Liraglutide 3.0 mg and mental health: can psychiatric symptoms be associated to adherence to therapy? Insights from a clinical audit.

INTRODUCTION: Liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) analogue, is a medication approved for obesity treatment. This study aimed to investigate the relationship between psychiatric symptoms, including depression, anxiety, and binge eating, and their impact on therapy adherence. METHODS: A clinical audit was carried out on a cohort of 54 adults with obesity treated with liraglutide 3.0 mg. We retrospectively analyzed the connection between psychiatric symptoms assessed through the State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Binge Eating Scale (BES). Adherence to therapy was assessed by the maximum dosage (MD) and treatment duration (TD). RESULTS: Notably, a discontinuation rate of 59% was encountered. However, among those who continued the treatment, we observed a negative association between anxiety symptoms (STAI score) and MD, depression symptoms (BDI score) and TD, and a higher likelihood of binge eating (BES score > 17) and TD. Moreover, presence of psychiatric symptoms did not compromise drug's effectiveness in achieving weight loss, which was 4.43% (± 5.5 SD) in the whole sample and 5.3% (± 6.3 SD) in the subgroup evaluated at 12 weeks. CONCLUSION: We observed a high discontinuation rate in real-life clinical setting, where Liraglutide 3.0 therapy is paid out-of-pocket. While psychiatric symptoms might play a role in diminishing adherence to therapy, they do not prevent drug's effectiveness to promote weight loss. This finding underscores the potential advantages of liraglutide 3.0 mg therapy for individuals contending with obesity while simultaneously managing mental health challenges. LEVEL OF EVIDENCE: Level V, descriptive studies.

Retrospective analysis of the effects of a highly standardized mixture of Berberis aristata, Silybum marianum, and monacolins K and KA in diabetic patients with dyslipidemia.

BACKGROUND: Berberine, an alkaloid with both glucose- and cholesterol-lowering action, is also characterized by an anti-diarrheal effect. Consequently, berberine-based therapies are recommended for diabetic patients with irritable bowel syndrome (IBS) or gut discomfort caused by metformin. AIM: As the anti-glycemic and cholesterol-lowering action of berberine is improved by co-administration with P-glycoprotein inhibitors and naturally derived statins, we have analyzed the effect of the food supplement Berberol®K (hereafter referred to as BSM) containing, berberine, silymarin, and a highly standardized red yeast rice containing monacolins K and KA in the ratio 1:1 but no secondary monacolins, dehydromonacolins, or citrinin (Monakopure™-K20). METHODS: We retrospectively evaluated the effects of BSM in 59 diabetic patients with dyslipidemia and compared the results to those obtained in patients without treatment. Enrolled subjects had a diagnosis of IBS (and diarrhea), had diarrhea caused by metformin, or were statin intolerant. RESULTS: After 6 months of BSM treatment, significant reductions of approximately 5%, 23%, 31%, and 20% were observed in glycated hemoglobin (HbA1c), total cholesterol (TC), low density lipoprotein-cholesterol (LDL), and triglyceride (TG) levels, respectively, and only five of the 31 treated subjects reported diarrhea compared with 22 of the 28 untreated patients. Regarding safety, treatment with BSM did not significant modify creatine phosphokinase (CPK), creatine, aspartate aminotransferase (AST) or alanine aminotransferase (ALT). CONCLUSION: BSM is a safe and effective food supplement likely useful as add-on therapy in diabetic subjects with dyslipidemia, especially if they are statin intolerant or with diarrhea caused by IBS or metformin.

Retrospective analysis of the effects of a highly standardized mixture of Berberis aristata, Silybum marianum, and monacolins K and KA in patients with dyslipidemia.

BACKGROUND: Berberis aristata, because of its berberine content, and Monascus purpureus fermented rice, because of the presence of monacolins (naturally derived statins), are widely investigated food-grade ingredients used to formulate cholesterol-lowering supplements. Although they are extensively used, berberine is poorly absorbed and monacolins are poorly chemically characterized, not standardized, and possibly contaminated with toxic compounds. Silymarin is reported to enhance berberine absorption, while Monakopure™-K20 (MK-20) is a highly standardized red yeast rice containing monacolins K and KA in the ratio of 1:1 but not secondary monacolins, dehydromonacolins, or citrinin. AIM: The effects of a cholesterol-lowering supplement (Berberol®K) containing berberine, silymarin, and MK-20 (BSM) in patients with dyslipidemia were clinically analyzed. METHODS: The clinical role of BSM in naïve and in statin-intolerant patients was retrospectively evaluated and the effects observed were compared with those obtained in patients without treatment or treated with lovastatin. RESULTS: Total cholesterol, low density lipoprotein, and triglyceride levels were approximately 4%, 6%, and 11% lower, respectively, and the creatine phosphokinase increase was reduced in patients treated with BSM compared to those treated with lovastatin. Similar results were also obtained in statin-intolerant subjects where BSM was administered as add-on therapy to ezetimibe or fenofibrate. CONCLUSION: BSM is a food supplement potentially useful 1) as a primary intervention in low-cardiovascular-risk subjects with dyslipidemia; 2) as add-on therapy in mildly statin-intolerant patients; and 3) in dyslipidemic patients with a negative perception of statins who prefer a treatment seen as natural.

