Impact of modern glucose-lowering therapies on metabolic dysfunction-associated steatotic liver disease in type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-mimetic agents that are effective adjuncts in the treatment of diabetes. This class of medications is also associated with promoting weight loss and a low risk of hypoglycemia, and some have been shown to be associated with a significant reduction of major cardiovascular events. Mounting evidence suggests that GLP-1 RAs have benefits beyond reducing blood glucose that include improving kidney function in people living with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), a common microvascular complication of T2DM. Several large clinical studies, the majority of which are cardiovascular outcome trials, indicate that GLP-1 RA therapy is safe and tolerable for people living with T2DM and compromised renal function, and also suggest that GLP-1 RAs may have renoprotective properties. Although evidence from clinical trials has shown GLP-1 RAs to be safe and efficacious in people living with T2DM and renal impairment, their use is uncommon in this patient population. With continuing developments in the field of GLP-1 RA therapy, it is important for physicians to understand the benefits and practical use of GLP-1 RAs, as well as the clinical evidence, in order to achieve positive patient outcomes. Here, we review evidence on GLP-1 RA use in people living with T2DM and CKD and summarize renal outcomes from clinical studies. We provide practical considerations for GLP-1 RA use to provide an added benefit to guide treatment in this high-risk patient population.Graphical

To the Editor: Incretin-based therapies for type 2 diabetes mellitus (T2DM) include incretin mimetics of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and incretin enhancers of dipeptidyl peptidase-4 (DPP-4) inhibitors.[1] With good hypoglycemic effects of incretin-based drugs that show no weight gain or hypoglycemia risk, these drugs are increasingly used in patients with T2DM. GLP-1 RAs are considered superior to DPP-4 inhibitors in controlling glycosylated hemoglobin, fasting blood glucose, and body weight.[2] However, the incidence of adverse events, such as adverse gastrointestinal reactions and dizziness caused by GLP-1 RAs, is higher than it is for DPP-4 inhibitors.[3] Unlike other anti-diabetic agents, safety concerns have been raised regarding the risk for gastrointestinal cancer associated with incretin-based treatments. Both a better understanding of their roles as second-line glucose-lowering treatments and a comprehensive assessment of their benefits and harms could inform the choice of treatment in clinical practice. Multicriteria decision analysis (MCDA), a general framework for constructing multicriteria decision models for benefit-risk assessment (BRA), has been widely used in health management and drug evaluation.[4,5] The stochastic multicriteria acceptability analysis (SMAA) model was developed from the traditional MCDA model to reduce the impact of the value preferences of decision-makers without requiring them to give subjective weight to decision-making indicators.[6,7] Previous studies have reviewed the multiple benefit and risk outcomes of GLP-1 RAs and DPP-4 inhibitors, but none have adopted the BRA evaluation model to synthesize multiple outcomes and obtain comprehensive comparison results. In this study, SMAA and network meta-analysis (NMA) were used to analyze the BRA of incretin-based treatments with other anti-diabetic agents to provide more comprehensive evidence for the clinical use of anti-diabetic agents in the treatment of T2DM. The risk/benefit outcomes were identified through reference to previous reviews, NMA, and drug information published by the Food and Drug Administration on incretin-based therapies. These included 26 outcomes, as shown in Figure 1 and Supplementary Table 1, https://links.lww.com/CM9/B446. Medline, Embase, ClinicalTrials.gov, and the Cochrane Library were searched from their inception to March 29, 2019. We used "Glucagon-Like Peptide-1 Receptors" and "Dipeptidyl-Peptidase IV Inhibitors" as keywords or MeSH terms, accompanied by EMTREE terms and relevant free words to search these databases.Figure 1: Value map of the BRA index of incretin-based therapies. Network plot presenting the trial data contributing evidence comparing incretin-based therapies for outcomes. (A) FPG, HbA1c, PPG, weight; (B) HDL, LDL, TC, TG; (C) DBP, heart rate, SBP; (D) Constipation, diarrhea, dyspepsia, gastroenteritis, nausea, vomiting; (E) All-cause death, hypertension, hypoglycemia, MACE, pancreatitis; (F) Arthralgia, cancers of digestive system, dizziness, headache. AGI: Alpha-glucosidase inhibitor; BRA: Benefit-risk assessment; DBP: Diastolic blood pressure; DPP-4: Dipeptidyl peptidase-4; FPG: Fasting plasma glucose; GLP-1 RAs: Glucagon-like peptide-1 receptor agonists; HbA1c: Glycosylated hemoglobin; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; MACE: Major adverse cardiovascular events; Met: Metformin; PPG: Postprandial plasma glucose; SBP: Systolic blood pressure; SGLT-2: Sodium-glucose co-transporter 2; SU: Sulfonylureas; TC: Total cholesterol; TG: Triglyceride; TZD: Thiazolidinediones.The inclusion criteria were as follows: (1) reports written in English; (2) randomized clinical trials (RCTs); (3) the subjects were T2DM; (4) the intervention measures were GLP-1 RAs or DPP-4 inhibitors; (5) metformin (Met), sulfonylureas (SU), thiazolidinediones (TZD), alpha-glucosidase inhibitor (AGI), sodium-glucose co-transporter 2 (SGLT-2) inhibitor, insulin, or placebo as control measures; (6) GLP-1 RAs and DPP-4 inhibitors as control drugs; and (7) relevant indicators appearing in the study are included in the literature. Exclusion criteria were as follows: (1) reports not written in English; (2) non-RCTs; (3) the subjects were not T2DM; (4) animal research and other basic research; (5) no GLP-1 RAs and DPP-4 inhibitors in the intervention; and (6) ongoing or unfinished experimental studies. Data were extracted, including trial information (author, title, publication year, sample size, trial duration, types of intervention, and control), population characteristics (diabetes duration, age, baseline level of glycosylated hemoglobin A1c (HbA1c), background treatment), types of intervention and control measures, benefit and risk indicators, and relevant results. Two investigators (FS and SBC) extracted data independently in duplicate. The quality of studies was assessed using the Cochrane risk of bias tool (generation of random sequence, allocation