mass Index (BMI) was estimated as patient’s weight (kg) divided a decrease in the use of sulfonylureas/glinides in the 81.6% of patients.

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M.E. Lunati et al. Pharmacological Research 199 (2024) 107040

In the group of patients treated with dapagliflozin plus oral semaglutide, 3.4. Renal function
basal insulin was suspended in the 89.2% of subjects, rapid insulin in
100% and there was a decrease in the use of sulfonylureas/glinides in Regarding renal function, at follow up serum creatinine remained
the 98.2% of patients. Regarding the use of antihypertensive medica­ stable in the dapa group with a slightly improvement in the dapa+sema
tions, it remained stable in the 93.9% of patients treated with dapagli­ group (Table 1) and albumin to creatinine ratio was improved in both
flozin and in the 97.4% treated with dapagliflozin plus oral semaglutide, treatment groups (Figs. 1D and 1H; Fig. 2D). Albumin creatinine ratio
while reduction was obtained, respectively, in the 9.9% and 4.3% of improved at a greater extent in the dapa group (Fig. 2D). Finally, we
subjects. evaluated changes in the KDIGO risk classes, considering the whole
population of patients. The statistically significant reduction in albu­
minuria, shown by our data together with the stability of eGFR values,
3.3. Glycometabolic control permitted an improvement in the overall KDIGO class of risk at follow-
up (Fig.3 Suppl. Online). Comparing KDIGO class of risk from baseline to
Glycometabolic parameters variation in the two subgroups during follow-up, the group of patients at low risk increased by 5%, while the
follow-up are reported in Table 1. As shown, in both groups there was a group of patients at moderate and high risk decreased by nearly 6%
significant improvement in all metabolic parameters, blood pressure and (Fig. 3 Suppl. online).
lipidic profile. Fasting plasmatic glucose, glycated hemoglobin and body
mass index were all improved in both treatment groups during follow-up 4. Discussion
(Figs. 1A, 1B, 1C, 1E, 1F and 1G; Figs. 2A, B, C and E). As expected, a
greater a reduction of Hb1Ac was observed in the dapa+sema group, This study investigates the effects of combination of SGLT2is and
while being improved in the dapa group only. Body mass index, fasting GLP-1RAs in a real-world population of patients with type 2 diabetes.
plasmatic glucose and glycated hemoglobin all improved at a greater Interestingly, in the dapagliflozin plus oral semaglutide group we
extent in the dapa+sema group (Fig. 2 A, B and C). A significant observed a mean reduction of HbA1c levels, from baseline after 6
reduction in total cholesterol and LDL cholesterol, with a slight increase months of treatment, of − 1.2%, as compared to the − 0.5% reduction
in HDL cholesterol, was observed in both groups, while triglycerides observed in the group treated with dapagliflozin only. This result is
were significantly reduced in the dapa group only. The achievement of consistent with the very few studies employing combined SGLT2i and
HbA1c < 6.5%, suggesting a pharmacological remission of type 2 dia­ GLP1-RA, although using a different combination as compared to our
betes, was obtained in 22.7% (94/415) of subjects in the dapa group and study [18–20]. As known, the two molecules act on glucose metabolism
in 51.8% (282/544) of patients in the dapa+sema group (Fig. 2E). We in a very different manners; indeed, GLP-1RAs reduce glycemia by
then compared the baseline characteristics of patients achieving enhancing insulin secretion and decreasing glucagon release, also
HbA1c< 6.5% (“responders”) as compared to (“non responders”) in delaying gastric emptying, reducing hepatic glucose production and
dapa+sema group. “Responders” were significantly younger with a whole body insulin sensitivity, while SGLT2is provide increased glucose
shorter diabetes duration. Comparing their baselines, they were char­ excretion by renal proximal tubule [18]. By contrast, they share a
acterized by a better glycometabolic state and higher body weight glucose-dependent mechanism of action, with very low hypoglycemia
values (Table 2). A logistical binary regression was performed to risk, together with a sustained weight loss through different mechanisms
determine the major contributors to the obtainment of HbA1c values [21]. These combination therapy increase cardiovascular and renal
lower than 6.5% considering the whole population and the two different benefits [22–24]. The results of this study seem to confirm that combi­
subgroups of patients. Considering the whole population, a better gly­ nation treatment with SGLT2i and GLP-1RA can lead to clinical benefits
cemic control and renal function at baseline and the use of dual therapy on glycemic control, systolic blood pressure, body weight and dyslipi­
(OR 4.9, 95% CI 2.794–8.531, p < 0.0001) were related to demia. Moreover, a recent meta-analysis, involving 1895 patients with
HbA1c< 6.5% at follow-up (Fig. 2 Suppl. online). By contrast, age, sex type 2 diabetes enrolled in 8 randomized clinical trials, confirmed that
and years of disease were not significantly related. Considering the two combination therapy led to a much more significant reduction in gly­
subgroups, the major determinant to HbA1c< 6.5% resulted, for both, a cemic levels [25], allowing additional HbA1c reduction of − 0.7%,
better glycemic control at baseline.

