Effectiveness, Safety, and Appropriateness in the Use of the Fixed-Ratio Combination of Insulin Glargine and Lixisenatide in Type 2 Diabetes: The ENSURE Retrospective Real-World Study

Introduction Pivotal trials documented glycemic benefits of fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi), with no weight gain and low hypoglycemia risk in type 2 diabetes (T2D). This study aimed at assessing effectiveness and patterns of use of iGlarLixi in a real-world setting. Methods This was a retrospective, multicenter, study, based on electronic medical records. All patients initiating iGlarLixi from May 2018 to July 2020 were considered. Results Overall, 25 centers provided data on 675 patients initiating iGlarLixi with the following characteristics: age 66.4 +/- 10.1 years, 54.2% men, T2D duration 15.5 +/- 11.5 years, HbA1c 8.6 +/- 1.4%, body mass index (BMI) 30.8 +/- 5.3 kg/m(2), 45.1% already treated with basal insulin, and 21.9% with basal bolus (+/- oral hypoglycemic agents). Metformin and sodium-glucose cotransporter-2 inhibitors were used in 76.0% and 0.9% of patients, respectively. Combinations of iGlarLixi with other glucose-lowering drugs such as sulfonylureas or short-acting insulin were found in 32.4% of patients. Effectiveness of iGlarLixi (N = 184) showed that HbA1c declined by 0.77% [95% confidence interval (CI) -1.00, -0.54] after 6 months. In combination with metformin and/or SGLT-2i (N = 117), HbA1c declined by -0.92% (95% CI -1.22, -0.62) and weight significantly decreased by 1.21 kg. iGlarLixi dose was suboptimally titrated. Safety data (N = 171) showed incidence rates of blood glucose <= 70 and < 54 mg/mL of 0.26 and 0.05 events per person-month during 6 months, respectively, with a risk reduction of about 75% with respect the 6 months before iGlarLixi initiation. No severe hypoglycemia was reported. Conclusion In adults with T2D, effectiveness and safety of iGlarLixi were documented in a real-world setting; appropriateness of use and adequate titration should be urgently improved so that clinical practice outcomes become more comparable to clinical trials results. Further real-world studies on the effect of iGlarLixi therapy are warranted

The Gastric CB1 Receptor Modulates Ghrelin Production through the mTOR Pathway to Regulate Food Intake

<div><p>Over the years, the knowledge regarding the relevance of the cannabinoid system to the regulation of metabolism has grown steadily. A central interaction between the cannabinoid system and ghrelin has been suggested to regulate food intake. Although the stomach is the main source of ghrelin and CB1 receptor expression in the stomach has been described, little information is available regarding the possible interaction between the gastric cannabinoid and ghrelin systems in the integrated control of energy homeostasis. The main objective of the present work was to assess the functional interaction between these two systems in terms of food intake using a combination of in vivo and in vitro approaches. The present work demonstrates that the peripheral blockade of the CB1 receptor by rimonabant treatment decreased food intake but only in food-deprived animals. This anorexigenic effect is likely a consequence of decreases in gastric ghrelin secretion induced by the activation of the mTOR/S6K1 intracellular pathway in the stomach following treatment with rimonabant. In support of this supposition, animals in which the mTOR/S6K1 intracellular pathway was blocked by chronic rapamycin treatment, rimonabant had no effect on ghrelin secretion. Vagal communication may also be involved because rimonabant treatment was no longer effective when administered to animals that had undergone surgical vagotomy. In conclusion, to the best of our knowledge, the present work is the first to describe a CB1 receptor-mediated mechanism that influences gastric ghrelin secretion and food intake through the mTOR pathway.</p></div

Primers for the real time qPCR analyses.

<p>Primers for the real time qPCR analyses.</p

Measures of pmTOR/mTOR levels in gastric mucosa and representative Western blots from animals in the fasting state treated with ip rimonabant and/or ip rapamycin chronically for 1 week (A).

<p>Phospho-S6K1/S6K1 in gastric mucosae from animals in the fasting state treated with rimonabant ip and/or rapamycin ip chronically for 1 week (B). The results are expressed as percentages over control (phospho-S6K1/S6K1). *p<0.05, vs control; ^#p<0.05 vs rimonabant. C: control, R: rimonabant, Ra: rapamycin; Ra+R: rapamycin+rimonabant.</p

Food Intake measures in rats after icv treatment with ghrelin/vehicle (6 µg/rat) and ip treatment with rimonabant (3 mg/kg ip)/vehicle under different nutritional statuses: A) <i>Ad libitum</i> fed, B) nocturnal fasting, c) animals subjected to overnight fasting and previously subjected to surgical vagotomy.

<p>*vs control, ^#vs. rimonabant+ghrelin.</p

Gastric ghrelin secretion from tissue explants (A) and plasma ghrelin levels (B) obtained from 36-hour fasted animals that received in vivo treatment with AM281 (3 mg/Kg ip).

<p>**p<0.01.</p

Measures of pmTOR/mTOR in the gastric mucosae and representative Western blots from animals in the fasting state treated with ip AM281 or vehicle (A).

<p>Phospho-S6K1/S6K1 in the gastric mucosae and representative Western blots from animals in the fasting state treated with ip AM281 or vehicle (control) (B). The results are expressed as percentage over control (phospho-S6K1/S6K1). *p<0.05.</p

mRNA expression levels measured by real-time PCR for ghrelin in <i>ad libitum</i> fed animals (A) or 36-hour fasted animals (B).

<p>Ghrelin protein levels and representative Western blot from the mucosa from <i>ad libitum</i> fed animals (C) or 36-hours fasted animals (D). Animals that received different in vivo treatments (control/rimonabant) and surgical procedures (vagotomy/sham-operated). C: control, R: rimonabant, V: vagotomy; V+R: vagotomy+rimonabant. CB1 receptor mRNA levels in the gastric mucosae of <i>ad libitum</i> fed animals (E) or 36-hour fasted animals (F) and animals that received different in vivo treatments (control/rimonabant) and surgical procedures (vagotomy/sham operated). *vs control.</p

Gastric ghrelin secretion (A).

<p>Ghrelin mRNA levels measured by real-time PCR in the gastric mucosae (B) and plasma ghrelin levels (C) from animals in fasting states treated with ip rimonabant and/or ip rapamycin chronically for 1 week.</p