hidden, blind method of the research object, results blind method, data integrity, selective reporting, and funded by company randomization). The Bayesian method was used to analyze each risk/benefit outcome. The measure of each risk/benefit outcome indicator was expressed as mean difference or odds ratio and its 95% confidence interval. The first main result of SMAA was acceptability, that is the probability of the scheme ranking in the evaluation system. The second main result was the confidence factor (CF). This refers to the probability that the alternatives rank first when the central weight vector is selected. Based on SMAA, the results of inconsistent comparison pairs in the NMA results were replaced with the direct comparison of the results of the meta-analysis, and indicators that could be related to each other in the outcome indicators were removed for sensitivity to test the stability of the model results. Of the 26 related BRA outcomes [Figure 1 and Supplementary Table 1, https://links.lww.com/CM9/B446], 11 were benefit indicators, including glycosylated HbA1c, fasting plasma glucose, postprandial plasma glucose, weight, blood lipids, blood pressure, and heart rate. In all, 15 were risk indicators, including all-cause death, pancreatitis, constipation, diarrhea, dyspepsia, gastroenteritis, nausea, vomiting, arthralgia, hypertension, cancers of the digestive system, dizziness, headache, hypoglycemia, and major adverse cardiovascular events. A total of 589 RCTs involving 295,908 patients with T2DM were included. In all, 34 RCTs (16,023 patients with T2DM) on GLP-1 RAs and DPP-4 inhibitors were head-to-head comparisons. In other comparisons, comparators included metformin, SU, TZD, AGI, SGLT-2 inhibitors, insulin, and placebo. The overall quality of the literature is high, except for the high risk associated with the research object, the use of blind methods of outcome evaluation, and corporate sponsorship. We compared the effects of DPP-4 inhibitors and GLP-1 RAs on benefit and risk indicators, respectively. The effects of incretin and insulin, Met, SGLT-2 inhibitors, SU, TZD, and AGI on the benefit and risk indicators were also compared. The acceptability of GLP-1 RAs was better than that of DPP-4 inhibitors in 84.5% of cases. The CF for GLP-1 RAs being better than DPP-4 inhibitors was 99.5%. The acceptability of DPP-4 inhibitors was better than that of insulin in 93.1% of cases, and that of GLP-1 RAs were better than insulin in 90.6% of cases. The CF for DPP-4 inhibitors being better than insulin was 99.5%, and for GLP-1 RAs being better than insulin was 99.9%. The acceptability of Met was better than that of DPP-4 inhibitors in 61.5% of cases, and that of GLP-1 RAs were better than Met in 70.4% of cases. The CF for Met being better than DPP-4 inhibitors was 88.7%, and for GLP-1 RAs being better than Met was 92.2%. The acceptability of SGLT-2 inhibitors was better than that of DPP-4 inhibitors in 93.5% of cases, and that of SGLT-2 inhibitors was better than that of GLP-1 RAs in 76.0% of cases. The CF for SGLT-2 inhibitors being better than DPP-4 inhibitors was 99.7%, and for SGLT-2 inhibitors being better than GLP-1 RAs was 92.9%. The acceptability of DPP-4 inhibitors was better than that of SU in 80.4% of cases, and that of GLP-1 RAs was better than that of SU in 94.2% of cases. The CF for DPP-4 inhibitors being better than SU was 96.4%, and for GLP-1 RAs being better than SU was 99.9%. The acceptability of TZD was better than that of DPP-4 inhibitors in 58.6% of cases, and that of GLP-1 RAs was better than that of TZD in 69.8% of cases. The CF for TZD being better than DPP-4 inhibitors was 90.9%, and that for GLP-1 RAs being better than TZD was 97.1%. The acceptability of DPP-4 inhibitors was better than that of AGI in 72.1% of cases, and that of GLP-1 RAs was better than that of AGI in 89.4% of cases. The CF for DPP-4 inhibitors being better than AGI was 84.6%, and that for GLP-1 RAs being better than AGI was 98.9%. Based on SMAA, GLP-1 RAs were more likely to be superior to DPP-4 inhibitors in terms of BRA. The acceptability of GLP-1 RAs was better than those of insulin, SU, TZD, and AGI but lower than that of SGLT-2 inhibitors. The acceptability of DPP-4 inhibitors was higher than those of insulin and SU but lower than that of Met and SGLT-2 inhibitors. SMAA is a derivative model of MCDA, which is widely used in various industries. As it is presently used in the medical field, MCDA has eight steps: clarifying the decision-making environment, determining the evaluation index, collecting the specific data from each index, normalizing the data collected by each index, giving each index weight, calculating BRA values, conducting sensitivity analyses, and interpreting the results. Unlike the traditional MCDA model, SMAA reduces the impact of the value preferences of evaluators on decision-making and does not need decision-makers to give subjective weight to decision-making indicators. This study had many advantages. First, a total of 589 RCT studies involving 295,908 patients with T2DM were systematically searched and included in it. The sample size was large, and the bias risk for each study was evaluated. Second, 26 risk/benefit outcome indicators related to the treatment of T2DM with incretin were included, and the indicators were comprehensive and representative. Third, the SMAA model used in this study can reduce the subjectivity of decision-makers as they weight the indicators, at least to a certain extent. Further analysis regarding patient-level characteristics and their values and preferences are warranted (Supplementary Link: https://links.lww.com/CM9/B369). (Table 1) Table 1 - Results of SMAA analysis. Drug name Rank acceptability index (%) CF (%) GLP-1 RAs-DPP-4 inhibitors 84.5 99.5 DPP-4 inhibitors-insulin 93.1 99.5 GLP-1 RAs-insulin 90.6 99.9 Met-DPP-4 inhibitors 61.5 88.7 GLP-1 RAs-Met 70.4 92.2 SGLT-2 inhibitors-DPP-4 inhibitors 93.5 99.7 SGLT-2 inhibitors-GLP-1 RAs 76.0 92.9 DPP-4 inhibitors-SU 80.4 96.4 GLP-1 RAs-SU 94.2 99.9 TZD-DPP-4 inhibitors 58.6 90.9 GLP-1 RAs-TZD 69.8 97.1 DPP-4 inhibitors-AGI 72.1 84.6 GLP-1 RAs-AGI 89.4 98.9 AGI: Alpha-glucosidase inhibitor; CF: Confidence factor; DPP-4: Dipeptidyl peptidase-4; GLP-1 Ras: Glucagon-like peptide-1 receptor agonists; Met: Metformin; SGLT-2: Sodium-glucose co-transporter 2; SMAA: Stochastic multi-criteria acceptability analysis; SU: Sulfonylureas; TZD: Thiazolidinediones. Funding This work was supported by a grant from the National Natural Science Foundation of China (No. 72074011). Conflicts of interest None.