Table 1
Glycometabolic parameters of patients that completed the 6 months follow-up.
Dapa (n = 415) Dapa+Sema (n = 544)

Basal Follow up Mean reduction P value Basal Follow-up Mean reduction P value

BMI (Kg/m2) 28.4 ± 4.4 27.5 ± 4.4 -0.9 0.001 28.6 ± 3.3 27.1 ± 3.0 -1.5 0.001
Weight (Kg) 79.6 ± 14.1 77.1 ± 13.9 -2.5 0.001 80.4 ± 13.5 76.2 ± 12.1 -4.2 0.001
FPG (mg/dL) 152.7 ± 35.8 136 ± 24.6 -16.7 0.001 177 ± 30.8 145.1 ± 19.5 -31.9 0.001
HbA1c (%) 7.4 ± 0.9 6.9 ± 0.7 -0.5 0.001 7.6 ± 0.7 6.4 ± 0.45 -1.2 0.001
S-Creatinine (mg/dL) 1.0 ± 0.3 1.1 ± 0.3 + 0.06 Ns 0.94 ± 0.19 0.91 ± 0.17 -0.03 0.001
eGFR (mL/min/1,73 m2) 72.8 ± 23.5 72.4 ± 37.5 -0.4 Ns 76.2 ± 24 75.1 ± 20.1 -1.1 ns
ACR (mg/g) 52.7 ± 157 31.7 ± 54.9 -21.0 0.001 66.2 ± 160 50.9 ± 111 -15.3 0.01
Tot-cholesterol (mg/dL) 166.4 ± 37.4 159.7 ± 32.0 -6.7 0.001 188 ± 31.7 172.5 ± 19.5 -15.5 0.001
HDL (mg/dL) 47.5 ± 12.3 47.8 ± 11.6 + 0.3 ns 42.9 ± 8.4 44.1 ± 7.1 + 1.2 0.01
LDL (mg/dL) 95.0 ± 35.1 84.0 ± 23.2 -6.5 0.001 116.4 ± 35.3 97.8 ± 25.3 -18.6 0.01
Triglycerides (mg/dL) 145.3 ± 65.1 135.0 ± 53.2 -10.3 0.000 142.8 ± 47.3 150.7 ± 29.7 + 7.9 0.001
SBP (mmHg) 134.1 ± 14.7 129.0 ± 12.0 -5.1 0.000 133.5 ± 13 123 ± 9,4 -10.5 0.001
DBP (mmHg) 80.1 ± 9.0 77.0 ± 8.4 -3.1 ns 80.7 ± 8.8 73.3 ± 8.3 -7.4 0.001
Basal Insulin treatment 68, 16.4 53, 12.7 -22 0.001 120, 22.1 13, 2.4 -89.2 0.001
Rapid Insulin 37, 8.9 25, 6.0 -32.4 0.001 5, 0.9 0, 0.0 -100 0.001
treatment
Sulfonylureas/glinides treatment 38, 9.1 7, 1.6 -81.6 0.014 55, 1.0 1, 0.2 -98.2 0.001

Abbreviations: BMI, body mass index; FPG, Fasting Plasma Glucose; HbA1c, glycated hemoglobin; eGFR Estimated Glomerular Filtration Rate; ACR, albumin/
creatinine ratio; HDL high density lipoprotein; LDL low density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure. T-test for repeated measures.
Data are expressed as mean ± SD; n, %.

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M.E. Lunati et al. Pharmacological Research 199 (2024) 107040

Fig. 1. Values of FPG – A, HbA1c - B, BMI - C and ACR - D at baseline and after 6 months of follow up in Dapa group; values of FPG - E, HbA1c - F, BMI - G and ACR -
H at baseline and after 6 months of follow up in Dapa+Sema group. Abbreviations: FPG, Fasting Plasma Glucose; HbA1c, glycated hemoglobin; BMI, body mass index;
ACR albumin/creatinine ratio. T-test for unpaired measures. Data are expressed as mean ± SD.

