Abstract
Introduction
Obesity and nonalcoholic fatty liver disease (NAFLD) are major public health problems, and their incidence and prevalence have been increasing over time. Though lifestyle changes are important for weight loss and a healthy life, both clinical trials and real-life studies have demonstrated that improvements shown with such interventions are often not sustained. Thus, pharmacotherapy and surgical treatment of weight loss are necessary to achieve desirable weight loss and reduce hepatic fat. In this article, we highlight five of the best published articles in the field of obesity, and five of the best articles in the field of NAFLD.
For the obesity and diabetes section of this book, we screened PubMed using the query “obesity and diabetes” [All Fields] with the year 2022 as a filter. Among the 11,483 results obtained, 440 items of the total were randomized clinical trials. We selected five manuscripts, three of which are clinical trials, one is a post hoc analysis of a previous trial, and the last is a registry-based study with a very large cohort. The articles were selected on the basis of their novelty and potential impact on the future clinical practice.
Broadly, there was a high interest in both pharmacological and diet approaches aimed at reducing body weight in patients with diabetes. Among these studies, we selected five particularly of interest. For the NAFLD and diabetes section of the book, we searched PubMed using “(nonalcoholic fatty liver disease, fatty liver, steatohepatitis, NASH, NAFLD) AND (Diabetes)” search terms. Only human studies (clinical trials or systematic review/meta-analysis) published in the last year (from July 2022 to August 10, 2023) were included. We selected the five best publications from 79 reviewed articles.
Key Articles Reviewed
Hoerster KD, Hunter-Merrill R, Nguyen T, Rise P, Barón AE, McDowell J, Donovan LM, Gleason E, Lane A, Plumley R, Schooler M, Schuttner L, Collins M, Au DH, Ma J
Jamshed H, Steger FL, Bryan DR, Richman JS, Warriner AH, Hanick CJ, Martin CK, Salvy SJ, Peterson CM
Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A for the SURMOUNT-1 Investigators
Wilding JPH, Batterham RL, Davies M, Van Gaal LF, Kandler K, Konakli K, Lingvay I, McGowan BM, Oral TK, Rosenstock J, Wadden TA, Wharton S, Yokote K, Kushner RF; STEP 1 Study Group
Ceriello A, Lucisano G, Prattichizzo F, La Grotta R, Franzén S, Gudbjörnsdottir S, Eliasson B, Nicolucci A
Hansen CD, Gram-Kampmann EM, Hansen JK, Hugger MB, Madsen BS, Jensen JM, Olesen S, Torp N, Rasmussen DN, Kjærgaard M, Johansen S, Lindvig KP, Andersen P, Thorhauge KH, Brønd JC, Hermann P, Beck-Nielsen H, Detlefsen S, Hansen T, Højlund K, Thiele MS, Israelsen M, Krag A
Jin Z, Yuan Y, Zheng C, Liu S, Weng H
Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, Lawitz E, Ratziu V, Sanyal AJ, Schattenberg JM, Newsome PN; NN9931-4492 investigators
Kongmalai T, Srinonprasert V, Anothaisintawee T, Kongmalai P, McKay G, Attia J, Thakkinstian A
Verrastro O, Panunzi S, Castagneto-Gissey L, De Gaetano A, Lembo E, Capristo E, Guidone C, Angelini G, Pennestrì F, Sessa L, Vecchio FM, Riccardi L, Zocco MA, Boskoski I, Casella-Mariolo JR, Marini P, Pompili M, Casella G, Fiori E, Rubino F, Bornstein SR, Raffaelli M, Mingrone G
OBESITY AND DIABETES
Effect of a Remotely Delivered Self-directed Behavioral Intervention on Body Weight and Physical Health Status among Adults with Obesity: The D-ELITE Randomized Clinical Trial
Hoerster KD1,2,3, Hunter-Merrill R1, Nguyen T1, Rise P1, Barón AE4, McDowell J1, Donovan LM1,5, Gleason E1, Lane A1, Plumley R1, Schooler M1, Schuttner L1,6, Collins M1, Au DH1,6, Ma J7
1VA Puget Sound Healthcare System, Seattle Division, Health Services Research and Development, Seattle, WA; 2VA Puget Sound Healthcare System, Seattle Division, Mental Health Service, Seattle, WA; 3Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA; 4Colorado School of Public Health, Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO; 5Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA; 6Department of Medicine, University of Washington, Seattle, WA; 7Department of Medicine, University of Illinois at Chicago, Chicago, IL
To determine the effectiveness of such programs in routine clinical practice, this study tested whether a self-directed, remotely administered behavioral lifestyle intervention improves weight and self-reported general health status compared with usual care.