Type 2 diabetes mellitus (T2DM) in children and adolescents is becoming an increasingly important public health concern throughout the world (1–17). Because of the relatively recent recognition of the problem in this age group, many children with new onset T2DM may be misclassified as having T1DM. Conversely, as the population becomes heavier, overweight adolescents with autoimmune diabetes may be misdiagnosed as having T2DM. T2DM is often associated with risk factors for cardiovascular disease that may already be present at the time of diagnosis, making normalization of blood glucose levels and diagnosis and treatment of hypertension and dyslipidemia important (18). T2DM occurs when insulin secretion is inadequate to meet the increased demand posed by insulin resistance (19). Thus, T2DM is commonly associated with other features of the insulin resistance syndrome [hyperlipidemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism, non-alcoholic fatty liver disease (NAFLD)] (20). Insulin secretion depends on disease status and duration, and can vary from delayed but markedly elevated in response to a glucose challenge, to absolutely diminished (19). Adults with symptoms have 50% reduction at the time of diagnosis, and may become insulin dependent within a few years (21). T2DM occurs: in youth most often during the second decade of life, with a mean age of diagnosis of ∼13.5 years. This coincides with the peak of physiologic pubertal insulin resistance, which may lead to onset of overt diabetes in previously compensated adolescents. in all races, but at a much greater prevalence in those of non-white European descent, e.g. those of black African descent, native North American, Hispanic (especially Mexican)-American, Asian, South Asian (Indian Peninsula), and Native Pacific islanders. The SEARCH for Diabetes in Youth population-based study found the proportion of physician diagnosed T2DM among 10–19-year-olds to vary greatly by ethnicity in the US: 6% for non-Hispanic whites, 22% for Hispanics, 33% for blacks, 40% for Asians/Pacific Islanders, and 76% for Native Americans (8). In Hong Kong > 90% of young onset diabetes is T2DM (10), in Taiwan 50% (11) and nearly 60% in Japan (Ogawa et al. personal communication). in > 75% of cases in youth in the USA there is a first or second-degree relative with T2DM. in youth in the USA and Europe with body mass index (BMI) above 85th percentile for age and sex. In Japan, however, ∼30% of T2DM are not obese (17), in Asian Indian urban children, half of those with T2DM had normal weight (< 120% ideal for height) (12), and half of Taiwanese children with T2DM were not obese (11). in some asymptomatic individuals in high-risk populations during medical, school, or sports examinations (22,23). in the presence of ketosis/ketoacidosis, one third or more of newly diagnosed patients (24). This presentation is responsible for misclassification of T2DM patients as T1DM. occasionally with severe dehydration (hyperosmolar hyperglycemic coma, hypokalemia) at presentation, which can be fatal (24,25) with a sex ratio (male:female) that varies from 1: 4–1:6 in native North Americans to 1:1 in Asians and Libyan Arabs without associated HLA specificities. without associated islet cell autoimmunity (see autoimmunity T2DM). The pathophysiology of autoimmune 'T2DM' is unclear. It most likely represents autoimmune T1DM in overweight or obese individuals with underlying insulin resistance. It has been postulated that obesity and insulin resistance may promote an inflammatory response to antigen exposure caused by apoptosis of beta cells (26). Youth and adults in US and Europe who are clinically diagnosed with T2DM are found to have T1DM-associated auto-antibodies in 15–40% of cases, including many who are not receiving insulin one year after diagnosis (27–30). Antibody positive young adult individuals with the T2DM phenotype are significantly less overweight and younger than antibody negative patients (21, 27). Hemoglobin (HbA1c) concentrations are significantly higher in young adults with T2DM who are antibody positive compared with those who are antibody negative (27). ß-cell function is significantly less in antibody positive individuals, the most dramatic difference being reported in younger adult patients (25–34 years), resulting in more rapid development of insulin dependence, usually by 3 years duration (27, 30). The presence of islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies in adults with clinically typical T2DM has been referred to as latent autoimmune diabetes of adults (27, 31). Neither the autoimmunity nor the diabetes is latent, however (26). Atypical diabetes mellitus (ADM) occurs throughout childhood, but rarely begins past age 40. It has only been described in young people of African descent. There is a strong family history in multiple generations with an autosomal dominant pattern of inheritance, but an abnormal sex ratio (M : F = 1 : 3). ADM is not associated with HLA specificities and islet autoimmunity does not occur. Ketosis or ketoacidosis is typical at onset. Insulin secretion is present but diminished and without long-term deterioration of function. Interestingly, insulin is often not required for survival after treatment of acute metabolic deterioration, although diabetes control may be poor and ketoacidosis may recur without insulin, e.g. with illness or pregnancy. ADM is not associated with obesity beyond that in the general population and it is not associated with insulin resistance. Monogenic diabetes (formerly referred to as maturity onset diabetes of the young or MODY) For more in depth information see the ISPAD Clinical Consensus Guidelines for Monogenic Diabetes (34). Identified in families with multigenerational diabetes; including asymptomatic individuals identified through testing of family members. Monogenic diabetes is not associated with obesity beyond that in the general population and it is not associated with insulin resistance The clinician is obliged to weigh the evidence in each individual patient to distinguish between T1DM and T2DM. The reasons for this conundrum are: with increasing obesity in childhood, as many as 15–25% of newly diagnosed T1DM (or monogenic diabetes) patients may be obese. the significant number of pediatric patients with T2DM demonstrating ketonuria or ketoacidosis at diagnosis (2). T2DM is common in the general adult population, with a random family history of ∼15% or greater in minority populations, reducing the specificity of a positive family history. positive family history for T2DM is increased for patients with T1DM as much as threefold over the non-diabetic population and T1DM is more frequent in relatives of patients with T2DM (35, 36). There is considerable overlap in insulin or C-peptide measurements between T1DM, T2DM and MODY at onset of diabetes and over the first year or so. This overlap is due to the recovery phase of autoimmune-mediated T1DM (the honeymoon) and degree of glucotoxicity/lipotoxicity impairing insulin secretion at the time of testing in both T1DM and T2DM. In addition the insulin resistance of obesity raises residual C-peptide levels in obese adolescents with T1DM. Such measurements are thus relatively valueless in the acute phase. [The role of C peptide may be more helpful in established diabetes as persistent elevation of C-peptide above the level of normal would be unusual in T1DM after 12–24 months.] The criteria and classification of diabetes are presented in greater detail in the ISPAD Clinical Practice Consensus Guidelines: Definition, Epidemiology, Diagnosis and Classification of Diabetes (37) Diagnostic criteria for diabetes are based on BG measurements and the presence or absence of symptoms (E) (38,39). Three ways to diagnose diabetes are possible and each, in the absence of unequivocal hyperglycemia, must be confirmed, on a subsequent day, by any one of the three methods given below. Diabetes is diagnosed when: A fasting plasma glucose (FPG) is ≥ 7.0 mmol/l (126 mg/dl) or The post challenge plasma glucose is > 11.1 mmol/l (200 mg.dl) performed as described by the World Health Organization (39), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. or Symptoms of diabetes and a casual plasma glucose ≥ 200 mg/dl (11.1 mmol/L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. Diabetes in children, including T2DM, usually presents with characteristic symptoms such as polyuria, polydipsia, blurring of vision, and weight loss, in association with glycosuria and, in some cases, ketonuria. In its most severe form, ketoacidosis or hyperglycemic hyperosmolar state may develop and lead to stupor, coma, and in absence of effective treatment, death. The diagnosis is usually confirmed quickly in symptomatic individuals by measurement of a marked elevation of the blood glucose level. In this situation, if ketones are present in the blood or urine, treatment is urgent. Waiting another day to confirm the hyperglycemia may be dangerous in allowing ketoacidosis or hyperosmolarity to evolve. In the absence of symptoms or presence of mild symptoms of diabetes, hyperglycemia detected incidentally or under conditions of acute infective, traumatic, circulatory, or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. The diagnosis of diabetes, in the absence of symptoms, should not be based on a single plasma glucose concentration. Diagnosis may require continued observation with fasting and/or 2-h postprandial BG levels and/or an oral glucose tolerance test (OGTT). An OGTT should not be performed if diabetes can be diagnosed using fasting, random, or postprandial criteria, as excessive hyperglycemia can result using a fasting OGTT in these circumstances. (E). If doubt remains, periodic re-testing should be undertaken until the diagnosis is established or refuted. There are individuals whose glucose levels do not meet the criteria for diabetes, but are too high to be considered normal. Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate stages in the natural history of disordered carbohydrate metabolism between normal glucose homeostasis and diabetes (E). IFG and IGT are not interchangeable and represent different abnormalities of glucose regulation. IFG is a measure of disturbed carbohydrate metabolism in the basal state, while IGT is a dynamic measure of carbohydrate intolerance after a standardized glucose load. Patients with IFG and/or IGT are now referred to as having 'pre-diabetes', indicating the relatively high risk for development of diabetes in these patients (38). IFG and IGT may be associated with the metabolic syndrome (MS), which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-high density lipoprotein type, and hypertension. Individuals who meet the criteria for IGT or IFG may be euglycemic in their daily lives as shown by normal or near-normal glycated hemoglobin levels, and those with IGT may manifest hyperglycemia only when challenged with an OGTT. FPG < 5.6 mmol/L (100 mg/dL)= normal fasting glucose. FPG 5.6–6.9 mmol/L (100–125 mg/dL)= IFG. FPG ≥ 7.0 mmol/L (126 mg/dL)= provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above under 'Diagnostic criteria for type 2 diabetes'). The corresponding categories for IGT when the OGTT is used are as follows: 2-h postload glucose < 7.8 mmol/l (140 mg/dl)= normal glucose tolerance. 2-h postload glucose 7.8–11.1 mmol/l (140–199 mg/ dl)= IGT. 2-h postload glucose > 11.1 mmol/l (200 mg/dl)= provisional diagnosis of diabetes (the diagnosis must be confirmed with additional testing, as described above). After the diagnosis of diabetes is established, autoantibody testing should be considered when diagnosing and treating T2DM. Diabetes autoantibody testing should be considered in all pediatric patients with the clinical diagnosis of T2DM because of the high frequency of islet cell autoimmunity in otherwise "typical" T2DM. Antibodies will indicate an earlier need for insulin as well as the need to monitor for thyroid autoimmunity and to consider other autoimmune disorders associated with T1DM. (E) Diabetes autoantibody testing also should be considered in overweight/obese children > 13 years of age with a clinical picture of T1DM (weight loss, ketosis/ketoacidosis), some of whom may have T2DM (E) Insulin resistance is an impaired response to the physiologic effects of insulin, including effects on glucose, lipid, and protein metabolism, and on vascular endothelial function. Insulin resistance occurs in most tissues including liver, muscle, and fat tissue and is influenced by sex, age, race/ethnicity, stage of sexual maturation, and total adiposity. While visceral adiposity is important in insulin resistance in adults, the specific contribution of visceral adiposity to insulin resistance in the pediatric population remains uncertain. Several events in development may be associated with increased risk for the insulin resistance syndrome. These include premature adrenarche in girls (pubic hair appearing before the age of 8 years) and being born small for gestational age. Girls with a history of premature adrenarche are at increased risk for ovarian hyperandrogenism and PCOS and thus, insulin resistance (40). Children born small for gestational age are at increased risk for insulin resistance related to decreased intrauterine growth (41) and also at increased risk for premature adrenarche. Diabetes is only one manifestation of the insulin resistance syndrome or the MS (22, 42–50). Other associations include: Obesity: Obesity has deleterious associations with morbidity and cardiovascular risk independent of effects related to insulin resistance and diabetes (51–54). Nephropathy: Albuminuria (either micro- or macro- ) is present at the time of diagnosis in a substantial number of adolescents with T2DM and prevalence increases with duration of diabetes (24). Proteinuria and focal segmental glomerular sclerosis have also been reported in African-American adolescents with severe obesity, in the absence of diabetes (55). Hypertension; Hypertension is estimated to account for 35–75% of diabetes complications, both microvascular and macrovascular (56). Diabetes or impaired glucose tolerance doubles the risk of developing hypertension (57). In addition, there is a possible genetic predisposition to hypertension in T2DM related to the associated angiotensin converting enzyme genotype (58). Hypertension in T2DM is due to volume expansion and increased vascular resistance (59) related to reduced (NO)-mediated vasodilatation and increased activity of the renin-angiotensin system. Dyslipidemia: Hypertriglyceridemia and decreased high-density lipoprotein cholesterol are the hallmarks of T2DM dyslipidemia. Additional findings include elevated very low-density lipoprotein (VLDL), elevated LDL-c, elevated lipoprotein(a), and increased small dense LDL particles. Decreased lipoprotein lipase activity, increased lipoprotein glycation and increased lipoprotein oxidation render the lipoproteins more atherogenic. (60,61) Ovarian hyperandrogenism and premature adrenarche (62): PCOS is being increasingly recognized in adolescents as part of the insulin resistance syndrome. Adolescents with PCOS have ∼40% reduction in insulin-stimulated glucose disposal compared to body composition matched non-hyperandrogenic control subjects (59). Decreasing insulin resistance may improve ovarian function and increase fertility. NAFLD: Hepatic steatosis is present in 25–45% of adolescents with T2DM and more advanced forms of NAFLD, such as non-alcoholic steatohepatitis, are increasingly common and associated with progression to cirrhosis (24, 64). NAFLD now represents the most common cause of cirrhosis in children and the most common reason for liver transplantation in adults in the US. Systemic inflammation: elevated C-reactive protein, inflammatory cytokines and white blood cell counts in obese adolescents have been associated with increased risk for cardiovascular disease in adults (54). Additional health problems related to obesity include Obstructive sleep apnea (OSA) with associated pulmonary hypertension (65), orthopedic problems resulting in diminishing physical activity (66,67), pancreatitis, cholecystitis and pseudotumor cerebri. In adults, there is a strong association between level of hyperglycemia and increased risk of macrovascular disease. Hyperglycemia, dyslipidemia, and hypertension are contributors to the acceleration of atherosclerosis in T2DM, along with oxidative stress, glycation of vascular proteins, and abnormalities of platelet function and coagulation. Defective endothelium dependent vasodilatation is an additional factor accelerating atherosclerosis in T2DM. It is an early sign of increased risk for cardiovascular disease, and predictive of cardiovascular events (68) (B) and occurs in obese children relative to their level of obesity and degree of insulin resistance (69) (B). Co-morbidities characteristic of the insulin resistance syndrome are commonly seen at diagnosis or appear early in the course of T2DM and should be tested for sooner than in T1DM, where these disorders are complications of the diabetes rather than co-morbid conditions (70, 71) (B). A more complete discussion of testing for complications/co-morbidities is presented in the ISPAD Clinical Practice Guidelines for microvascular and macrovascular complications (72). Either micro- or macro-albuminuria, may be present at the time of diagnosis and albuminuria should be evaluated at diagnosis and annually thereafter (55, 72)(E). Likewise, hypertension may be present at, or prior to diagnosis of diabetes and each individual should be evaluated at every visit for hypertension. Dyslipidemia is more common in type 2 diabetes and in family members, (60,61) and should be screened for when metabolic stability is achieved. Evaluation for NAFLD should be done at diagnosis and annually thereafter (24)(E). Inquiries about puberty, menstrual irregularities and obstructive sleep apnea should be made at diagnosis and regularly thereafter (65)(E). Additional information is available in the ISPAD Clinical Practice Guidelines on complications. (72). Dyslipidemia, hypertension and albuminuria are more common in type 2 diabetes compared to type 1 diabetes and may be present at diagnosis and should be assessed after blood glucose control has been optimized. Confirmed hypertension (BP> 95% for age, gender and height) or albuminuria should be treated with an ACE inhibitor or, if not tolerated, an angiotensin receptor blocker (E). Combination therapy may be required if hypertension or albuminuria does not normalize on single agent treatment (E). Side effects are cough, hyperkalemia, headache and impotence (73). In addition, major congenital malformations have been reported with first trimester exposure to ACE inhibitors but not with other antihypertensive agents in non-diabetic women (74). Testing for dyslipidemia should be performed soon after diagnosis when BG control has been achieved and annually thereafter. (60,61) E Goal is LDL-C < 2.6 mmol (100 mg/dl) (68). If LDL-C is borderline (2.6-3.4 mmol;100–129 mg/ dl), or elevated (≥ 3.4 mmol; 130 mg/dl), repeat lipid profile should be performed in 6 months and dietary intervention to decrease total and saturated fat initiated. If LDL-C remains elevated after 3-6 months of attempting to optimize blood glucose control and diet, pharmacotherapy is warranted (72). Statin therapy has been shown to be safe and effective in children as in adults and should be the first pharmacologic intervention (72) although long term safety data are not available. Special attention should be paid to symptoms associated with muscles and connective tissues, as there is an increased risk of rhabdomyolysis The of T2DM in children and adolescents has required that with the of T1DM in children and adolescents the between the treatment of these T1DM is throughout the population to T2DM in North and Europe those with e.g. levels, less less well This has not been described for Asian T2DM. age. T1DM occurs throughout childhood, when is T2DM occurs in when family of families with a with T1DM have family with the disease, while 75% or more of families of the with T2DM have such The of these family to control weight and is with complications in the family and a of and in the treatment In most T1DM, beyond insulin and glucose is only for those individuals who are overweight and In all youth with T2DM, the is on and on glucose and effects of have the of T1DM and blood glucose insulin In in with an that dense increasingly and have to the of T2DM in children and its in of of including hypertension, dyslipidemia, and in the of complications may require more control in insulin T2DM than in T1DM, and attention to as by the Diabetes (21). also the ISPAD Clinical Practice Guidelines for diabetes and family for youth with type 2 diabetes is as important as it is in type 1 diabetes. and for T2DM will on and in insulin therapy and may not be required in T2DM will a greater on dietary and physical activity than is required for T1DM. should be given by with and of the and of youth with T2DM should be in a and age Because the of youth with T2DM are the ISPAD Guidelines for are to the of youth and families with T2DM The family will need to the of treatment of T2DM and to the of the required to T2DM should that the in the diagnosis type 1 type in a minority of patients can be and for the youth and The can be by the of blood glucose metabolism using therapy is to the metabolic of the specific of the of diabetes. is the of treatment of T2DM The family and should the of obesity and T2DM. must have an of the health and of the to an effective should be made in small and with the that these need to be The patient and family should be to monitor the and of and physical in any a and is for The and treatment for T2DM should include a and/or to a with and in of children with is should be to family and should be to all The family should be to dietary with including for weight reduced total and saturated fat increased and increased physical activity specific dietary are given in the ISPAD Guidelines for dietary should include: on and in of these and and for can result in substantial weight and is one of the most important for weight loss. and for the family and for the patient in an age including about dietary and activity related to and activity by of and using for that should be on in one with other activity as a family and should be in a or and not from a or of high density and in the the of and control of positive of or weight reduction in high and for and activity as for of and activity and for and should be for each patient and family that are to family and and should be to all A family or should be identified who is available to in physical activity with the may be to patients and family members. to with the dietary and is important to the of the should include: and an daily is to the of increased at reducing such as the and the time in related may be the most effective activity to be as a This should include daily to be more such as using of or to and to and and (E). for to and physical activity, including increases in daily (E). of blood glucose should be performed of should be and include a of fasting and postprandial glucose have been fasting a and daily post after the are while the within the (E). If the impaired glucose tolerance more frequent testing should be for of acute illness or when symptoms of or patients should more frequent testing and be in with their diabetes for (E). Patients on insulin or need to monitor for asymptomatic (E). should be at a year and if insulin is being used or metabolic control is should be continued in addition to pharmacologic therapy The of pharmacologic therapy is to decrease insulin resistance, increase insulin or to postprandial glucose The first used should be It has the over of reduction in without the risk of weight is decreased or remains and LDL-C and levels decrease during for type 2 diabetes in children and adolescents. of with over 3 months the need to a or insulin or in with a or a inhibitor Patients for should be on the effects of diabetes and oral agents on and oral agent should be used during pregnancy.

Endocrinology for the hepatologist.

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

With nearly 100 million people affected in the United States with nonalcoholic fatty liver disease (NAFLD) and projections for the advanced stages of NAFLD to soon become the leading indication for liver transplantation, nonalcoholic steatohepatitis (NASH) remains a significant area of unmet medical need. Therapeutic options for NASH are a critical priority for clinicians, drug developers and regulatory authorities. The epidemic proportions have led to a surge in the development of novel drugs aimed at the complex pathogenesis of NASH and in regulatory submissions. There are currently no approved drugs in the United States for the treatment of adult or paediatric NASH. Potential therapeutic targets include steatosis, glucose metabolism, lipogenesis, oxidative stress, apoptosis, fibrosis and immunomodulation, all intended to alter the pathophysiology of NASH and remedy its associated complications. While over 50 candidate drugs are currently under development in the United States, it has yet to be determined the extent to which single agents will be impactful on the multifactorial aetiology of NASH based on publicly available preliminary data.1 The primary challenges in NASH drug development have included the appropriateness of biopsy-based end-points and related statistical handling, drug development for cirrhosis, a cure-based focus (ie only a handful of programmes evaluating symptom-based indications such as ascites, hepatic encephalopathy and variceal bleeding) and paediatric drug development. In addition to the possible role for combination therapies, novel approaches are likely needed within discovery and regulatory science to actualize health solutions for NASH patients across the globe. Such solutions should include further exploration of the relationship between NASH and other metabolic diseases of energy homeostasis such as obesity, dyslipidaemia and type 2 diabetes mellitus (T2DM). This article will discuss the current regulatory landscape for NASH and examines the overlap of the regulatory perspectives between NASH and other metabolic diseases. The FDA currently supports commercial drug development in NASH with advanced stage fibrosis as these patients are at a higher risk for liver-related adverse clinical outcomes. There are two types of regulatory approval pathways: traditional (also known as regular or "full") and accelerated approval. Traditional approval relies on clinical benefit end-points which directly measure how a patient feels, functions and survives (eg morbidity and mortality) and would require durations in the order of decades for trials in precirrhotic NASH patients. Accelerated approval2 is one of FDA's expedited programmes intended to facilitate drug development for serious medical conditions, for example those with unmet need, lack available therapy or where lengthy trials would be required to measure the direct clinical benefit of a drug. This pathway ensures that therapies for serious conditions are available to patients as soon as it can be concluded that the therapies' benefits justify their risks. Accelerated approval relies on appropriate surrogate or intermediate clinical end-points that are more readily measured and considered reasonably likely to predict clinical benefit. A post-market study to further define the clinical benefit and confirm the prediction is generally underway at the time of accelerated approval. Due to the long duration needed to assess