Fig. 2. Mean reduction in: A - FPG, B - HbA1c, C - BMI and D - ACR after 6 months of follow up according to the treatment groups. E - Distribution of HbA1c (%)
values at baseline (green line) and after 6 months of treatment (blue line) in the 2 groups. The dark violet area represents the area under the curve of patients within
the range of pharmacological remission. Abbreviations: FPG, Fasting Plasma Glucose; HbA1c, glycated hemoglobin; BMI, body mass index; ACR albumin/creatinine
ratio. T-test for unpaired measures. Data are expressed as mean ± SE. (For interpretation of the references to color in this figure legend, the reader is referred to the
web version of this article.)

compared to monotherapy treatment. In particular, combination ther­ effects, available data are not consistent; indeed, in some studies, the
apy provides a better control in postprandial glucose levels and allows combination regimen seems to be effective only in reducing systolic
greater body weight reduction [25]. Interestingly, in our population we blood pressure [31], whereas in others, a reduction in both systolic and
observed a higher mean reduction of body mass index (− 0.6 kg/m2) and diastolic blood pressure was observed [32,33]. When evaluating the
body weight (− 1.7 kg) in the combination regimen as compared to changes in the KDIGO risk classes during follow-up, a reduction in the
monotherapy group. These values are slightly higher compared to the risk of renal function decline was observed, with an increased in the
data presents in literature [26]. A partial explanation may be related to number of patients at very low risk. We observed no synergistic effect on
short time of follow up. In fact, both SGLT2is and GLP-1RAs can directly the kidney function with the association with dapa+sema. This could be
reduce body weight with particular effectiveness [14–16,27–30]; the explained by different hypothesis: the benefit on the kidney function is
first increasing energy loss and the second inhibiting energy intake and mainly guaranteed by SGLT2i alone, on the other hand, with a longer
inducing thermogenesis of brown adipose tissue. These effects are syn­ period of observation, it might be demonstrated also the positive effect
ergistic although they may decrease over time. In our study we have also of the add-on semaglutide treatment. Multiple events, including hemo­
found a significant reduction of LDL cholesterol and total cholesterol dynamic changes, reduction of blood pressure, improvement of cardiac
levels and a mild increase in HDL, suggesting a potential role of this metabolism are responsible of the observed positive effects on renal
combination in type 2 diabetes patients with dyslipidemia. Indeed, these function; furthermore, the demonstrated anti-inflammatory, anti-­
data are in line with a recent meta-analysis, that reported a significant atherosclerotic and anti-oxidative properties, may protect the kidney
reduction in low-density lipoprotein cholesterol (− 23.4 mmol/L) among [23,34–36]. Both SGLT2is and GLP1-RAs play a role in mediating
patients treated with combination regimen, even if the effect on TG, TC anti-infiammatory and immunological effects. Both receptors are indeed
and HDL levels was not significant [25]. Concerning blood pressure expressed in different sub-types of cells involved in immune response