Methods
Between February 15, 2018, and December 18, 2018, this randomized clinical trial enrolled 511 adults with a body mass index (BMI) of ≥ 30 and ≤ 45 based on their electronic health record (EHR) weight and height from 30 Veterans Health Administration (VHA) sites (final follow-up evaluation on February 18, 2021). After being randomly assigned to the intervention group (n = 254) or the control group (n = 257), all participants received usual care, but the Diabetes Prevention Program (DPP) group also received self-directed videos, handouts, and coaching messages via an online platform or postal mail for 12 months. The participants' weight was measured in primary care and recorded in the EHR; at the 12-month follow-up evaluation, their general health status was self-reported via the Medical Outcomes Study 12-Item Short Form Health Survey (SF-12) physical component score (PCS), on which higher scores were better (range: 0–100). The between-group minimal clinically important differences were 3 kg for weight and 5 points for the SF-12 PCS. The linear mixed models used weight and SF-12 PCS measured at either time point, with the participants analyzed according to their randomization assignment. For each coprimary outcome, a 2-sided α level of 0.025 was considered statistically significant.
Results
The study enrolled and randomized 511 participants: mean age 57.4 ± 13.9 SD years; 231 women (45%); 429 (84.0%); and weight based on the EHR. For 410 participants (80.2%), SF-12 PCS data was available at 12 months. In the intervention group, the unadjusted mean weight at 12 months declined from 102.7 kg to 99.8 compared with 101.9 kg to 101.0 kg in the control group (adjusted between-group mean difference, −1.93 [97.5% CI, −3.24 to −0.61]; P = 0.001). At 12 months, the unadjusted mean SF-12 PCS scores declined from 44.8 to 44.3 among DPP participants compared with 44.5 to 43.2 among control participants (adjusted between-group mean difference, intervention minus control, 0.69 [97.5% CI, −1.11 to 2.49]; P = 0.39). The highest percentage of serious adverse events were cardiovascular, representing 25% of events in the DPP group and 35% in the control group.
Conclusions
Among adults with obesity, a remotely delivered, self-directed, behavioral lifestyle intervention resulted in statistically significantly greater weight loss at 12 months compared with usual care, but the difference was not clinically important. The participants' self-reported general physical health status at 12 months showed no statistically significant difference.
Effectiveness of Early Time-restricted Eating for Weight Loss, Fat Loss, and Cardiometabolic Health in Adults with Obesity: A Randomized Clinical Trial
Jamshed H1,2, Steger FL1,3, Bryan DR1, Richman JS4, Warriner AH5, Hanick CJ1, Martin CK6, Salvy SJ7, Peterson CM1
1Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL; 2Department of Integrated Sciences and Mathematics, Habib University, Karachi, Sindh, Pakistan; 3Department of Endocrinology, Genetics and Metabolism, University of Kansas Medical Center, Kansas City, KS; 4Department of Surgery, University of Alabama at Birmingham, Birmingham, AL; 5Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; 6Ingestive Behavior Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, LA; 7Cedars-Sinai Medical Center, Los Angeles, CA
The effectiveness of intermittent fasting for losing weight and body fat may depend on the timing of the eating window. This randomized trial compared time-restricted eating (TRE) with eating over a period of 12 or more hours while matching weight-loss counseling across groups to determine whether practicing TRE by eating early in the day (eTRE) is more effective for weight loss, fat loss, and cardiometabolic health than eating over a period of 12 or more hours.
Methods
Between August 2018 and April 2020, a 14-week, parallel-arm, randomized clinical trial recruited adults aged 25 to 75 years with obesity for the Weight Loss Medicine Clinic at the University of Alabama at Birmingham Hospital. All participants received weight-loss treatment (energy restriction [ER]); the participants were randomized to eTRE plus ER (8-hour eating window from 7:00 to 15:00) or the control eating intervention (CON) plus ER (≥ 12-hour window). The main outcomes were weight loss and fat loss, and the secondary outcomes were measures of blood pressure, heart rate, glucose levels, insulin levels, and plasma lipid levels.
Results
Ninety participants were enrolled: 72 women (80%) with a mean body mass index (BMI) of 39.6 ± 6.7 SD and mean age of 43 ± 11 SD years. The eTRE + ER group adhered 6.0 ± 0.8 SD days per week. The eTRE + ER intervention was more effective for losing weight (−2.3 kg [95% CI, −3.7 to −0.9 kg]; P = 0.002) but affected neither body fat (−1.4 kg [95% CI, −2.9 to 0.2 kg]; P = 0.09) nor the ratio of fat loss to weight loss (−4.2% [95% CI, −14.9% to 6.5%]; P = 0.43). The effects of eTRE + ER were equivalent to reducing calorie intake by an additional 214 kcal/d. The eTRE + ER intervention also improved diastolic blood pressure (−4 mm Hg [95% CI, −8 to 0 mm Hg]; P = 0.04) and mood disturbances, including fatigue-inertia, vigor-activity, and depression-dejection. Between the groups, all other cardiometabolic risk factors, food intake, physical activity, and sleep outcomes were similar. The secondary analysis of 59 completers found eTRE + ER was more effective for losing body fat and trunk fat than CON + ER.
Conclusions
Over 14 weeks' time, eating earlier in the day was more effective for losing weight and improving diastolic blood pressure and mood than eating over a window of 12 or more hours.
