This study documented the effectiveness and tolerability of semaglutide in patients with uncontrolled T2DM.
After 32 weeks of treatment, HbA1c levels and body weight significantly decreased ( − 1.38% and − 6.03 kg, respectively) and the entity of the reduction was in line with results obtained in the SUSTAIN program [13, 19, 20], where HbA1c was reduced from 1.1 to 1.5% with semaglutide 0.5 mg and from 1.4 to 1.8% with semaglutide 1 mg; weight was reduced from 3.5 to 4.6 kg with semaglutide 0.5 mg and from 4.5 to 6.5 kg with semaglutide 1 mg. In addition, real-world studies conducted in US and Europe confirmed the effectiveness and safety of semaglutide when administered under routine clinical practice conditions, although the magnitude of benefits varied based on patient profiles and settings [21,22,23,24,25,26,27].
In addition to the effect on HbA1c and weight, in our study we documented improvements in lipid profile and blood pressure.
Finally, our population presented multiple associated risk factors (dyslipidemia, hypertension, obesity), 50% had organ damage and 23.1% had history of cardiovascular event.
Comparison with existing knowledge
The recent documentation of the positive CV effects of semaglutide in reducing the MACE risk  is extremely encouraging in relation to the clinical use of this drug. Furthermore, a post-hoc analysis of the LEADER and SUSTAIN 6 CV outcome trials confirmed the importance of addressing multiple risk markers in T2DM to reduce CV and renal risk, therefore stressing the importance of multifactorial interventions targeting all risk markers .
Following these findings, in July 2021 new AMD-SID (Associazione Medici Diabetologi; Societa’ Italiana di Diabetologia) Italian Guidelines stated that GLP1-RA can be prescribed as a first line therapy in T2DM with a previous cardiovascular event. ADA Guidelines (ADA 2022) also suggested to consider GLP1-RA as a first choice therapy in high cardiovascular risk patients [29, 30].
In our study population and in general T2DM population, obesity is present in the majority of patients and its role as main driver of the disease is well known . Weight loss is one of the most important therapeutic goals and is associated with an improvement of all the cardiovascular risk factors – cholesterol, tryglicerides, blood pressure—and with an improvement of cardiac function and overall prognosis (ESC 2021) . GLP1-RAs were the first glucose-lowering drugs that induce weight loss [33,34,35] due to their pleiotropic actions including a central nervous system interaction with reward circuits and food intake. Semaglutide effect was demonstrated to be superior to that of dulaglutide (SUSTAIN 7) and liraglutide (SUSTAIN 10) in T2DM at therapeutic doses [36, 37].
Semaglutide produces significant benefits on cardiovascular risk, as demonstrated in SUSTAIN 6, where a significant lower rate vs. placebo of 3 points MACE was documented . The reduction of CV risk is mediated by improvements in risk factors. In our study, total cholesterol level significantly decreased by 18.14 mg/dl, LDL-cholesterol by10.93 mg/dl and tryglicerides by 49.1 mg/dl at T1. However, it is noteworthy that in spite of the significant LDL-cholesterol reduction – from 105 to 95 mg/dl – many patients did not reach the recommended targets for T2DM (ESC 2021) . Furthermore, non-HDL cholesterol is an established but seldom investigated cardiovascular risk factor [9,10,11,12]. Its therapeutic goal is stringent (< 100 mg/dL) in high risk population [6, 7]. In our study, it decreased by 20.75 mg/dl, but at T1 mean level was 125 mg/dL . These findings reinforce the urgent need to intensify lipid-lowering therapy and dietary education, with semaglutide contributing to the achievement of the target.
Important information comes also from the analysis of treatment schemes. The present study substantially involved T2DM patients treated with 1 or 2 OHAs with elevated baseline levels of HbA1c. A small minority of patients were already treated with GLP1-RA and 1 out of 10 patients were treated with insulin before starting semaglutide. This picture underlines the existence of a certain clinical inertia, due, as known, to multifactorial reasons, such as COVID-19 pandemics, long waiting lists, transfer of new patients from other hospitals, low patient adherence, etc.… However, at semaglutide initiation, the proportion of patients treated with insulin and with more than 1 OHA decreased. Even the use of antihypertensive drugs slightly diminished. These data support the most recent evidence on simplification of therapy as a key strategy to overcome clinical inertia .
Finally, DTSQ average values documented high levels of satisfaction with treatment (median score was 33 against a maximum score of 36) [15, 16]. Satisfaction with treatment is an important mediator of patient adherence and achievement of targets .
Reduced appetite and energy intake, with less preference for energy‐rich foods, were investigated in previous studies and were identified as a possible mechanism to explain the weight loss observed with once-weekly and oral semaglutide [14, 39, 40].
In our setting, we administered a translated and modified version of COEQ adapted for Italian T2DM patients: after 32 weeks of therapy a lower fatty food preference was declared (61%) with a relatively preserved proteic (fish, meat) and carbohydrate rich food (grains, bread, pasta) intake. In another study on 3685 obese subjects, semaglutide induced specific fat mass loss, and energy intake reduction; COEQ questionnaire documented food habits changes with lower craving .
In our study, semaglutide significantly improved glucose control and reduced body weight (HbA1c decrease: −1.38%; weight loss: −6.03 kg with 0.5 mg of semaglutide) confirming or even surpassing results of SUSTAIN studies [36, 37, 41]. In addition to drug effect, in our real-world setting, even the attention to the individual dietetic plan, based on Mediterranean Diet model, and dietary/lifestyle education played a role . In the future, it will be interesting to investigate the hepatological impact of this treatment approach in T2DM patients with Nonalcoholic Fatty Liver Disease.
Strenghts and limitations
The major strength was the inclusion of clinically important but seldom investigated endpoints: non-HDL cholesterol, reduction of antihypertensive drugs prescribed, treatment satisfaction, and eating behaviors. Among limitations, it should be underlined the lack of administration of DTSQ and COEQ at T0 to assess changes over time in the scores and the lack of information about mild hypoglycemia and glycemic variability.