4
M.E. Lunati et al. Pharmacological Research 199 (2024) 107040

Table 2 CRediT authorship contribution statement

Baseline characteristics of subjects achieving HbA1c values < 6.5% (Responder)
or not (Non responder) after 6 months of follow up in the Dapa+Sema group. Disoteo Olga Eugenia: Data curation, Supervision. Desenzani
Responder Non responder P Paolo: Data curation. Terranova Rosa: Data curation. Ghelardi
(n = 282) (n = 262) value Renata: Data curation. Girelli Angela: Data curation. Ben Nasr Mou­
Age (years) 61.7 ± .7.2 63.7 ± 8.3 0.001 fida: Methodology, Supervision. D’addio Francesca: Methodology,
Years of disease 6.2 ± 5.4 9.3 ± 5.9 0.001 Supervision. Folli Franco: Conceptualization, Supervision. Cimino
Gender M/F (%) 57.3/42.7 49.1/50.9 0.05 Vincenzo: Formal analysis, Writing – original draft. Berra Cesare: Data
BMI (Kg/m2) 28.8 ± 2.8 28.3 ± 3.8 ns
curation, Methodology, Supervision. Lunati Maria Elena: Data cura­
Weight (Kg) 82.3 ± 12.3 78.2 ± 14.5 0.01
FPG (mg/dL) 174.6 ± 26.4 178.8 ± 37.1 ns tion, Formal analysis, Writing – original draft. Gandolfi Alessandra:
HbA1c (%) 7.4 ± 0.56 7.7 ± 0.75 0.001 Data curation. Bucciarelli Loredana: Data curation. Bernasconi
S-Creatinine (mg/dL) 0.93 ± 0.2 0.94 ± 0.2 ns Davide: Investigation. Morpurgo Paola Silvia: Data curation, Meth­
eGFR (mL/min/1,73 m2) 78.5 ± 26.0 75.2 ± 23.3 ns odology. Fiorina Paolo: Conceptualization, Project administration,
ACR (mg/g) 96.0 ± 310.5 65.2 ± 111.3 ns
Tot-cholesterol (mg/dL) 190.2 ± 32.1 184.0 ± 31.9 0.001
Supervision, Writing – review & editing. Lazzaroni Elisa: Data curation.
HDL (mg/dL) 42.2 ± 7.3 46.0 ± 23.9 ns Tinari Camilla: Data curation, Methodology. Muratori Milena: Data
Triglycerides (mg/dL) 143.8 ± 50.5 144.5 ± 48.0 ns curation. Baruffaldi Laura: Data curation. Pastore Ida: Data curation.
Basal Insulin Treatment 2.1 2.6 ns Montefusco Laura: Data curation. Franzetti Ivano Giuseppe: Data
(%)
curation. Rossi Antonio: Data curation. Manfrini Roberto: Data
Rapid Insulin Treatment 0 1.7 0.05
(%) curation. Muratori Fabrizio: Data curation.

Abbreviations: BMI, body mass index; FPG, Fasting Plasma Glucose; HbA1c,
glycated hemoglobin; eGFR Estimated Glomerular Filtration Rate; ACR albu­
Declaration of Competing Interest
min/creatinine ratio; HDL high density lipoprotein; Data are expressed as mean
± SD or %. None.

(lymphocytes T and B, macrophages, iNTK cells, eosinophils and neu­ Data availability
trophils for GLP1-RAs and monocytes for SGLT2is) and have demon­
strated to reduce inflammatory cytokines production during clinical Data will be made available on request.
trials. [23,35] In our study, the use of combination therapy with dapa­
gliflozin plus oral semaglutide lead to the suspension of basal and rapid Acknowledgements
insulin in one third of patients and a superb reduction in sulfonylur­
eas/glinides use in almost all patients. Considering that with combina­ We are grateful to Fondazione Romeo and Enrica Invernizzi for the
tion treatment the risk of hypoglycemia is very low, the use of this amazing and unconditional support.
regimen can be useful in the more fragile classes of patients, such as
elderly [37,38]. It is noteworthy that more than half of the treated pa­ Appendix
tients in the dapa+sema group achieved a HbA1c levels < 6.5%. Even if
the presence of active pharmacological treatment cannot allow a full Other participants to the study: Andrea Laurenzi, Annalisa Creanza,
definition of diabetes remission, which requires the absence of usual Antonio Luigi Belviso, Baldassarre Grassa, Bernadetta Pasquino, Chiara
glucose-lowering pharmacotherapy for at least three months [39], the Mauri, Cristiana Scaranna, Cristina Mascadri, Danila Marta Camozzi;
achievement of HbA1c goal of less than 6.5% in such a proportion of Elena Cimino, Elena Mion, Emanuela Zarra, Enrico Pigni, Erika Pedone,
patients can reasonably permit us to highlight this result as a "pharma­ Fabrizio Guerci, Francesca Pesenti, Giacomo Sturniolo, Giorgio Ragni,
cological remission". In fact, is well known that the obtainment of a Giosuè Ghilardi, Giulia Massari, Laura Menicatti, Luca Zenoni, Maria­
sustained glycemic control over time, without a significant increase in claudia Tusi, Maria Elena Malighetti, Mario Buizza, Paolo Erpoli, Raf­
hypoglycemia risk, is associated with reduced odds of the faella Radin, Roberto Pollastri, Roberta Serra, Rosalia Bellante, Valeria
diabetes-related complications of cardiovascular disease, metabolic Brami.
disease, neuropathy, nephropathy, and peripheral vascular disease [40].
This was probably facilitated by few characteristics at baseline, Appendix A. Supporting information
including age and duration, suggesting that in order to maximize the
clinical results, this treatment should be offered to younger patients and Supplementary data associated with this article can be found in the
early in the natural history of the disease. The beneficial role of the online version at doi:10.1016/j.phrs.2023.107040.
intensive diabetes management during the earliest stages of the disease
is particularly important due to the legacy effect. In fact, intensive References
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