Tirzepatide Once Weekly for the Treatment of Obesity
Jastreboff AM1, Aronne LJ2, Ahmad NN3, Wharton S4, Connery L5, Alves B6, Kiyosue A7, Zhang S3, Liu B3, Bunck MC3, Stefanski A3, for the SURMOUNT-1 Investigators
1Section of Endocrinology and Metabolism, Department of Medicine, and the Section of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, CT; 2Comprehensive Weight Control Center, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York, NY; 3Eli Lilly, Indianapolis, IN; 4McMaster University, Hamilton, and York University and Wharton Weight Management Clinic, Toronto, ON, Canada; 5Intend Research, Norman, OK; 6Centro Paulista De Investigação Clínica (Cepic), Sao Paulo, Brazil; 7Tokyo-Eki Center-Building Clinic, Tokyo, Japan
This study evaluated the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity.
Methods
This phase 3, double-blind, randomized, controlled trial assigned 2539 adults with a body-mass index (BMI) ≥ 30 or ≥ 27 with at least one weight-related complication (excluding diabetes) in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. The outcomes of interest were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population.
Results
At baseline, the participants had a mean body weight of 104.8 kg and mean BMI of 38.0; 94.5% of participants had a BMI of ≥ 30. After weekly doses of tirzepatide, the mean percentage change in weight at week 72 was −15.0% (95% CI, −15.9 to −14.2) with 5 mg, −19.5% (95% CI, −20.4 to −18.5) with 10 mg, and −20.9% (95% CI, −21.8 to −19.9) with 15 mg compared with −3.1% (95% CI, −4.3 to −1.9) with placebo (P < 0.001 for all comparisons with placebo). The percentage of participants who had a weight reduction of 5% or more was 85% (95% CI, 82–89), 89% (95% CI, 86–92), and 91% (95% CI, 88–94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30–39) with placebo. A reduction in body weight of 20% or more was experienced by 50% (95% CI, 46–54) and 57% (95% CI, 53– 61) of participants in the 10 mg and 15 mg groups, respectively, compared with 3% (95% CI, 1 to 5) in the placebo group (P < 0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events were gastrointestinal, most were of mild to moderate severity, and they occurred primarily during dose escalation. Adverse events contributed to treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5 mg, 10 mg, and 15 mg doses and placebo, respectively.
Conclusions
In this 72-week trial of once-weekly tirzepatide in participants with obesity, 5 mg, 10 mg, and 15 mg doses all provided substantial and sustained reductions in body weight.
Weight Regain and Cardiometabolic Effects after Withdrawal of Semaglutide: The STEP 1 Trial Extension
Wilding JPH1, Batterham RL2,3,4, Davies M5,6, Van Gaal LF7, Kandler K8, Konakli K8, Lingvay I9, McGowan BM10, Oral TK8, Rosenstock J11, Wadden TA12, Wharton S13, Yokote K14, Kushner RF15, STEP 1 Study Group
1Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK; 2University College London Centre for Obesity Research, Division of Medicine, University College London, London, UK; 3National Institute of Health Research, UCLH Biomedical Research Centre, London, UK; 4Centre for Weight Management and Metabolic Surgery, University College London Hospital, London, UK; 5Diabetes Research Centre, University of Leicester, Leicester, UK; 6NIHR Leicester Biomedical Research Centre, Leicester, UK; 7Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium; 8Novo Nordisk A/S, Søborg, Denmark; 9Departments of Internal Medicine/Endocrinology and Department of Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX; 10Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK; 11Dallas Diabetes Research Center at Medical City, Dallas, TX; 12Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; 13York University, McMaster University and Wharton Weight Management Clinic, Toronto, Ontario, Canada; 14Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University and Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan; 15Division of Endocrinology, Feinberg School of Medicine, Northwestern University, Chicago, IL
The STEP 1 Trial randomized 1961 nondiabetic adults with a BMI ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight-related comorbidity) to a lifestyle intervention plus once-weekly subcutaneous semaglutide at 2.4 mg or placebo for 68 weeks (including 16 weeks of dose escalation). The STEP 1 Trial Extension explored the changes in the participants' body weight and cardiometabolic risk factors after STEP 1's conclusion.
Methods
For 1 year, this further exploratory extension examined a representative subset of 327 participants who had completed the 68 weeks of the STEP 1 treatment semaglutide and lifestyle intervention. All eligible participants from any site in Canada, Germany, and the United Kingdom and the sites in the United States and Japan with the highest main-phase recruitment were invited to participate.
Results
From weeks 0 to 68, the mean weight loss was 17.3% ± 9.3% SD with semaglutide versus 2.0% ± 6.1% SD with placebo. After treatment withdrawal, the semaglutide and placebo participants regained 11.6 ± 7.7 SD and 1.9 ± 4.8 SD percentage points of their lost weight, respectively, by week 120, resulting in net losses of 5.6% ± 8.9% SD and 0.1% ± 5.8% SD, respectively, from weeks 0 to 120. The cardiometabolic improvements seen from weeks 0 to 68 with semaglutide reverted toward baseline at week 120 for most variables.
Conclusions
One year after they had ended the semaglutide plus lifestyle intervention, the trial participants regained two-thirds of their lost weight, and a similar reversion was seen in the participants' cardiometabolic variables. These findings not only confirm the chronicity of obesity but suggest that ongoing treatment is required to maintain improvements in weight and health.
