Metabolic, Multi-organ and Microvascular Effects of a Low-calorIe Diet in Younger Obese With Prediabetes and/or Metabolic Syndrome
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 44
- 试验地点
- 2
- 主要终点
- Changes in liver fat >5 percent, determined by MRI, from baseline to after 12 months of intervention.
研究概览
简要总结
Significant weight reduction, achieved by low-calorie diet (LCD), will mobilise ectopic fat (visceral and particularly liver fat), improving insulin sensitivity and other metabolic syndrome components, with secondary beneficial effects on cardiac structure and function.
This CALIBRATE study (metabolic, multi-organ and effects of low-calorie diet in younger obese patients with pre-diabetes) will compare the effects of a safe and effective 12-month weight management intervention, initially using a low-calorie, liquid replacement diet for 12 weeks, anticipating at least 10% reduction in body weight. The investigators will examine how much the weight loss improves the metabolic abnormalities that precede type 2 diabetes (T2D), and in reversing the pre-clinical/subtle clinical abnormalities of the liver and heart that precede liver and cardiovascular disease (CVD).
This study will compare the effects of a safe and effective 12-month weight management intervention, initially using a low-calorie, liquid replacement diet for 12 weeks, followed by a weight maintenance phase. The investigators will examine how much the weight loss improves the metabolic and neuropathic abnormalities that precede and accompany type 2 diabetes (T2D), and in reversing the pre-clinical/subtle clinical abnormalities of the liver and heart that precede liver and cardiovascular disease. In an additional optional sub-study, the investigators will additionally assess how the weight loss impacts upon appetite regulation within the brain with functional MRI (fMRI).
详细描述
Prediabetes affects up to 35% of the population. It is defined as an intermediate metabolic state of glucose dysregulation between normoglycaemia and type 2 diabetes (T2D). Prediabetic individuals have 3-12 times higher annual incidence of type 2 diabetes than the general population. Further, these individuals have a considerable increased risk of cardiovascular disease (CVD), (myocardial infarction, stroke, CV death) and even in the absence of coronary artery disease, an increased risk of heart failure. Individuals with prediabetes manifest the same clustering of cardiovascular risk factors (dysglycaemia, dyslipidaemia, hypertension, obesity, physical inactivity, insulin resistance, pro-coagulant state, endothelial dysfunction, inflammation) that confer the high risk for macrovascular complications in type 2 diabetes. For example, 37% and 51% of individuals with prediabetes have hypertension and dyslipidaemia.
Results of large randomised control trials focusing on diabetes management have shown improvements in cardiovascular and renal outcomes and treatments for patients with established type 2 diabetes. Studies examining cardiovascular and renal burdens in patients with prediabetes have demonstrated that the same therapeutic benefits have not been observed in adults with prediabetes. This study focuses on a younger age group considering the aggressive phenotype of young-onset type 2 diabetes as it provides the opportunity to address and effectively manage the associated cardio-metabolic risk factors, prevent progression from prediabetes to type 2 diabetes and reduce the burden of cardiovascular disease, heart failure and liver-related burden.
Liver fat predicts both cardiovascular disease and type 2 diabetes independent of obesity. NAFLD is a growing clinical problem which has become the most prevalent chronic liver disease in Western society. It can be associated with isolated hepatic triglyceride accumulation (steatosis), through steatosis plus hepatocellular damage with inflammation and fibrosis (non-alcoholic steatohepatitis (NASH), which may ultimately progress to liver fibrosis/cirrhosis and hepatocellular carcinoma.
Non-Alcoholic Fatty Liver Disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome and is commonly associated with insulin-resistant states including obesity, a higher prevalence of prediabetes and type 2 diabetes (T2D).
NAFLD has a bi-directional relationship with prediabetes and T2D being a risk factor for Non-Alcoholic Fatty Liver Disease but conversely, individuals with prediabetes and type 2 diabetes have significantly increased liver fat versus non-diabetic control subjects with a higher risk of NAFLD than Body Mass Index (BMI) -matched non-diabetic controls.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •The investigators shall recruit participants with the following characteristics:
- •Men and women
- •aged 18-55 years*,
- •BMI 30-40 kg/m2 , BMI>27 kg/m2 for Chinese/South Asians
- •Any one of the following three metabolic criteria:
- •a diagnosis of prediabetes (HbA1c 42-47 mmol/mol), OR
- •NAFLD (based on fatty liver index, FLI >60). FLI will be determined using waist circumference, BMI, serum triglyceride and GGT (gamma-glutamyltransferase). OR
- •a diagnosis of metabolic syndrome using the IDF metabolic syndrome criteria (see below,
- •Exclusion criteria:
- •Individuals with normal glucose tolerance (NGT) or type 1 or type 2 diabetes (T2D).