Preliminary study about the possible glycemic clinical advantage in using a fixed combination of Berberis aristata and Silybum marianum standardized extracts versus only Berberis aristata in patients with type 2 diabetes.

BACKGROUND: Berberine is an isoquinoline alkaloid widely used to improve the glucidic and lipidic profiles of patients with hypercholesterolemia, metabolic syndrome, and type 2 diabetes. The limitation of berberine seems to be its poor oral bioavailability, which is affected by the presence, in enterocytes, of P-glycoprotein - an active adenosine triphosphate (ATP)-consuming efflux protein that extrudes berberine into the intestinal lumen, thus limiting its absorption. According to some authors, silymarin, derived from Silybum marianum, could be considered a P-glycoprotein antagonist. AIM: The study aimed to evaluate the role played by a possible P-glycoprotein antagonist (silymarin), when added to a product containing Berberis aristata extract, in terms of benefits to patients with type 2 diabetes. METHODS: The study enrolled 69 patients with type 2 diabetes in suboptimal glycemic control who were treated with diet, hypoglycemic drugs, and in cases of concomitant alterations of the lipid profile, hypolipidemic agents. The patients received an add-on therapy consisting of either a standardized extract of Berberis aristata (titrated in 85% berberine) corresponding to 1,000 mg/day of berberine, or Berberol®, a fixed combination containing the same standardized extract of Berberis aristata plus a standardized extract of Silybum marianum (titrated as >60% in silymarin), for a total intake of 1,000 mg/day of berberine and 210 mg/day of silymarin. RESULTS: Both treatments similarly improved fasting glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, and liver enzyme levels, whereas glycosylated hemoglobin (HbA1c) values were reduced to a greater extent by the fixed combination. CONCLUSION: The association of berberine and silymarin demonstrated to be more effective than berberine alone in reducing HbA1c, when administered at the same dose and in the form of standardized extracts in type 2 diabetic patients.

The role of lifestyle change in the prevention and treatment of NAFLD.

Healthy habits in terms of food intake and physical activity are first-line approach to prevention and treatment of nonalcoholic fatty liver disease, but difficulties arise in turning attempts into practice. Independently of the specific role of individual nutrients, not universally proven, overweight, obesity and diabetes are the specific conditions most frequently associated with hepatic fat accumulation. Accordingly, weight loss is mandatory in the majority of patients; this can be achieved by dietary restriction, but is rarely maintained in the long-term. Physical activity programs, both aerobic and resistance exercise may improve cardiorespiratory fitness, reduce the multiple conditions associated with the metabolic syndrome and help weight loss maintenance. However, motivating sedentary individuals to move is difficult and is favored by structured programs carried out along the lines of cognitive-behavior therapy. The role of behavior therapy is now supported by pilot studies, observational studies and finally by a randomized controlled study with histological outcomes. In the future, behavior interventions might be supported by important technological advances, such as smart phone technology and webbased platforms to facilitate interactive engagement amongst patients and with their health care providers. Lifestyle programs must also incorporate methods of overcoming barriers to accessing health service, engaging with workplace health programs and linking with community attempts to improve public health.

Pilot study on the additive effects of berberine and oral type 2 diabetes agents for patients with suboptimal glycemic control.

BACKGROUND: Suboptimal glycemic control is a common situation in diabetes, regardless of the wide range of drugs available to reach glycemic targets. Basic research in diabetes is endeavoring to identify new actives working as insulin savers, use of which could delay the introduction of injectable insulin or reduce the insulin dose needed. Commonly available as a nutraceutical, berberine is a potential candidate. METHODS AND RESULTS: Because its low oral bioavailability can be overcome by P-glycoprotein inhibitors like herbal polyphenols, we have tested the nutraceutical combination of Berberis aristata extract and Silybum marianum extract (Berberol(®)) in type 2 diabetes in terms of its additive effect when combined with a conventional oral regimen for patients with suboptimal glycemic control. After 90 days of treatment, the nutraceutical association had a positive effect on glycemic and lipid parameters, significantly reducing glycosylated hemoglobin, basal insulin, homeostatic model assessment of insulin resistance, total and low-density lipoprotein cholesterol, and triglycerides. A relevant effect was also observed in terms of liver function by measuring aspartate transaminase and alanine transaminase. The product had a good safety profile, with distinctive gastrointestinal side effects likely due to its acarbose-like action. CONCLUSION: Although further studies should be carried out to confirm our data, Berberol could be considered a good candidate as an adjunctive treatment option in diabetes, especially in patients with suboptimal glycemic control.