Risk Factor Variability and Cardiovascular Risk among Patients with Diabetes: A Nationwide Observational Study
Ceriello A1, Lucisano G2, Prattichizzo F1, La Grotta R1, Franzén S3,4, Gudbjörnsdottir S5, Eliasson B4,5, Nicolucci A2
1IRCCS MultiMedica, Milan, Italy; 2CORESEARCH—Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy; 3Health Metrics, Department of Public Health and Community Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 4Center of Registries, Västra Götaland, Gothenburg, Sweden; 5Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
Because the control of cardiovascular risk factors fluctuates over time and can be affected by multifactorial interactions, the risk factors themselves, rather than their variability or interplay with one another, are used to define a population at risk. This study examined the association between variability of risk factors and cardiovascular morbidity and mortality risk among patients with type 2 diabetes mellitus (T2D).
Methods
Registry-derived data yielded 29,471 people with T2D, who did not have cardiovascular disease at baseline and had had at least five measurements of risk factors. Variability for each variable was expressed as quartiles of the standard deviation during 3 years (exposure). The incidence of myocardial infarction, stroke, and all-cause mortality was assessed during 4.80 (2.40–6.70) years after the exposure phase. The association between the measures of variability and the risk of developing the outcome was investigated through multivariable Cox proportional-hazards regression analysis with stepwise variable selection. Then, the recursive partitioning and amalgamation (RECPAM) algorithm was used to explore the interaction among the variability of risk factors associated with the outcome.
Results
The variability of hemoglobin A1c (HbA1c), body weight, systolic blood pressure, and total cholesterol was found to be associated with the outcomes of myocardial infarction, stroke, and all-cause mortality. Among the six classes of risk identified by RECPAM, patients with a high variability of both body weight and blood pressure had the highest risk (class 6, hazard ratio [HR], 1.81 [95% CI, 1.61–2.05]) compared with patients who had low variability in both body weight and total cholesterol (class 1, reference), despite a progressive reduction in the mean level of risk factors during their successive visits. Patients with high weight variability but low-moderate systolic blood pressure variability (class 5; HR, 1.57 [95% CI, 1.28–1.68]), with moderate/high weight variability associated with high/very high HbA1c variability (class 4, HR, 1.33 [95% CI, 1.20–1.49]), and with moderate/high weight variability and with low/moderate HbA1c variability (class 3, HR, 1.12 [95% CI, 1.00–1.25]), as well as those with low weight variability associated with high/very high total cholesterol variability (class 2, HR, 1.14 [95% CI, 1.00–1.30]) also showed a significant increase in the risk of an event.
Conclusions
Combined high variability in two risk factors—particularly in body weight and blood pressure—is associated with cardiovascular risk among patients with T2D, which indicates that continuous balancing of multiple risk factors is important.
Comments
The digital era we are living in is accompanied by the continuous development of apps and of other technologies aimed at promoting healthy behaviors and facilitating therapies. Electronic health-based interventions are progressively gaining attention for their potential to implement health care without frequent visits or costly interventional programs. Hoerster and colleagues performed a randomized trial substantiating the usefulness of such an approach to promote weight loss in obese people. Indeed, the participants receiving a Diabetes Prevention Program–based intervention of self-directed videos, handouts, and coaching messages delivered via an online platform or postal mail for 12 months lost more weight, with an adjusted between-group mean difference of roughly 2 kg, when compared with patients receiving the usual care. This difference was statistically significant but cannot be considered clinically meaningful. However, the results of this trial might prompt the design of additional studies testing the effectiveness of eHealth-based interventions.
Intermittent fasting, also in absence of caloric restriction, has been suggested as a potential approach to promote weight loss and improve overall cardiometabolic health in a wide range of preclinical studies, with promising evidence of efficacy on a large range of diseases in animal models. The trial conducted by Jamshed and colleagues is the first to substantiate the possible efficacy of such an approach in humans. Indeed, obese patients subjected to both energy restriction and time-restricted eating early during the day (eTRE), with the possibility to eat only from 7:00 to 15:00 for 6 days a week, lost a mean of 2.3 kg more when compared with patients undergoing the same energy restriction without the time restriction. The effects of eTRE were estimated to be equivalent to a further reduction of calorie intake by an additional 214 kcal/day. Other parameters were also improved, including diastolic blood pressure.
The differences in these studies were much smaller in magnitude when compared with those gained with recently developed pharmacological interventions such as tirzepatide. The eTRE study only lasted 14 weeks, but it clearly demonstrated the potential of specific and relatively novel dietetic approaches for weight loss.
Previous data from a clinical trial testing the effect of glucagon-like peptide-1 receptor (GLP-1R) agonists had already evidenced the ability of this class to induce very consistent weight losses. Now this approach has been extended with the development of tirzepatide, a novel, dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1R agonist. In the SURMOUNT-1 trial, obese patients without diabetes who were treated with this drug for 72 weeks experienced tremendous weight loss—up to 20% of baseline weight with the highest drug dose—compared with placebo. These data extend those obtained in 2021 with the same drug in patients with obesity and diabetes (i.e., the SURPASS trial). Such dramatic weight losses could eventually change the trajectory of metabolic and cardiovascular diseases (CVD), given the key role of adiposity in driving their pathogenesis. However, whether this weight loss is maintained after drug withdrawal is unknown: a follow-up study suggested that these changes are not permanent and that continuous treatment may be necessary.