- •Anyone engaged in active weight loss (>5kg weight loss in the last 6 months), currently engaged with weight management service, previous bariatric surgery, on weight-lowering medications (e.g. orlistat or liraglutide) or with a history of an eating disorder.
- •planning pregnancy/6 months post-partum,
- •known structural cardiac disease or anyone with major atherosclerotic disease
- •history of stroke within the last 3 months
- •Active mental health illness (e.g. severe depression, bipolar disorder, schizophrenia or other psychotic disorders). Use of drug with known major effects on bodyweight (e.g. corticosteroid, anti-psychotic, anticonvulsants etc).
- •Planning pregnancy within the next 6 months and until >6 months post-partum or breastfeeding
- •Substance abuse e.g. drugs/alcohol.
- •Eating disorder, previous bariatric surgery, currently taking weight loss drugs or already engaged with weight management service
- •Learning difficulties
- •A contraindication to magnetic resonance scanning will exclude the patient from the MRI component of the study
排除标准
- 未提供
结局指标
主要结局
Changes in liver fat >5 percent, determined by MRI, from baseline to after 12 months of intervention.
时间窗: Changes will be measured at baseline and at 12 months.
For liver fat, diagnosis of NAFLD is based on a threshold of a value \>5.5 percent. The investigators anticipate having a 45 percent difference in the proportion in whom liver fat percentage reduces by at least 5 percent between the groups (50 percent of LCD will have an absolute reduction in liver fat of 5 percent vs. 5 percent of controls). The investigators chose an absolute reduction of liver fat of 5 percent as this reduction is clinically meaningful.
次要结局
- Body Mass Index(Changes will be measured at baseline and at 12 months.)
- Body weight(Changes will be measured at baseline and at 12 months.)
- Markers of fibrosis in liver(Changes will be measured at baseline and at 12 months.)
- Metabolic measures of fatty liver(Changes will be measured at baseline and at 12 months.)
- Measures of neuropathy: Change in sural nerve velocity(Changes will be measured at baseline and at 12 months.)
- Multi organs pancreas, spleen and kidney volume(Changes will be measured at baseline and at 12 months.)
- Multi organs pancreas, spleen and kidney fat content(Changes will be measured at baseline and at 12 months.)
- Waist Circumference(Changes will be measured at baseline and at 12 months.)
- Liver biochemistry: Alanine transaminase(Changes will be measured at baseline and at 12 months.)
- Lipid profile(Changes will be measured at baseline and at 12 months.)
- Changes in insulin secretion(Changes will be measured at baseline and at 12 months..)
- Measures of neuropathy: Change in sural nerve amplitude(Changes will be measured at baseline and at 12 months.)
- Functional MRI(Changes will be measured at baseline and at 12 months.)
- Cardiac health: LV Mass Indexed to Body Surface Area(Changes will be measured at baseline and at 12 months.)
- Cardiac health: Multi-parametric cardiac MRI(Changes will be measured at baseline and at 12 months.)
- Charcterisation of organ fat content(Changes will be measured at baseline and at 12 months.)
- Blood pressure(Changes will be measured at baseline and at 12 months.)
- Changes in HbA1c(Changes will be measured at baseline, at 12 weeks, at 24 week and at 12 months.)
- Peripheral insulin sensitivity(Changes will be measured at baseline and at 12 months.)
- MRI-derived fat volumes(Changes will be measured at baseline and at 12 months.)
- Cardiac structure (volumes)(Changes will be measured at baseline and at 12 months.)
- Cardiac health: cardiac magnetic resonance imaging(Changes will be measured at baseline and at 12 months.)
- Multi-organ MRI measure for pancreas, spleen and kidney(Changes will be measured at baseline and at 12 months.)
- Changes in early diastolic strain rate by cardiovascular magnetic resonance(Changes will be measured at baseline and at 12 months.)
- Changes in hepatic insulin sensitivity(Changes will be measured at baseline and at 12 months.)
- Changes in fatty acid metabolism(Changes will be measured at baseline and at 12 months.)
- Measures of neuropathy: Change in intra-epidermal nerve fibres densities, length and branch densities.(Changes will be measured at baseline and at 12 months.)
- Changes in load and contractility of the cardiac function(Changes will be measured at baseline and at 12 months.)
- The NAFLD scoring screening tool(Changes will be measured at baseline and at 12 months.)
- Appetite measurement(Changes will be measured at baseline and at 12 months.)