Glucagon-like-1 receptor agonists and sodium/glucose cotransporter-2 inhibitors combination—are we exploiting their full potential in a real life setting?

BACKGROUND The sodium/glucose cotransporter-2 inhibitors(SGLT-2i)and glucagon-like-1 receptor agonists(GLP-1RA)are antidiabetic agents effective both in hemoglobin A1c(HbA1c)reduction(with a low risk of hypoglycemia)and cardiovascular event prevention.In patients with type 2 diabetes,the add-on value of combination therapy of GLP-1RA and an SGLT-2i seems promising.AIM To investigate whether the efficacy of GLP-1RA and SGLT-2i combination observed in randomized controlled trials translates into therapeutic benefits in the Croatian population during routine clinical practice and follow-up.METHODS We included 200 type 2 diabetes patients with poor glycemic control and analyzed the effects of treatment intensification with(1)GLP-1RA on top of SGLT-2i,(2)SGLT-2i on top of GLP-1RA compared to(3)simultaneous addition of both agents.The primary study endpoint was the proportion of participants with HbA1c<7.0%and/or 5%bodyweight reduction.Secondary outcomes included changes in fasting plasma glucose(FPG),prandial plasma glucose,lowdensity lipoprotein cholesterol,estimated glomerular filtration rate(eGFR),and cardiovascular(CV)incidents assessment over a follow-up period of 12 mo.RESULTS The majority of patients were over 65-years-old,had diabetes duration for more than 10 years.The initial body mass index was 39.41±5.49 kg/m2 and HbA1c 8.32±1.26%.Around half of the patients in all three groups achieved target HbA1c below 7%.A more pronounced decrease in the HbA1c seen with simultaneous SGLT-2i and GLP-1RA therapy was a result of higher baseline HbA1c and not the effect of initiating combination therapy.The number of patients achieving FPG below 7.0 mmol/L was significantly higher in the SGLT-2i group(P=0.021),and 5%weight loss was dominantly achieved in the simultaneous therapy group(P=0.044).A composite outcome(reduction of HbA1c below 7%(53 mmol/mol)with 5%weight loss)was achieved in 32.3%of total patients included in the study.Only 18.2%of patients attained composite outcome defined as HbA1c below 7%(53 mmol/mol)with 5%weight loss and low-density lipoprotein cholesterol<2.5 mmol/L.There were no significant differences between treatment groups.No differences were observed regarding CV incidents or eGFR according to treatment group over a follow-up period.CONCLUSION Combination therapy with GLP-1RA and SGLT-2i is effective in terms of metabolic control,although it remains to be determined whether simultaneous or sequential intensification is better.

What is the gut feeling telling us about physical activity in colorectal carcinogenesis?

In the last decades,more efforts are focused on the prevention and treatment of malignant diseases,given the increase in all cancers incidence A lifestyle change,including healthy eating habits and regular physical activity,has significantly impacted colorectal cancer prevention.The effect of dose-dependent physical activity on mortality and recurrence rates of colorectal carcinoma has been unequivocally demonstrated in observational studies.However,clear recommendations are not available on the frequency,duration,and intensity of exercise in patients with colorectal cancer due to the lack of evidence in randomized clinical trials.Regarding pathophysiological mechanisms,the most plausible explanation appears to be the influence of physical activity on reducing chronic inflammation and insulin resistance with a consequent positive effect on insulin growth factor 1 signaling pathways.

Complications, Mineral and Vitamin Deficiencies: Comparison between Roux-en-Y Gastric Bypass and Sleeve Gastrectomy

Objective: Nutritional deficiencies are known side-effects of bariatric surgeries, specifically in those that bypass the proximal intestine. Therefore, in clinical practice, vitamin and mineral supplementations are often necessary after such operations. It was our intention to evaluate, whether alimentary deficiencies occur with the same frequency in patients following Sleeve-Gastrectomy (SG) compared to Roux-en-Y Gastric Bypass (RYGB) surgeries. Methods: We conducted a retrospective data analysis of 171 patients (121 RYGB, 50 SG). Vitamin levels were compared between SG and RYGB patients over the first post-operative year. Furthermore, regression analysis was performed with regard to vitamin and iron supplementations and their recommended dosages. Complications occurring within the first post-surgical year were documented as well. Results: Other than vitamin B6 deficiency, which was found to be more frequent in SG patients, there was no other significant difference regarding the type of operation and the number of patients who had these deficiencies. There was no significant difference in average vitamin and iron levels between RYGB and SG. A minimum dose of 1000 IU vitamin D per day was necessary to affect vitamin D levels. The intramuscular administration of vitamin B12 was the only route found to be effective. Complications within the first year were rare. Conclusions: Against common assumptions, vitamin and iron deficiencies in SG patients are not less frequent in the first post-surgical year?in comparison to RYGB patients. Standard supplementations should include iron in premenopausal women: Vitamin D at least 1000 IU per day and vitamin B12 i.m. administration in case of a deficiency.

Coagulation and Endothelial Dysfunction Associated with NAFLD:Current Status and Therapeutic Implications

Non-alcoholic fatty liver disease(NAFLD)is closely related to insulin resistance,type 2 diabetes mellitus,and obesity.It is nowadays considered a multisystem disease with a strong association with cardiovascular disease and arterial hypertension,which interfere with changes in the coagulation system.Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage.Patients with NAFLD may have preserved overall hemostatic profile,but many studies suggest a trend toward a procoagulant state.Hypercoagulable state in NAFLD patients may even induce progression of hepatic injury.Endothelial dysfunction is present in the systemic and portal vein circulation in NAFLD patients,and platelets are being recognized as modulators of liver diseases through various mechanisms.Through a literature review,we discuss possible disorders in the coagulation cascade and fibrinolysis,endothelial dysfunction,and platelet abnormalities in patients with NAFLD.Considering the processes and mechanisms involved in the hemostatic abnormalities associated with NAFLD,directly related to liver disease or indirectly related through inflam-matory processes and metabolic disorders,several potential therapeutic targets have been identified and reviewed here.

Obesity Paradox in Chronic Liver Diseases:Product of Bias or a Real Thing?

In recent years,evidence supporting the theory of obesity paradox has increased,showing that obese/overweight people with prevalent chronic diseases experience lower mortality compared with patients of normal weight.So far,evidence is most comprehensive in cardiovascular and chronic renal diseases;however,published studies are prone to many biases,enabling us to reach a definite conclusion.Available data in chronic liver disease is scarce and ambiguous.Obesity is traditionally associated with nonalcoholic fatty liver disease and steatosis in viral hepatitis and as such one would not expect the obesity paradox to be a real possibility in liver disease.Yet,there seem to be new data indicating the opposite-the obesity paradox exists in severe and end-stage liver cirrhosis,which could be attributed to a better lean mass in patients with higher body mass index,meaning that sarcopenia,as one of the most important prognostic factors of survival,is less likely to be present.Nonetheless,the problem of various methodological problems addressing the association between body weight and mortality,which is present both in liver disease and other chronic diseases,are preventing us from attaining an unanimous conclusion.Still,we should be aware that the obesity paradox might be true,especially in severe and end-stage illness.This suggests focusing our efforts toward preserving or building up fat-free mass and decreasing infiammatory activity responsible for catabolism and sarcopenia,and implying that the underlaying cause should be treated.