In an observational follow-up to the STEP 1 trial, Wilding and colleagues asked whether the weight loss induced during the study by semaglutide, a GLP-1R agonist, was maintained 1 year after drug withdrawal. They found that, on average, the STEP 1 participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables, thus suggesting that continuous treatment is needed to benefit from the use of these drugs. This aspect is not trivial: beyond the lack of benefit driven by an only transitory weight loss, recent data suggest that variability of body weight (i.e., its oscillations over time) might represent an independent risk factor for cardiovascular outcomes.
Variability in body weight is emerging as an independent risk factor associated with the development of CVD. In this study, Ceriello and colleagues took advantage of a large registry of patients with type 2 diabetes to study whether the variability of multiple risk factors during five successive visits was associated with the subsequent incidence of a composite of myocardial infarction, stroke, and all-cause mortality. They found that body weight variability, measured as quartiles of the standard deviation during 3 years, was the factor with the greatest association with the outcome in terms of magnitude. In addition, they found evidence of clusters of risk according to the variability of multiple risk factors, with the cluster of patients who showed high variability in both body weight and systolic blood pressure having the highest risk, despite an overall decreasing trend for these two variables. These findings suggest that body weight variability might be considered a novel risk factor for CVD and that programs inducing weight loss should be accompanied by strategies aimed at avoiding weight regain, a hypothesis that should be explored by future studies.
DIABETES AND NAFLD/NASH
Effect of Calorie-unrestricted Low-Carbohydrate, High-Fat Diet versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial
Hansen CD1, Gram-Kampmann EM2, Hansen JK3, Hugger MB1, Madsen BS3, Jensen JM3, Olesen S3, Torp N1, Rasmussen DN3, Kjærgaard M1, Johansen S1, Lindvig KP4, Andersen P3, Thorhauge KH1, Brønd JC5, Hermann P6, Beck-Nielsen H2, Detlefsen S7, Hansen T8, Højlund K2, Thiele MS1, Israelsen M3, Krag A9
1Department of Gastroenterology and Hepatology, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; 2Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark; 3Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; 4Department of Gastroenterology and Hepatology, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark, Odense SV, Denmark; 5Department of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; 6Department of Medical Endocrinology, Odense University Hospital, Odense, Denmark; 7Institute of Clinical Research, University of Southern Denmark, and Department of Pathology, Odense University Hospital, Odense, Denmark; Novo Nordisk Foundation, Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; 9Department of Gastroenterology and Hepatology, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark, Odense C, Denmark
This 6-month, randomized, controlled trial with a 3-month follow-up period examined the effect of a calorie-unrestricted, low-carbohydrate, high-fat (LCHF) diet with no intention of weight loss on type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) as compared with a high-carbohydrate, low-fat (HCLF) diet.
Methods
From November 2016 until June 2020, 165 participants with T2D were recruited at Odense University Hospital in Denmark for two calorie-unrestricted diets: (1) a LCHF diet with 50–60 energy percent (E%) fat, < 20E% carbohydrates, and 25E%–30E% proteins, and (2) a HCLF diet with 50E%–60E% carbohydrates, 20E%–30E% fats, and 20E%–25E% proteins. To assess the diets' effect in NAFLD, glycemic control, serum lipid levels, metabolic markers, and liver biopsies were measured. The mean age of the participants was 56 years ± 10 SD, and 58% were women.
Results
Compared with the HCLF diet, the participants on the LCHF diet showed greater improvements in hemoglobin A1c (mean difference in change, −6.1 mmol/mol [95% CI, −9.2 to −3.0 mmol/mol] or −0.59% [95% CI, −0.87% to −0.30%]) and lost more weight (mean difference in change, −3.8 kg [95% CI, −6.2 to −1.4 kg]). At 6 months, both groups had higher high-density lipoprotein cholesterol and lower triglyceride levels. The LCHF diet group showed fewer changes in low-density lipoprotein cholesterol compared with the HCLF diet group (mean difference in change, 0.37 mmol/L [95% CI, 0.17–0.58 mmol/L] or 14.3 mg/dL [95% CI, 6.6–22.4 mg/dL]). No statistically significant between-group changes were detected in the NAFLD assessment, and the changes were not sustained at the 9-month follow-up visit. Note that this was an open-label trial with self-reported adherence and no intent to promote weight loss; there was no adjustment for multiple comparisons.
Conclusions
Individuals with T2D on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight when compared with those on an HCLF diet, but those changes were not sustained 3 months after the intervention.
Effects of Sodium-Glucose Co-transporter 2 Inhibitors on Liver Fibrosis in Non-alcoholic Fatty Liver Disease Patients with Type 2 Diabetes Mellitus: An Updated Meta-analysis of Randomized Controlled Trials
Jin Z1, Yuan Y1, Zheng C1, Liu S2, Weng H1
1Fudan University School of Pharmacy, Shanghai, China; 2Department of Clinical Epidemiology and Biostatistics, Child Health Advocacy Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
In previous clinical practice, sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been shown to improve nonalcoholic fatty liver disease (NAFLD). This study investigated the effects of SGLT2 inhibitors on liver fibrosis in NAFLD patients with type 2 diabetes mellitus (T2D).
