BTI320 (SUGARDOWN®) on Post-Prandial Hyperglycaemia in Subjects With Pre-Diabetes

In a recent national survey, 11% of adults in China have diabetes and 50% have pre-diabetes defined by fasting plasma glucose (FPG) 5.6-6.9 mmol/l and/or 2-hour post glucose (PG) 7.8-11.0 mmol/L using 75 gram oral glucose tolerance test (75g OGTT) and/or glycated haemoglobin (HbA1c) 5.7-6.4%. Depending on the presence of other risk factors, the annual conversion rate of pre-diabetes averages 3-10% with pre-diabetes associated with 1.5-2.0 fold increased risk for cardiovascular disease. Once diabetes is established, life expectancy is reduced by 6 years if not diagnosed, treated or controlled, especially in young-to-middle aged subjects who will face long disease duration of diabetes.

In the Hong Kong Diabetes Registry, depending on control of glucose and other risk factors, 3-10% of Chinese subjects with diabetes may die or develop a major event every year including heart disease, stroke, kidney failure and /or all-site cancer.

Besides glycaemic control as defined by HbA1c, post prandial hyperglycaemia and glycaemic variability have also been shown to predict cardiovascular and renal events in both pre-diabetic and diabetic patient. Genetic variants discovered in large-scale epidemiological studies including those from China and Hong Kong have been found to be associated with beta cell dysfunction which can be further exacerbated by glucotoxicity and lipotoxicity, often due to co-existing obesity giving rise to early onset diabetes. Several studies including those from Asian populations indicated that subjects with pre-diabetes exhibit reduced early phase insulin secretion resulting in postprandial hyperglycaemia which can impose metabolic stress on the beta cells leading to eventual beta cell failure.

BTI320, also known as SUGARDOWN®, is derived from galactomanan which acts by blocking the key carbohydrate hydrolyzing enzymes including amylase, maltose, lactose and sucrose in the gastrointestinal tract. It also acts to bind to ingested polysaccharides and slow their absorption with each meal thereby reducing post prandial glucose excursion. The mechanism of action for BTI320 is similar to Acarbose®, an alpha glucosidase inhibitor, which has been shown to improve glycaemic control and has been approved for prevention of diabetes in China.

24-hour continuous glucose monitoring system (CGMS) measures mean blood glucose (MBG), mean area under the curve for blood glucose above 10mmol/l (180mg/dl) (AUC-180), mean postprandial maximum glucose (MPMG), mean amplitude of glucose excursion (MAGE) over 72 hours. These parameters correlate well with plasma fructosamine (FA) alternatively known as glycated albumin, which reflects short-term glycaemic control during the preceding 2 weeks.

Inclusion criteria

• Adult subjects ≥ 18-70 years inclusive
• Chinese ethnicity
• High risk subject with pre-diabetes as defined by meeting at least 2 of the following criteria from (a), (b) and (c):

• FPG ≥ 5.6-6.9 mmol/l and/or 2-hour PG ≥ 7.8-11.0 mmol/l during 75 gram OGTT
• HbA1c ≥ 5.7-6.4%
• At least one of the following risk factors:-

• History of gestational diabetes
• Family history of diabetes in first degree relative
• 2 components or more of the metabolic syndrome (triglyceride ≥ 1.7 mmol/L, blood pressure (BP) ≥ 130/80 mmHg, high density-lipoprotein (HDL) cholesterol <1.3 mmol/L in women or <1.1 in men and waist circumference ≥ 80 cm in women or ≥ 90 cm in men). Patients on anti-hypertensive agent for treatment of hypertension or lipid lowering drug for the treatment of hyperlipidaemia will respectively be considered to have one component of the metabolic syndrome.
• Subject is capable of giving informed consent prior to the initiation of any study related procedures
• A female subject of childbearing potential who is sexually active with a non-sterilized male partner agrees to use routinely adequate and effective contraception to avoid pregnancy during the study period and up to 30 days after the final visit.
• The subject is able and willing to consistently record food diary to facilitate CGMS evaluation.

Exclusion criteria

• Subject has received anti-diabetic agents within 6 weeks prior to screening visit.
• On dietary supplement known to affect glucose or galactose metabolism.
• History of acute cardiovascular disease including myocardial infarction, acute coronary syndrome or stroke which required hospitalization in the last 12 months.
• Significant renal impairment with estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2
• Known lactose or galactose intolerance.
• History of eating disorder.
• Pregnant or lactating female subjects.
• Subjects with gastrointestinal disease that may interfere with absorption of the investigational product.
• Subject has received any investigational product within 30 days of randomization visit.
• Reduced life expectancy or any condition considered by the investigator as unsuitable for enrolment.