NASH outcomes, an accelerated approval pathway using biopsy-based surrogate end-points that are reasonably likely to predict clinical benefit in noncirrhotic NASH has been recommended as discussed below. FDA draft guidance regarding drug development in noncirrhotic NASH with liver fibrosis was published in 20183 with primary aims to facilitate clinical development of drugs for the treatment of noncirrhotic NASH patients with liver fibrosis who are at risk for liver-related adverse outcomes. The target population for these trials should have a histological diagnosis of NASH with liver fibrosis based on a NAFLD activity score (NAS) equal to or >4 with at least 1 point each in inflammation and ballooning in addition to a NASH Clinical Research Network fibrosis score of stage 2 or 3 prior to enrolment. Currently, there is no specific weight criterion for enrolment, but weight should be stable for at least 3 months prior to enrolment. Patients with T2DM can also be enrolled in NASH clinical trials if at least moderately controlled and on stable doses of anti-diabetic medications for at least 3 months. Concomitant medications with the potential to confound the interpretation of efficacy or safety, for example by contributing to the therapeutic effect of a drug for NASH (eg Vitamin E or pioglitazone), should either be discontinued or have been on a stable dose for at least 6-12 months. Biopsy-based end-points of (a) resolution of steatohepatitis on overall histopathologic interpretation and no worsening of fibrosis, (b) one or more stage reduction of fibrosis with no worsening of NAS or (c) both improvement of NAS and fibrosis are the primary basis to support accelerated approval. A candidate drug's effect(s) on the end-point(s) will be dependent on the mechanism of action of the drug with a potential for improvement in either NAS or fibrosis, both or neither in an individual patient. Phase 4 (post-market) confirmatory trials verifying the clinical benefit of these histological end-points and using composite outcome end-points of progression of cirrhosis, reduction of decompensation events, changes in model for end-stage liver disease (MELD) score, liver transplant and all-cause mortality, should generally be underway at the time of submission of the marketing application for accelerated approval. End-point selection and planned statistical testing should be discussed with the FDA review division on a case by case basis. The guidance was posted for public comments in December 2018.3, 4 FDA considers these comments prior to finalizing the guidance in order to make revisions where appropriate. Presently, there are 734 global NASH studies in various stages of completion, of which 298 are being conducted in the United States.1 Submitted protocol sample sizes have ranged from 300 to 500 subjects in phase 2 trials, 1000-2000 subjects in pivotal phase 3 trials and 1000-2500 subjects in phase 4 trials. Histology remains an imperfect reference standard for NASH diagnosis and monitoring because its use is accompanied by drawbacks including the invasiveness of liver biopsies (particularly in paediatric patients), sampling error due to at most 1/50 000th of the entire liver sampled, intra- and interobserver variability, costs and a low but observable risk of serious complications. While it is not yet known whether the effect of any particular drug will be precisely and comprehensively characterized by the inflammatory and fibrotic components of NASH injury as assessed by the histological method or whether the current 12-18 months duration of clinical trials will be sufficiently long to allow detection of treatment effects, what is known is that the fibrosis component of the NASH pattern of injury is the strongest predictor for adverse outcomes in patients.5 The early failed trials in NASH,6 while instructive in identifying certain trial issues such as the placebo effect and the natural course of disease, provided limited information in elucidating the causes of trial failure. For example, it is unclear whether the expected changes in histology were too subtle for current modalities of detection such as the one-stage reduction in fibrosis, and/or whether a much longer period of time is required prior to assessments when considered in the context of a life-long chronic disease. In terms of the latter, there could be ethical concerns raised if patients were asked to enrol in exceedingly long outcome trials without preliminary evidence of benefit during the conduct of such trials. However, there is little dispute that knowledge obtained from trials with negative findings in conjunction with the increased collaborative efforts in collection of natural history information and biomarker development7-10 are laying the foundation for future NASH trial designs. The described limitations and complications of biopsy assessments support the urgent need of noninvasive diagnostic tools through increasing research and fit-for-purpose use. Currently, multiple biomarkers11 for NASH including biochemical, imaging, genetic and various omics platforms are being explored in early phase clinical trials. Some of the important regulatory considerations for biomarker use in drug development are the use of standardized definitions,12 identification of appropriate context of use(s), qualification13 for specified drug development needs and validation through multiple studies. The feasibility of optional/voluntary biopsies performed concurrently with noninvasive tests, and outcome assessments should be considered in NASH clinical trials for obtaining a potential correlation of results between these modalities. DGIEP has employed the recommendation of a much smaller alpha (ie probability of concluding that there is a treatment effect, when in fact there is none) to achieve statistical significance for biopsy-based NASH end-point(s) in phase 3 trials and allow greater certainty in predicting the relationship between histology and clinical benefit. Another increasingly recognized challenge that is essential to trial design is maintenance of ongoing trial conduct and integrity after accelerated approval or public dissemination of interim data which should be prospectively planned. A detailed unblinding plan, careful selection of database lock and cut-off date, projections of patient adherence and retention, subject awareness through updates to the informed consent document, and measurement of operational characteristics over time are important considerations for maintaining post-approval, ongoing trial integrity. For clinical outcome trials, there may be drivers of the clinical benefit end-point (eg progression to cirrhosis component may contribute a greater number of events as it will occur more frequently than other components comprising the composite end-point); while this may allow earlier completion of trials in a shorter duration, it may not evaluate all aspects of the disease and this will need to be factored into the data review and analysis to ensure that a positive treatment response is not an isolated effect. FDA draft guidance regarding drug development in NASH with compensated cirrhosis was published in 2019.14 Drug development for NASH with cirrhosis is challenged with appropriately defining this inherently higher risk population for clinical trials and recognizing end-points that have an observable impact on the advanced disease physiology. Noninvasive evidence of cirrhosis may be acceptable in early phase trials, while trials intended to support a marketing application should provide evidence of histologic confirmation of the treatment effect. The current emphasis is placed on trials in a compensated cirrhosis population with end-points of reduction of decompensation events; however, composite end-points using markers of liver synthetic and functional capacity could be explored in current and future trials to counter the potential for heterogeneity in the target population secondary to the substages of cirrhosis. In general, FDA has not recommended combining precirrhotic and cirrhotic patients in the same trial because of the differences in monitoring and management which will likely complicate trial design. If both patient populations are included in the same trial, separate inclusion/exclusion criteria, independent powering of the two subpopulations and a differential schedule of clinic monitoring are recommended. Significant efficacy results in the overall trial population will need to be supported by positive results from each of the subpopulations. The guidance does not recommend inclusion of patients with decompensated cirrhosis or those nearing a decompensated stage because the clinical status of these patients may not be sufficiently stable for the recommended duration of these trials. At present, FDA recommends that clinical trial protocols in populations with NASH with compensated cirrhosis not exceed 25%-30% cryptogenic cirrhosis patients, a proportion similar to that expected for the upper range15 of real-world biopsies, unless otherwise adequately justified. Trials agnostic to cirrhosis aetiology may avoid the challenge of attributing NASH causality in the diagnostic dilemma of cryptogenic cirrhosis.16 The Agency has encouraged obtaining