Methods
We conducted a comprehensive literature search of the databases PubMed, Embase, Web of Science, and Cochrane Library, and extracted continuous data in the form of mean and standard deviation of the difference before and after treatment. We used RevMan 5.3 software to chart the pooled forest plot and perform heterogeneity, sensitivity, and subgroup analyses. The study was conducted under the protocol registered with the Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY protocol 4946, INPLASY202360058).
Results
The analysis comprised a total of 16 articles involving 699 patients. Indicators of liver fibrosis—including the liver stiffness measurement (LSM), controlled attenuation parameter (CAP), serum ferritin, serum type 4 collagen 7s, and the fibrosis-4 (FIB-4) index—were found to be considerably reduced by SGLT-2 inhibitor medication, and the subgroup analysis manifested pronounced dose-dependence. Additionally, SGLT-2 inhibitor therapy decreased body mass index, lipid buildup, and insulin resistance.
Conclusions
SGLT-2 inhibitors significantly improved liver fibrosis, liver fat content, body conditions, and insulin resistance, demonstrating that SGLT-2 inhibitors might reduce the risk of the progression of liver fibrosis and have a positive effect on NAFLD patients with T2D.
Semaglutide 2 · 4 mg Once Weekly in Patients with Non-alcoholic Steatohepatitis-related Cirrhosis: A Randomised, Placebo-Controlled Phase 2 Trial
Loomba R1, Abdelmalek MF2, Armstrong MJ3,4, Jara M5, Kjær MS5, Krarup N5, Lawitz E6, Ratziu V7, Sanyal AJ8, Schattenberg JM9, Newsome PN3,4, NN9931-4492 Investigators
1NAFLD Research Center, Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, CA; 2Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; 3National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 4Centre for Liver & Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; 5Novo Nordisk A/S, Søborg, Denmark; 6Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX; 7Institute for Cardiometabolism and Nutrition, Sorbonne Université, Hôpital Pitié–Salpêtrière, Paris, France; 8Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA; 9Metabolic Liver Research Program, I Department of Medicine, University Medical Centre, Mainz, Germany
Cirrhosis patients with nonalcoholic steatohepatitis (NASH) are at high risk of liver-related and all-cause morbidity and mortality. This study investigated the efficacy and safety of semaglutide, a glucagon-like peptide-1 analogue, in patients with NASH and compensated cirrhosis.
Methods
This double-blind, placebo-controlled phase 2 trial enrolled patients from 38 centers in Europe and the United States. Adults with biopsy-confirmed NASH-related cirrhosis and body mass index (BMI) of 27 kg/m2 or more were randomly assigned (2:1) to receive either 2.4 mg of subcutaneous semaglutide once a week or a visually matching placebo. The participants were randomly allocated via an interactive Web response system, stratified by presence or absence of type 2 diabetes. The patients, investigators, and those assessing outcomes were masked to the treatment assignments. The primary end point was the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH after 48 weeks, as assessed by biopsy in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug.
Results
Between June 18, 2019, and April 22, 2021, 71 patients were enrolled, of which 49 patients (69%) were women and 22 (31%) were men. The mean age of the patients was 59.5 years ± 8.0 SD, the mean BMI was 34 · 9 kg/m2 ± 5.9 SD, and 53 patients (75%) had diabetes. Forty-seven patients were randomly assigned to the semaglutide group and 24 to the placebo group. After 48 weeks, the two groups had no statistically significant difference between them in the proportion who showed an improvement in liver fibrosis of one stage or more without worsening of NASH: 5 of 47 patients (11%) in the semaglutide group versus 7 of 24 (29%) in the placebo group (odds ratio, 0.28 [95% CI, 0.06–1 · 24], P = 0.087). There was also no significant difference between groups in the proportion of patients who achieved NASH resolution (P = 0.29). Similar proportions of patients in each group reported adverse events (42 patients [89%] in the semaglutide group vs 19 [79%] in the placebo group) and serious adverse events (6 [13%] vs 2 [8%]). The most common adverse events were nausea (21 [45%] vs 4 [17%]), diarrhea (9 [19%] vs 2 [8%]), and vomiting (8 [17%] vs 0). Hepatic and renal function remained stable in both groups, and there were no decompensating events or deaths.
Conclusions
Treatment with semaglutide did not significantly improve fibrosis in patients with NASH and compensated cirrhosis, nor did it achieve NASH resolution versus placebo.
New Anti-diabetic Agents for the Treatment of Non-alcoholic Fatty Liver Disease: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials
Kongmalai T1, Srinonprasert V2,3,4, Anothaisintawee T5, Kongmalai P6, McKay G7, Attia J8, Thakkinstian A4,5
1Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 2Siriraj Health Policy Unit, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 3Division of Geriatric Medicine, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 4Mahidol University Health Technology Assessment Graduate Program, Mahidol University, Bangkok, Thailand; 5Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 6Department of Orthopaedics, Faculty of Medicine, Srinakharinwirot University, Ongkharak, Nakhon Nayok, Thailand; 7Centre for Public Health, School of Medicine, Dentistry, and Biomedical Sciences, Queen's University, Belfast, Ireland; 8School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia
This network meta-analysis compared the efficacy and safety of new antidiabetic medications for the treatment of nonalcoholic fatty liver disease (NAFLD).