Treatment of non-alcoholic fatty liver disease with focus on emerging drugs.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is becoming one of the most common causes of chronic liver disease worldwide. The economic and social cost of disease is very high and there is a need for effective treatments. AREAS COVERED: The available and potential future treatments for NAFLD are reviewed. EXPERT OPINION: Weight loss remains the cornerstone of treatment of hepatic steatosis, but difficult to pursue. A pragmatic approach relies on generic recommendations for weight loss and physical activity in the whole population and limiting interventions to subject at risk of disease progression, but the type of preferred treatment remains a matter of debate. The large number and mechanistic diversity of drugs that have so far been investigated bear testimony to the lack of a specific, effective agent. Insulin resistance remains the pivotal alteration responsible for liver disease and its progression and insulin sensitizers are regarded as the treatment of choice. Several ongoing studies are testing the effectiveness of new approaches on histological outcomes and new metabolic pathways are under scrutiny.

Clinical and psychological correlates of health-related quality of life in obese patients.

BACKGROUND: Health-related quality of life (HRQL) is poor in obese subjects and is a relevant outcome in intervention studies. We aimed to determine factors associated with poor HRQL in obese patients seeking weight loss in medical units, outside specific research projects. METHODS: HRQL, together with a number of demographic and clinical parameters, was studied with generic (SF-36, PGWB) and disease-specific (ORWELL-97) questionnaires in an unselected sample of 1,886 (1,494 women; 392 men) obese (BMI > 30 kg/m2) patients aged 20-65 years attending 25 medical units scattered throughout Italy. The clinics provide weight loss treatment using different programs. General psychopathology (SCL-90 questionnaire), the presence of binge eating (Binge Eating scale), previous weight cycling and somatic comorbidity (Charlson's index) were also determined. Scores on SF-36 and PGWB were compared with Italian population norms, and their association with putative determinants of HRQL after adjustment for confounders was assessed through logistic regression analysis. RESULTS: HRQL scores were significantly lower in women than in men. A greater impairment of quality of life was observed in relation to increasing BMI class, concurrent psychopathology, associated somatic diseases, binge eating, and weight cycling. In multivariate analysis, psychopathology (presence of previously-diagnosed mental disorders and/or elevated scores on SCL-90) was associated with lower HRQL scores on both psychosocial and somatic domains; somatic diseases and higher BMI, after adjustment for confounders, were associated with impairment of physical domains, while binge eating and weight cycling appeared to affect psychosocial domains only. CONCLUSIONS: Psychopathological disturbances are the most relevant factors associated with poor HRQL in obese patients, affecting not only psychosocial, but also physical domains, largely independent of the severity of obesity. Psychological/psychiatric interventions are essential for a comprehensive treatment of obesity, and to improve treatment outcome and to reduce the burden of disease.

Metabolic syndrome and insulin resistance in subjects with morbid obesity.

BACKGROUND: There is evidence that a group of subjects with obesity fits the characteristics of metabolically healthy but obese population. We aimed to assess the prevalence of the metabolic syndrome (MS) in nondiabetic subjects with morbid obesity (body mass index (BMI) > or = 40 kg/m2) and its correlation with insulin resistance. METHODS: We analyzed the data of 211 patients (55 males and 156 females) with morbid obesity and without overt diabetes, consecutive referred for weight loss management. All subjects underwent an oral glucose tolerance test, and insulin resistance was calculated by the homeostasis model assessment (HOMA) at baseline and by the oral glucose insulin sensitivity (OGIS) during the glucose and insulin curve. Clinical and biochemical features of MS were also determined. RESULTS: The criteria for MS were fulfilled in 74% of cases, and 10 patients had obesity as the sole feature. HOMA-R was normal in 26% of cases, whereas, OGIS was normal only in three females. HOMA-R and OGIS significantly differed in relation to the presence of MS, and a trend was observed in both tests as function of the number of factors of MS (P < 0.001). At logistic regression analysis, after adjustment for age, sex, BMI at age 20 years, present BMI, and waist circumference, OGIS was the only parameter of insulin resistance significantly associated with MS (odds ratio, 2.42; 95% confidence interval, 1.63-3.60). CONCLUSIONS: A small number of metabolically healthy, but obese cases exist also in the subgroup of patients with morbid obesity in which insulin resistance maintains its pivotal role.

