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.

Hepatitis C Virus, Insulin Resistance, and Steatosis

Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide.Liver steatosis is a common finding in many hepatic and extrahepatic disorders,the most common being metabolic syndrome (MS).Overtime,it has been shown that the frequent coexistence of these two conditions is not coincidental,since many epidemiological,clinical,and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements.Here,we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association.It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms.Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly,inducing the production of several proinflammatory cytokines.HCV replication,assembly,and release from hepatocytes require close interactions with lipid droplets and host lipoproteins.This modulation of lipid metabolism in host cells can induce hepatic steatosis,which is more pronounced in patients with HCV genotype 3.The risk of steatosis depends on several viral factors (including genotype,viral load,and gene mutations) and host features (visceral obesity,type 2 diabetes mellitus,genetic predisposition,medication use,and alcohol consumption).HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life,due to their association with resistance to antiviral therapy,progression of hepatic fibrosis,and development of hepatocellular carcinoma.Finally,HCV-induced IR,oxidative stress,and changes in lipid and iron metabolism lead to glucose intolerance,arterial hypertension,hyperuricemia,and atherosclerosis,resulting in increased cardiovascular mortality.