Methods
PubMed and Scopus were searched from the study's inception to March 27, 2022, to identify all randomized controlled trials (RCTs) in NAFLD patients. The outcomes included reductions in intrahepatic steatosis (IHS) and liver enzyme levels. The efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and other therapies were indirectly compared using a network meta-analysis approach. Unstandardized mean difference (USMD) with 95% confidence intervals were calculated.
Results
The analysis included 31 RCTs for a total of 2252 patients. Standard-of-care treatment with “add-on” GLP-1R agonists showed significantly reduced IHS when compared with the standard of care alone (USMD, −3.93% [95% CI, −6.54% to −1.33%]). The surface under the cumulative ranking curve (SUCRA) identified GLP-1R agonists had the highest probability to reduce IHS (SUCRA, 88.5%), followed by DPP-4 inhibitors (SUCRA 69.6%) and pioglitazone (SUCRA 62.2%). Add-on GLP-1R agonists were also the most effective treatment for reducing liver enzyme levels; aspartate aminotransferase (USMD, −5.04 [95% CI, −8.46 to −1.62]), alanine aminotransferase (USMD, −9.84 [95% CI, −16.84 to −2.85]), and γ-glutamyl transferase (USMD, −15.53 [95% CI, −22.09 to −8.97]) compared with the standard of care alone. However, the largest number of adverse events were associated with GLP-1 agonists.
Conclusions
For T2D and NAFLD patients, GLP-1 agonists may be the most promising antidiabetic treatment to reduce hepatic steatosis and liver enzyme activity, but longer-term studies are required to determine whether this treatment can delay the progression of liver cirrhosis in patients with NAFLD and T2D.
Bariatric-Metabolic Surgery versus Lifestyle Intervention Plus Best Medical Care in Non-alcoholic Steatohepatitis (BRAVES): A Multicentre, Open-Label, Randomised Trial
Verrastro O1, Panunzi S2, Castagneto-Gissey L3, De Gaetano A2, Lembo E1, Capristo E1,4, Guidone C4, Angelini G1, Pennestrì F4, Sessa L4, Vecchio FM5, Riccardi L1,4, Zocco MA1,4, Boskoski I1,4, Casella-Mariolo JR6, Marini P6, Pompili M1,4, Casella G4, Fiori E3, Rubino F7, Bornstein SR8,9, Raffaelli M1,4, Mingrone G1,4,8
1Università Cattolica del Sacro Cuore, Rome, Italy; 2CNR-IASI, Laboratorio di Biomatematica, Consiglio Nazionale delle Ricerche, Istituto di Analisi dei Sistemi ed Informatica, Rome, Italy; 3Department of Surgical Sciences, Sapienza University of Rome, Rome, Italy; 4Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; 5Department of Pathology and Laboratory Medicine, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy; 6Department of Endocrine and Bariatric-Metabolic Surgery, San Camillo Hospital, Rome, Italy; 7Bariatric and Bariatric-Metabolic Surgery, School of Cardiovascular and Metabolic Medicine & Sciences, King's College Hospital, London UK; 8Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College Hospital, London UK; 9Department of Medicine III, Universitätsklinikum Carl Gustav Carus an de Technischen Universität Dresden, Dresden, Germany
Because observational studies have suggested that bariatric-metabolic surgery might greatly improve nonalcoholic steatohepatitis (NASH), this randomized trial investigated the efficacy of surgery in NASH in comparison with lifestyle interventions and medical therapy.
Methods
Patients aged 25–70 years with obesity (body mass index [BMI], 30–55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH were recruited for a multicenter, open-label, randomized trial at three major hospitals in Rome, Italy. The participants were randomly assigned (1:1:1) to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. At the 1-year follow-up, the participants were evaluated for histological resolution of NASH without worsening of fibrosis.
Results
Between April 15, 2019, and June 21, 2021, 431 participants underwent biopsy screening; of these, 103 (24%) did not have histological NASH, and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n = 96 [33%]), Roux-en-Y gastric bypass (n = 96 [33%]), or sleeve gastrectomy (n = 96 [33%]). In the intention-to-treat analysis, the percentage of participants who showed histological resolution of NASH was significantly higher in the Roux-en-Y gastric bypass (54 [56%]) and sleeve gastrectomy (55 [57%]) groups compared with the lifestyle modification (15 [16%]; P < 0.0001). The calculated probability of NASH resolution was 3.60 times greater (95% CI, 2.19–5.92; P < 0.0001) in the Roux-en-Y gastric bypass group and 3.67 times greater (95% CI, 2.23–6.02; P < 0.0001) in the sleeve gastrectomy group compared with the lifestyle modification group. In the per-protocol analysis (236 [82%] participants who completed the trial), the primary end point was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (P < 0.0001). No deaths or life-threatening complications were reported in this study. Ten participants (6%) in the bariatric-metabolic surgery group experienced severe adverse events, but additional surgery was not required; the complications were resolved with medical or endoscopic management.