Psychological distress in morbid obesity in relation to weight history.

BACKGROUND: Very few data are available on psychological distress in morbidly obese subjects in relation to the history of their weight. In subjects with childhood obesity, psychological distress might be better than in adult-onset obesity, because of progressive adaptation to the social stigma. METHODS: Psychological distress was tested in relation to BMI at age 20 years (BMI-20), weight history and somatic co-morbidities in 632 treatment-seeking, morbidly obese participants from the QUOVADIS cohort (130 men, 502 women; mean age 45.5 years). The number of dieting attempts/year, BMI increase and cumulative BMI loss since age 20 were calculated as weight cycling parameters. The Symptom Check List-90 (SCL-90), the Psychological General Well-Being (PGWB), the Binge-Eating Scale, and the ORWELL-97 questionnaire were used to score psychometry and health-related quality of life (HRQL). Complications were quantitatively assessed by a modified Charlson's score. RESULTS: BMI-20 was normal in 35% of cases and >35 kg/m2 in only 14%. Psychometric scores were not different in relation to BMI-20, when corrected for age, with the exception of the General Health scale of PGWB, showing a greater distress in subjects with normal BMI-20. In most cases, the prevalence of pathological results of questionnaires showed a J-shaped curve, with participants with normal BMI-20 or those with Class II-III obesity in early adulthood having the highest prevalence of psychological/psychiatric distress and poor HRQL. Weight cycling was a risk factor for binge-eating, depression and interpersonal sensitivity in SCL-90, whereas somatic co-morbidities adversely affected most SCL-90 and all PGWB scales. CONCLUSION: Weight cycling and somatic co-morbidities, but not age of onset of obesity, are the main factors negatively influencing psychological health in treatment-seeking, morbidly obese subjects.

Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is consistently associated with features of the metabolic syndrome, a condition carrying a high risk of cardiovascular events. We measured the vasodilatory response of the brachial artery in response to ischemia (a test of endothelial function) (FMV) as well as cardiovascular risk profile in 52 NAFLD cases and 28 age- and sex-matched controls. The 10-year risk of coronary events was calculated according to the Framingham equation and the scores derived from the PROCAM study and NCEP-ATPIII proposals. FMV was 6.33% +/- 5.93% in NAFLD versus 12.22% +/- 5.05% in controls (P < .0001), and higher in pure fatty liver (9.93%) compared with nonalcoholic steatohepatitis (4.94%) (P = .010). No differences were observed in flow-independent vasodilation (response to sublingual nitroglycerin). Percent FMV was negatively associated with insulin resistance (homeostasis model assessment) in the whole population (r = -0.243; P = .030). In logistic regression analysis, NAFLD was associated with a percent FMV in the lower tertile (OR, 6.7; 95% CI, 1.26-36.1), after adjustment for age, sex, body mass index, and insulin resistance. Among NAFLD patients, low FMV was associated with nonalcoholic steatohepatitis (adjusted OR, 6.8; 95% CI, 1.2-40.2). The 10-year probability of cardiovascular events was moderately increased in NAFLD, and particularly in nonalcoholic steatohepatitis. In conclusion, our study provides evidence of endothelial dysfunction and increased risk of cardiovascular events in NAFLD. The risk of advanced liver disease is well recognized in NAFLD patients, but the large majority of cases might experience cardiovascular disease in the long term, indirectly limiting the burden of liver failure.

A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease.

OBJECTIVES: Metformin proved useful in the treatment of nonalcoholic fatty liver disease (NAFLD), but its superiority over nutritional treatment and antioxidants has never been demonstrated. We aimed to compare the usefulness of metformin versus prescriptive diet or vitamin E. METHODS: In an open label, randomized trial, nondiabetic NAFLD patients were given metformin (2 g/day; n = 55) for 12 months. The control cases were given either vitamin E (800 IU/day; n = 28) or were treated by a prescriptive, weight-reducing diet (n = 27). Outcome measures were liver enzymes, insulin resistance (homeostasis model assessment), parameters of the metabolic syndrome, and histology. RESULTS: Aminotransferase levels improved in all groups, in association with weight loss. The effects in the metformin arm were larger (p < 0.0001), and alanine aminotransferase normalized in 56% of cases (odds ratio (OR) versus. controls, 3.11; 95% confidence interval (CI), 1.56-6.20; p= 0.0013). In multivariate analysis, metformin treatment was associated with higher rates of aminotransferase normalization, after correction for age, gender, basal aminotransferases, and change in body mass index (OR, 5.98; 95% CI, 2.05-17.45). Differences were maintained when the two control groups were separately analyzed. The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm (p= 0.001, signed rank test). A control biopsy in 17 metformin-treated cases (14 nonresponders) showed a significant decrease in liver fat (p= 0.0004), necroinflammation, and fibrosis (p= 0.012 for both). No side effects were observed during metformin treatment. CONCLUSIONS: Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling. Limited histological data support an association between improved aminotransferases and biopsy findings, which require confirmation in a double-blind trial with appropriate statistical power based on liver histology.

Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): treatment.

Non-alcoholic fatty liver disease is now recognized as a cause of potentially progressive liver damage, posing patients at risk of advanced liver failure. Unfortunately, the natural history of disease is only partly known, the disease is slowly progressive and therapeutic outcomes are difficult to define. These factors have limited therapeutic trials to pilot studies, and very few randomized-controlled studies are available. The concept that insulin-resistance, coupled with oxidative stress, may be the underlying mechanism responsible for fat accumulation and disease progression points to insulin-sensitizing agents (metformin, thiazolidinediones) as the most promising drugs. They proved effective in reducing enzyme levels in the short period, but very limited information is available on liver histology, not to say progression to liver cell failure. Large, long-term, placebo-controlled randomized studies are eagerly awaited. Outside controlled studies, nutritional counselling and physical exercise aimed at moderate weight loss remain the basis of any therapeutic intervention.

Plasma ghrelin concentrations, food intake, and anorexia in liver failure.

Ghrelin is related to feeding behavior and nutrition in several physiological and pathological conditions. We tested the hypothesis that the anorexia and the decreased food intake of advanced liver failure might be associated with hyperghrelinemia. Fasting ghrelin was measured in 43 cirrhotic patients, food intake was self-assessed using the Corli score and a 3-d dietary record (n = 25), and anorexia/hunger was tested by a Likert scale. Fifty healthy subjects, matched for age and body mass index, served as controls. Ghrelin levels were not systematically increased in cirrhosis (414 +/- 164 vs. 398 +/- 142 pmol/liter in controls) but increased with decreasing Corli score (P = 0.014) and along the scale of anorexia/hunger (P = 0.0001), which were both related to the 3-d dietary record (P = 0.009 and P < 0.0001, respectively). Logistical regression confirmed that high ghrelin (>500 pmol/liter) was significantly associated with a low calorie intake [odds ratio (OR), 3.03 for any 100-calorie reduced intake; P = 0.015], a reduced Corli score (OR, 3.09; P = 0.031), and the anorexia score (OR, 3.37; P = 0.009), after adjustment for body mass index. The study confirms the previously observed relationship of fasting ghrelin with food intake in disease-associated malnutrition. In the presence of anorexia, hyperghrelinemia might indicate a compensatory mechanism trying to stimulate food intake, which is nonetheless ineffective in the physiological range.

Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) has been associated with the insulin-resistance syndrome, at present defined as the metabolic syndrome, whose limits were recently set. We assessed the prevalence of the metabolic syndrome in 304 consecutive NAFLD patients without overt diabetes, on the basis of 3 or more criteria out of 5 defined by the U.S. National Institutes of Health (waist circumference, glucose, high-density lipoprotein [HDL]-cholesterol, triglycerides, and arterial pressure). The prevalence of the metabolic syndrome increased with increasing body mass index, from 18% in normal-weight subjects to 67% in obesity. Insulin resistance (Homeostasis Model Assessment method) was significantly associated with the metabolic syndrome (odds ratio [OR], 2.5; 95% CI, 1.5-4.2; P <.001). Liver biopsy was available in 163 cases (54%). A total of 120 patients (73.6%) were classified as having nonalcoholic steatohepatitis (NASH); 88% of them had a metabolic syndrome (vs. 53% of patients with pure fatty liver; P <.0001). Logistic regression analysis confirmed that the presence of metabolic syndrome carried a high risk of NASH among NAFLD subjects (OR, 3.2; 95% CI, 1.2-8.9; P =.026) after correction for sex, age, and body mass. In particular, the syndrome was associated with a high risk of severe fibrosis (OR, 3.5; 95% CI, 1.1-11.2; P =.032). In conclusion, the presence of multiple metabolic disorders is associated with a potentially progressive, severe liver disease. The increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension, and ultimately the metabolic syndrome puts a very large population at risk of forthcoming liver failure in the next decades.