historical biopsies to confirm prior presence of steatohepatitis to support a diagnosis of NASH as the underlying aetiology when enrolling patients with cryptogenic cirrhosis. Trials examining symptomatic improvement of cirrhosis complications such as ascites, variceal bleeding and hepatic encephalopathy currently represent only a small proportion of the NASH-trial landscape but are greatly needed in improving morbidity and symptomatic burden of patients while awaiting development and approval of disease-modifying therapeutic options. The perceived challenges of such trials may be related to the disease severity of the target population, lack of available validated patient-reported outcome (PRO17-19) instruments, associated regulatory requirements and few examples of approved labelling based on PROs within FDA in general. Use of fit-for-purpose instruments with appropriate conceptual frameworks and evidence of content validity along with early engagement with the FDA are necessary to promote drug development that incorporates the patient voice.20 The primary safety conundrum for NASH drug development is that investigational agents intended to treat liver disease can also result in liver injury.21 For this reason, early hepatic impairment studies are encouraged to better characterize the study drug prior to studies in higher risk populations (eg cirrhosis) and because patients may progress to cirrhosis during the conduct of clinical trials. Detailed drug-induced liver injury (DILI) evaluation and management algorithms in addition to close monitoring as per the DILI guidance22 are recommended in the setting of suspected DILI. While the DILI guidance may not be fully applicable to patients with underlying liver disease and elevated liver biochemical baselines, it remains the cornerstone for liver safety monitoring in clinical trials. The Agency is aware of this knowledge gap and is engaged globally in collaborative discussions23, 24 to address the need for guidelines specific to patients with pre-existing liver disease. It has been estimated that as many as 75% of patients with obesity have NAFLD and 20% have NASH.25, 26 Obesity, insulin resistance, T2DM and dyslipidaemia increase the risk of progression from nonalcoholic fatty liver (NAFL) to NASH.27, 28 The treatment of obesity provides an opportunity to simultaneously address co-existing metabolic diseases, including NASH. Likewise, weight loss strategies—including lifestyle and surgical interventions—have the potential to improve outcomes in NASH patients by normalizing liver enzymes, inducing regression in hepatic pathology, and mitigating cardiovascular risk factors.5, 29 There are limited data to suggest whether drug-induced weight loss can directly mediate these effects; however, therapies that could effectively treat obesity, its related co-morbidities and NASH are highly desirable. The most recently updated FDA draft guidance for weight management was published in 2007.28 The draft guidance outlines the patient population, programme size and duration, and end-points for evaluation of obesity drugs in all phases of development. Patients with BMIs greater than or equal to 30 kg/m2 or greater than or equal to 27 kg/m2 in the presence of weight-related co-morbidities are thought to be at significant risk for weight-related morbidity and mortality that would justify the use of drug treatment. The draft guidance cites the examples of T2DM, hypertension, dyslipidaemia, sleep apnoea and cardiovascular disease as weight-related co-morbidities. Although not specifically discussed in the draft guidance, obesity drug trials likely enrol many patients with NAFLD given the overlap in these populations. Special attention should be given to enrolment criteria and safety monitoring plans when including a significant proportion of NASH patients, particularly in those drug development programmes that have demonstrated potential for nonclinical and/or clinical signals of liver toxicity. Weight change from baseline is the primary efficacy end-point in placebo-controlled trials for obesity drugs, and the guidance specifies that weight loss should be demonstrated over the course of at least one-year duration. The goals of weight loss in obesity management are to prevent or slow the progression of obesity-related health outcomes and improve quality of life. Weight loss of 5 per cent—evaluated as mean change from baseline and in a categorical analysis of the proportion of patients losing 5 per cent body weight—is generally considered clinically meaningful in patients with obesity as it has been associated with improvements in cardiometabolic biomarkers, such as blood pressure, lipids and fasting glucose.30 There are currently 5 drugs that are FDA-approved for chronic weight management in patients with obesity: orlistat (gastrointestinal lipase inhibitor), lorcaserin (serotonin 2C receptor agonist), phentermine/topiramate (combination of a sympathomimetic anorectic and an antiepileptic drug), bupropion/naltrexone (combination of an aminoketone antidepressant and an opioid antagonist) and liraglutide (GLP-1 receptor agonist). One-year placebo-subtracted weight loss from baseline body weight as described in the prescribing information ranges from 3% to 9% and depends to a large extent on the patient population, background lifestyle intervention, treatment adherence, study discontinuation rate and the statistical methods used to address missing data. The labelled prescribing information for these drugs includes changes in weight-related secondary end-points, such as blood pressure and lipids, but currently does not include liver-related efficacy end-points, or claims related to the reduction of cardiovascular morbidity and mortality or improvement in quality of life. To date, no obesity drug has demonstrated cardiovascular risk reduction in a dedicated trial. Obesity and severe obesity in children and adolescents ages 2 and above are often defined as a BMI at or above the 95th percentile of sex-specific BMI-for-age and BMI at or above 120% of the 95th percentile, respectively.31 With the rise in paediatric obesity over the last several decades, the prevalence of associated metabolic diseases including NAFL and NASH is also increasing.32-34 As with adults with obesity or NASH, the mainstay of treatment of children and adolescents is lifestyle modification, with the hope and expectation that effective diet and physical activity interventions can prevent or delay many of the associated co-morbidities. Currently, there are limited pharmacological treatment options in children and adolescents with obesity, with only one drug, orlistat, labelled for long-term weight management in patients ages 12 and above. The assessment of certain drugs and biologics in children is required under the Pediatric Research Equity Act,35 and new drugs to treat obesity in children are currently under evaluation. Primary end-points in studies to evaluate obesity treatment in growing children are typically based on changes in BMI or related parameters, and the selection of primary and secondary end-points depends upon the patient population, research question and drug. This is an active area of research, and sponsors are encouraged to discuss their paediatric plans for obesity drugs with the Agency. Paediatric studies in NASH are few and, as with adults, there are no FDA-approved drugs. While several drug manufacturers have identified the need for paediatric studies in NASH as early as possible in their initial paediatric study plans, the path forward is less clear because of the differences in adult and paediatric NASH histopathologic features making it impracticable to extrapolate efficacy from adult data to children, lack of natural history information to define feasible end-points, ethical and regulatory requirements that enrolment of children in drug intervention trials be adequately justified through demonstration of prospect of direct benefit36 to the subject and the need for age-appropriate formulations. Notably, the pressing need for end-points with acceptable invasiveness that can be assessed in a timely manner and will predict clinical outcomes cannot be overstated. There has been some suggestion that assessing delays in the time to onset or prevention of NASH co-morbidities may be possible end-points; however, the sample size and trial duration needed for such paediatric studies as well as the clinical relevance or likelihood that these would predict direct clinical benefit for NASH may still be limiting factors. Historically, drugs used to treat obesity have focused on the primary end-point of weight and amelioration of traditional weight-related co-morbidities, such as T2DM and dyslipidaemia. However, given the overlap of these conditions with NAFLD, drugs to treat obesity are being considered for treatment of NASH.37 Drug development and regulatory pathways in metabolic and endocrine disorders are increasingly intersecting with NASH through overlapping patient populations, drug classes and mechanisms of action, end-points and clinical trial designs. At least 25% of the active NASH Investigational New Drug (IND) submissions within FDA have benefited from collaboration between DGIEP and