Conclusions
Bariatric-metabolic surgery is more effective than lifestyle interventions or optimized medical therapy in the treatment of NASH.
Comments
Weight loss is necessary to improve glycemic control as well as NAFLD in people with type 2 diabetes (T2D). A low-calorie diet has been shown to reduce weight, but these types of diet are not sustainable. Little is known about weight loss with diets that are low-carbohydrate but calorie-unrestricted. In a randomized controlled trial, Hansen and colleagues demonstrated that a calorie-unrestricted, low-carbohydrate, high-fat diet had greater clinically meaningful improvements in glycemic control and weight compared with a high carbohydrate and low-fat diet, but the changes were not sustained 3 months after the intervention. There were no statistically significant differences in NAFLD, high-density lipoproteins, or triglycerides between two groups. The findings of this study are in agreement with previous studies of various dietary interventions: these are effective in the short term, but the change is difficult to sustain over a long period of time. Therefore, pharmacological or surgical interventions are necessary to achieve optimal weight loss and improvement in outcomes related to diabetes or fatty liver disease.
Sodium-glucose cotransporters (SGLT-2) and glucagon-like peptide 1 receptor (GLP-1R) agonists have been shown to reduce weight, optimize glycemic outcomes, and reduce cardiovascular and renal mortality among people with T2D. These drugs are becoming a mainstay of treatment in T2D. In their meta-analysis of 16 randomized trials, Jin and colleagues found that SGLT-2 inhibitors ameliorated liver fibrosis and liver fat content along with improvements in insulin resistance, suggesting positive effects of this class of drugs on NAFLD outcomes in patients with T2D. However, a large phase 3 randomized controlled trial of SGLT-2 inhibitor with NASH/liver fibrosis as a primary outcome has yet to be performed.
In their multicenter, randomized, controlled trial of semaglutide, a long-acting, GLP-1R agonist (2.4 mg, once per week), in people with biopsy-proven, NASH-related cirrhosis and body mass index of ≥ 27 kg/m2, Loomba and colleagues found no improvement in fibrosis or NASH resolution. These data suggest that it is difficult to reverse the pathophysiology once the disease is advanced. Therefore, focusing on early stages of the disease and treating obesity may be better in preventing NASH and related complications. In their network meta-analysis of 31 randomized trials, Kongmalai and colleagues reported that GLP-1RA treatment showed significant reductions in intrahepatic steatosis (HIS) and had highest probability to reduce HIS compared with dipeptidyl peptidase-4 (DPP-4) inhibitors and pioglitazone. GLP-1RA remains a potential therapeutic strategy for prevention and treatment of fatty liver diseases in people with T2D, but more research is needed before it can be considered as a potential therapeutic for NAFLD.
A number of studies have shown better weight reduction with bariatric surgery than lifestyle modification alone. In a multicenter, open label, randomized trial from Italy, Verrastro and colleagues found that Roux-en-Y gastric bypass was the most effective intervention for weight loss when compared with sleeve gastrectomy or lifestyle modification. The calculated probability of NASH resolution was 3.6 times higher in the Roux-en-Y gastric bypass group compared with the lifestyle modification group. This trial reiterates what we have learned from previous trials of bariatric surgery: surgical treatment offers better, sustained weight loss in people with obesity and may have potential for NASH prevention or treatment.
Conclusion and Future Prospects
Obesity, insulin resistance, T2D, and liver diseases are intricately interconnected. As a result, novel interventions targeting any of these conditions are likely to yield benefits for the others as well. There is a dedicated ongoing effort to uncover novel therapeutic targets and to adapt existing treatment options to effectively address these complex disorders. SGLT-2 inhibitors and GLP-1R agonists have been revealed to be groundbreaking therapies for T2D. Their expanding range of advantages now encompasses the treatment obesity in absence of diabetes (e.g., GLP-1R agonists) and possibly NASH. Anticipated research will unveil the efficacy and utility of employing these drug classes to tackle NASH independently of diabetes. Furthermore, investigations will delve into the potential synergy between these medications in halting the progression of such highly prevalent conditions. This combination of drug classes holds promise for addressing the diverse facets of T2D; potentially their early stage application could hinder the disease's advancement or even induce its regression. Future studies will assess the feasibility of this approach.
Finally, there is an increasing trend toward eHealth-based approaches and novel dietetic regimens to promote weight loss. Although the results at this stage have been modest, such programs may be useful for prevention purposes at the population level. More work in this area is expected in upcoming years.
Footnotes
Author Disclosure Statement
AC is on advisory board and has done consultancy and lectures for: Astra Zeneca, Bayer, Berlin Chemie, Guidotti, Eli Lilly, Elsevier, Merck, Novo Nordisk, Roche Diagnostics, Sanofi, Servier, Theras.
VNS's institution, University of Colorado, receives research support from Tandem Diabetes Care, Alexion, Insulet, NovoNordisk, JDRF, and NIH and has received consulting or speaking fees from Sanofi, NovoNordisk, Medscape, Embecta, Insulet, Dexcom, and Tandem Diabetes Care outside the submitted work.
FP has been a lecturer for BERLIN-CHEMIE.