Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients With Concurrent Type 2 Diabetes Mellitus and Non-Alcoholic Steatohepatitis: A Review of the Evidence

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and more than half of individuals diagnosed with type 2 diabetes concurrently present with NAFLD. There is a bidirectional pathological relationship between the two conditions, whereby NAFLD increases the risk of type 2 diabetes, and type 2 diabetes contributes to and accelerates the progression of NAFLD. Furthermore, over 30% of patients with NAFLD progress to non-alcoholic liver steatohepatitis (NASH), which then increases the risk of cirrhosis and hepatocellular carcinoma. Despite its high prevalence and the potential clinical implications, the underlying pathogenesis of NAFLD has yet to be fully elucidated, and there is no consensus regarding standard diagnosis and treatment for either NALFD or NASH. As patients with both NASH and type 2 diabetes have impaired hepatic function owing to chronic inflammation and the resulting structural changes caused by hepatic fat accumulation, they face reduced options for antidiabetic treatment. SGLT-2 inhibitors inhibit glucose reabsorption in the proximal tubule, with increased excretion of glucose in urine and decreased glucose levels in plasma, and their glycemia-lowering effect is insulin-independent. Several other beneficial effects have been reported for SGLT-2 inhibitors, including reduced risks of cardiovascular and renal diseases, improved blood pressure control, body weight reduction, and reductions in liver fat content. Experimental studies in mouse models have suggested that SGLT-2 inhibitors may have beneficial modulatory effects on NAFLD/NASH. Several trials in patients with type 2 diabetes have also suggested that these drugs may be useful in treating both type 2 diabetes and NAFLD or NASH. However, further research is needed to identify the mechanisms by which SGLT-2 inhibitors affect fatty liver and steatohepatitis. In this state-of-the-art review, we explore the literature on the efficacy of SGLT-2 inhibitors in patients with type 2 diabetes and NASH, and present arguments for and against the use of SGLT-2 inhibitors in this patient population.

Preparation of O/W nano-emulsion containing nettle and fenugreek extract and cumin essential oil for evaluating antidiabetic properties

The oil-in-water (O/W) nano-emulsion (NE) is expanded to enhance the bioavailability of hydrophobic compounds. The NE can be prepared by herbal extract and essential oil as herbal medicines for antidiabetic treatment. In the present study, the O/W NE was prepared by fenugreek extract (FE), nettle extract (NE), and cumin essential oil (CEO) using tween 80 and span 80 surfactants in an ultrasonic bath, at room temperature within 18 min. The antidiabetic property was evaluated by determining glucose absorption using cultured rat L6 myoblast cell line (L6) myotubes and insulin secretion using the cultured mouse pancreatic beta-cell (RIN-5) for NEs. The samples were investigated by dynamic light scattering (DLS) to examine the size distribution and size, zeta potential for the charge determination, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) to investigate morphology and size. The rheological properties were studied by viscosity. The sample stability was evaluated at different temperatures and days by DLS and SEM analyses. The cytotoxicity of samples was explored by MTT assay for HEK293 human cell line as a specific cell line originally derived from human embryonic kidney cells at three different concentrations for three periods of time. The NEs with nanometer-size were observed with antidiabetic properties, low cytotoxicity, and suitable stability. This study provides definitive evidence for the NE as a plant medicine with antidiabetic properties. The NE can be a good candidate for biomedical applications.

Metabolically Abnormal But Normal-Weight Individuals Had a Higher Risk of Type 2 Diabetes Mellitus in a Cohort Study of a Chinese Population

AimsObesity is a heterogeneous disease in terms of body mass index (BMI) and metabolic status. The purpose of this study was to investigate the risk of type 2 diabetes mellitus (T2DM) in subjects with metabolically abnormal but normal weight (MANW) in China.Materials and MethodsA prospective cohort with a total of 17,238 participants of the Zhejiang metabolic syndrome cohort was recruited. According to the standard of the Working Group on Obesity in China, general obesity is defined. Metabolic abnormality was defined as two or more abnormal components (elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), elevated systolic blood pressure (SBP) or diastolic blood pressure (DBP) or use of antihypertensive therapy, and elevated fasting plasma glucose or antidiabetic treatment). The hazard ratio (HR) and its 95% CI were calculated using a multiple regression model, adjusted for the potential confounding factors.ResultsCompared with metabolically normal and normal weight (MNNW) subjects, the metabolically abnormal and obesity/overweight (MAO) subjects had the highest risk of T2DM disease, with an HR of 4.67 (95% CI: 3.23–6.76), followed by MANW subjects (HR = 2.61, 95% CI: 1.74–3.92) and metabolically normal but obesity/overweight (MNO) subjects (HR = 2.09, 95% CI: 1.29–3.38) after adjusting for age, sex, smoking, drinking, physical activity, and family history of diabetes. Compared with that in the MNNW subjects, the HR in MANW subjects was significantly higher than that in MNO subjects. In normal-weight subjects, the HR of T2DM was significantly positively correlated with the number of components with metabolic abnormalities.ConclusionsMANW subjects had a higher risk of T2DM. MANW subjects should be given more attention in the prevention and control of common chronic diseases.