DMEP. Similarly, programmes regulated within DMEP for metabolic diseases such as obesity and dyslipidaemia have explored liver-related end-points and enrichment with NASH populations. For these reasons, patients with NASH could be specifically targeted in obesity and other metabolic drug programmes to enrich for cardiometabolic risk factors, or to evaluate NASH end-points as part of the efficacy assessments to support obesity drug approval. However, equating benefit from one metabolic disorder to the next may be more complicated than foreseen even if it were possible to attribute relatedness of differential outcomes (ie improvement of metabolic derangements equals an improvement in NASH). As this is a fairly novel approach in already complex pathophysiology, drug manufacturers and investigators are encouraged to discuss such study proposals with the Agency. Examples of overlapping drug classes or mechanisms in the pipeline for NASH and other metabolic diseases include glucagon-like peptide-1 receptor agonists, peroxisome proliferator-activated receptor agonists, sodium glucose cotransporter-2 inhibitors, fibroblast growth factor-21 analogs, and others.1 Complementary targets and mechanisms create opportunities for approved drugs and investigational agents for other metabolic indications to be reconsidered or used as part of combination therapies, to potentially expand the armamentarium for NASH. Combination drug development programmes will need to address the fixed combination rule, which states that "[t]wo or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labelling for the drug".38 A draft rule39 was published on 23 December 2015 that to the fixed combination drug Although the has not yet been the to the FDA's on how to the contribution of each component of the fixed combination drug to the claimed A at the of the pathophysiology for these metabolic diseases may be needed to aimed at pathways in addition to The of risk factors, of drug mechanisms of action, biomarkers, outcomes and regulatory frameworks may in the next of therapeutic options. The future remains and for NASH drug development. to and for their review of this to DGIEP from and and the NASH also to and for to and for their review of this The no of the for the and is the primary on drugs to treat obesity and other metabolic diseases. to the and of the The that the is and has not been for specific ethical approval or informed consent was required for this

The management of type 2 diabetes mellitus (T2DM) has evolved substantially with the development of incretin-based therapies targeting the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide (GIP) receptor, and glucagon receptor. This review provides a comprehensive overview of the mechanisms, clinical efficacy, and therapeutic relevance of GLP-1 receptor agonists (GLP-1 RAs), dual GLP-1/GIP receptor agonists, and emerging triple agonists targeting GLP-1, GIP, and glucagon receptors. GLP-1 RAs, now well-established in clinical practice, offer robust glycemic control, weight reduction, and proven cardiovascular and renal benefits through glucose-dependent insulinotropic effects, appetite suppression, and cardiometabolic protection. Dual agonists, such as tirzepatide, expand upon these benefits by simultaneously activating the GIP receptor, yielding superior glycemic efficacy and unprecedented weight loss, alongside potential insulin-sensitizing effects. The latest innovation, triple agonists like retatrutide, incorporate glucagon receptor activation to further enhance energy expenditure, fat loss, and metabolic flexibility, with promising early results in obesity, diabetes, and nonalcoholic fatty liver disease. Together, these agents represent a significant therapeutic advancement in T2DM, with increasing potential for comprehensive cardiometabolic disease management. This review summarizes current evidence from clinical trials and mechanistic studies, discusses comparative benefits, and highlights future directions for optimizing their clinical use.

Comparison of Characteristics Between Chinese Patients Taking Glucagon-like Peptide 1 Receptor Agonists and Insulin: A Cross-sectional Database Analysis

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes: A Multinational, Federated Analysis of LEGEND-T2DM

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

Type 2 diabetes mellitus (T2DM) can lead to structural pancreatic changes potentially predisposing to acute pancreatitis (AP), increasing morbidity and mortality. Scarce data exist on the outcomes of AP in patients with T2DM who are taking glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The study aim was to evaluate AP outcome and all-cause mortality in patients with T2DM using GLP-1 RAs. A retrospective cohort study was performed using population-based data from the TriNetX platform. Patients with T2DM receiving GLP-1 RAs drugs (semaglutide, liraglutide, dulaglutide, and tirzepatide) between January 1, 2015, and October 31, 2023, were included. This patient cohort was matched with patients with T2DM who did not receive GLP-1 RAs according to age, demographics, comorbidities, and medication by using 1:1 propensity matching. To avoid confounding, etiologies of AP including alcohol-induced, trauma, biliary, class Ia drug-induced, hypertriglyceridemia, and postendoscopic retrograde cholangiopancreatography were excluded from both cohorts. Primary outcomes were risk of developing AP, need for parenteral nutrition, systemic complications (sepsis, systemic inflammatory response syndrome, shock, mechanical ventilation, acute kidney injury), and local pancreatic complications. The secondary outcome was all-cause mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs). A total of 740,370 patients with T2DM were identified with 29,423 on GLP-1 RAs; 20,459 of those 29,423 (mean [SD] age, 58.1 [11.9] years; 10,190 [49.85%] female) were matched with 20,459 individuals (mean [SD] age, 57.5 [13.9] years; 10,301 [50.35%] female) who did not take GLP-1 RAs. The GLP-1 RAs group had lower risk of complicated pancreatitis (HR 0.32; 95% confidence interval [CI] 0.14-0.74), parenteral nutrition needs (HR 0.28; 95% CI 0.09-0.83), sepsis (HR 0.71; 95% CI 0.59-0.84), acute kidney injury (HR 0.54; 95% CI 0.49-0.60), shock (HR 0.52; 95% CI 0.36-0.75), and mechanical ventilation support during admission (HR 0.23; 95% CI 0.16-0.33) compared with the non-GLP-1 RAs group. In addition, all-cause mortality was decreased in the GLP-1 agonist group compared with the non-GLP-1 agonist group (HR 0.45; 95% CI 0.41-0.49). Important to note that the GLP-1 RAs group had a tendency of lower risk of uncomplicated pancreatitis (HR 0.71; 95% CI 0.49-1.01) but without statistically significant result. No difference was found between the groups in risk of developing systemic inflammatory response syndrome if it occurs. GLP-1 RAs use does not increase AP risk is associated with lower complications in those who developed AP and linked with lower all-cause mortality in patients with T2DM. Prospective studies are needed to determine the mechanisms behind these findings.

PDB52 - A Comparison of Patient Characteristics Between Glp-1 Ra and Insulin Initiators in China

Differential effects of GLP-1 receptor agonists on components of dysglycaemia in individuals with type 2 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is characterized by an increased prevalence of polycystic ovary syndrome (PCOS) with its negative metabolic consequences, including increased cardiovascular risk. Both diseases affect patients, significantly deteriorating the quality of life. During the treatment of patients with T1DM and PCOS, lifestyle modification and increased physical activity resulting in weight reduction should always be recommended. Pharmacological treatment should be applied in accordance with the current standards. In most of these patients metformin alone or with combined oral contraceptive pills could be considered for cycle regulation. In obese patients with T1DM and PCOS glucagon-like peptide-1 receptor agonists (GLP-1 Ras) (liraglutide, semaglutide) and dual glucose-dependent insulinotropic polypeptides (GIP)/GLP-1 RAs (tirzepatide) are regarded as a safe approach. Anti-androgens could also be considered especially to treat hirsutism and hyperandrogenism in women with PCOS. There are relatively limited evidence on anti-androgens in PCOS and we should consider use them in only selected cases. Some other substances may have a positive effect on patients with T1DM and PCOS include inositol, alpha-lipoic acid, folic acid, vitamins (B1, B6, B12, D, K, E, A), chromium and selenium compounds, as well as omega-3 fatty acids. The gut microbiome is also considered as a critical modulator of the predisposition to PCOS and T1DM and may be the future goal of the treatment. The proper treatment of PCOS will translate into a reduction in the severity of typical symptoms and also into the improvement in the metabolic control of diabetes and the patients' quality of life.

Glucagon-like Peptide-1 Receptor Agonists Are Associated With Improved Survival and Reduced Liver-Related Events in Patients With Type 2 Diabetes and Metabolic Dysfunction-Associated Liver Disease: A Large Real-World Retrospective Study.