Adherence to antidiabetic treatment and impaired hypoglycemia awareness in type 2 diabetes mellitus assessed in Spanish community pharmacies: the ADHIFAC study

IntroductionAdherence to treatment and hypoglycemia awareness are strongly linked to glycemic control and hypoglycemia risk in people with type 2 diabetes mellitus (T2DM). Community pharmacies are suitable facilities to detect these conditions, and should be involved in the strategies to minimize the associated risks and burden.Research design and methodsThis cross-sectional study conducted at community pharmacies across Spain assessed the prevalence of low adherence to antidiabetic treatments, the frequency of impaired hypoglycemia awareness, and their predictive factors. Adherence was measured with the 8-item Morisky Medication Adherence Scale (MMAS-8) and electronic records of dispensed treatments. The Clarke questionnaire was used to assess impaired hypoglycemia awareness. Healthcare counseling provided in the pharmacy was collected.ResultsSeventy-nine pharmacists and 618 subjects with T2DM participated in the study. Mean age in the overall T2DM population was 67 years, being the majority (69%) pensioners. Adherence was high in 41% of participants, medium in 35%, and low in 24% according to the MMAS-8. Impaired hypoglycemia awareness was observed in 25% of participants. Main determinants of low adherence were the level of education, the number of treatments per patient, hypoglycemia awareness, and the type of pharmacy. Predictive factors of impaired hypoglycemia awareness were the level of education, information on diabetes-related complications, adherence levels, and the type of pharmacy. The proportion of participants who had healthcare counseling was 71% in the overall population and 100% in subjects with impaired hypoglycemia awareness and low adherence. Healthcare counseling comprised diabetes education (69%), pharmacotherapeutic assessment (20%), and physician referrals (11%).ConclusionLack of adherence to antidiabetic treatments and impaired hypoglycemia awareness are frequent and correlate in T2DM. Community pharmacies can detect these conditions and should have an active role in the design of strategies to minimize them.

Characterisation of type 2 diabetes subgroups and their association with ethnicity and clinical outcomes: a UK real-world data study using the East London Database

Background: Subgroups of type 2 diabetes (T2DM) have been well characterised in experimental studies. However, it is unclear whether T2DM subgroups can be identified in UK based real-world populations and if they impact clinical outcomes. Aim: To derive T2DM subgroups using primary care data from a multi-ethnic population, evaluate associations with glycaemic control, treatment initiation and vascular outcomes, and understand how these vary by ethnicity. Design and setting: An observational cohort study in the East London Primary Care Database from 2008-2018. Method: Latent class analysis using age, sex, glycated haemoglobin, and body mass index at diagnosis was used to derive T2DM subgroups in White, South Asian, and Black groups. Time to treatment initiation and vascular outcomes was estimated using multivariable Cox-proportional hazards regression. Results: 31,931 adults with T2DM were included: 47% south Asian, 25% White, 20% Black. We replicated two previously described subgroups, "Mild Age-Related Diabetes" (MARD), "Mild Obesity-related Diabetes" (MOD), and characterised a third "Severe Hyperglycaemic Diabetes" (SHD). Compared to MARD, SHD had the poorest long term glycaemic control, fastest initiation of antidiabetic treatment (HR 2.02, 1.76-2.32), and highest risk of microvascular complications (HR 1.38, 1.28-1.49). MOD had the highest risk of macrovascular complications (HR 1.50, 1.23-1.83). Subgroup differences in treatment initiation were most pronounced for the White group, and vascular complications for the Black group. Conclusions: Clinically useful T2DM subgroups, identified at diagnosis, can be generated in routine real-world multi-ethnic populations, and may offer a pragmatic means to develop stratified primary care pathways and improve healthcare resource allocation.

Idiopathic Frozen Shoulder in Individuals with Diabetes: Association with Metabolic Control, Obesity, Antidiabetic Treatment and Demographic Characteristics in Adults with Type 1 or 2 Diabetes from the DPV Registry

Aims To examine the association of frozen shoulder (FS) with demographic and diabetes-related outcomes in individuals with type 1 (T1D) or type 2 (T2D) diabetes aged ≥30 years. Materials and methods Multivariable logistic regression models, adjusted for demographics were used to calculate the proportion of FS in association with age, gender, diabetes duration, body mass index (BMI), haemoglobin A1C (HbA1c) and diabetes treatment. Results The unadjusted percentage of FS was higher in T1D compared to T2D (0.22% vs. 0.06%). In T1D, adjusted regression models revealed higher prevalence of FS in women than men (0.26 [0.20–0.34] % vs. 0.15 [0.11–0.21] %, p=0.010). No significant relationship of age and BMI with FS was found in both diabetes types. Longer diabetes duration was associated with a higher proportion of FS in T1D (p<0.001) and T2D (p=0.004). In T1D, HbA1c >7% was related to a higher proportion of FS compared to HbA1c ≤7% (0.25 [0.19–0.32] vs. 0.12 [0.08–0.20] %, p=0.007), while an inverse relationship was found in T2D (HbA1c ≤7%: 0.08 [0.07–0.10] vs. HbA1c >7%: 0.05 [0.04–0.06] %, p=0.001). Conclusions Different associations of FS with gender and HbA1c were observed for T1D and T2D; however, longer diabetes duration increases the risk for FS independent of diabetes type. Musculoskeletal diseases are still underreported in individuals with diabetes and awareness should be raised for FS as a specific diabetes complication.

Functional Predictors of Treatment Induced Diabetic Neuropathy (TIND): a Prospective Pilot Study Using Clinical and Neurophysiological Functional Tests

Background: A sudden drop of HbA1c has been linked to TIND. Method: From 60 recruited patients with severe diabetes only 21 patients adhered to the study protocol over one year with autonomic nervous system tests before and after antidiabetic treatment initiation. Results: With a pronounced drop of HbA1c some parameters tended to deteriorate with later improvement. Conclusion: Poor adherence appears as major obstacle in this type of study.Trial registration: Ethic Committee University of Leipzig 439/15-ek. Registered 22 April 2016