Clinical trial NCT02917928: The Potential of Carnosine Supplementation in Optimising Cardiometabolic Health
Official title: The Potential of Carnosine Supplementation in Optimising Cardiometabolic Health in Patients With Prediabetes and Type 2 Diabetes: a Randomsied, Double-blinded, Placebo-controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Poor Glycemic Control
Cardiovascular Risk Factors
Cognitive Function 1, Social
Keywords: carnosine, type 2 diabetes, cardiovascular factors
Lead sponsor: Monash University
Sponsor class: OTHER
First posted: 2016-09-28
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The investigators hypothesise that carnosine supplementation will improve:

1. glycaemic control
2. cardiovascular risk factors
3. cognitive outcomes

in patients with prediabetes and type 2 diabetes, and this will be modulated by reduction in chronic low grade inflammation, oxidative stress and circulating advanced glycation end products levels.

3. Aims

To determine the potential of carnosine supplementation for 14 weeks to improve glycaemic control in type 2 diabetes, reduce risk factors for cardiovascular disease and improve cognitive function as well as identify metabolic pathways involved, specifically by:

1. Improving glycaemic control (HBA1c, fasting and 2 hour glucose and glucose area under the curve after oral glucose tolerance test)
2. Reducing cardiovascular risk factors (lipids; arterial (aortic) stiffness; central blood pressure (cBP); endothelial function).
3. Improve cognitive function (global cognitive score formed by a composite of 4 cognitive tests)
4. Decrease the chronic low grade inflammation, oxidative stress, advanced glycation end products, and advanced lipoxidation end products, and increase detoxification of reactive carbonyl species (RCSs).

Detailed description: Type 2 diabetes is a major public health problem worldwide. Obesity itself markedly increases the risk of type 2 diabetes (DM2), which now affects every second obese person. With 60% of adult Australians overweight or obese and 25% of Australians aged over 25 years having prediabetes or diabetes, the quality-of-life and cost impact is inescapable. In Australia, direct healthcare costs for DM2 are currently estimated as $1.1 billion annually, with the prospect of doubling by 2025. Obesity and DM2 dramatically increase the risk of cardiovascular disease (CVD) with \~80% of individuals with both obesity and DM2 develop CVD. The annual healthcare costs for CVD in Australia now amount to $7.7 billion; and the total aggregated costs, including loss of income, are much higher again. Treating DM2 and CVD is expensive and often unsatisfactory. Weight loss and exercise are the mainstay of prevention and therapy but they are difficult and costly to achieve on a large scale; hence the DM2 epidemic continues unabated. Therefore, interventions at low cost and easy to implement at the population level is urgently required.

Neurodegenerative diseases often occurs in people with DM2, and DM2 is in turn associated with increased risk of cognitive decline. Neurodegenerative diseases such as Alzheimer's disease are also associated with metabolic impairment. They share many common pathogenic features with DM2 such as insulin resistance, chronic low-grade inflammation, vascular disease, oxidative stress and accumulation of advanced glycation endproducts (AGEs). Progression of these diseases over years-decades is also worsened by a sedentary life-style. Therefore not surprisingly, regular physical activity is beneficial in those patients, likely due to improvement of neurological, motor and cardiometabolic profile. However, it is difficult and costly to achieve on a large scale, and thus, safe and low-cost strategies are needed.

Type 2 diabetes is associated with increased amounts of ectopic fat depots in muscle including intramyocellular lipids (IMCL), and adipocytes located between muscle groups (inter-muscular) and also between muscle fascicles (intramuscular). Both IMCL and intra- and inter-muscular adipose tissue (IMAT) may deleteriously effect muscle metabolism and insulin sensitivity through increased local secretion of pro-inflammatory adipokines, and inter-muscular fat may additionally impair insulin action through reductions in blood flow to muscle.

Could carnosine be that strategy? Strong molecular and animal data (\>2000 papers) suggests that it has great potential, with all the relevant properties. Carnosine, is present in several tissues including muscle and brain, easily crosses the blood-brain barrier, and extensive animal data show that carnosine has chelating properties and modulates glucose metabolism, advanced glycation, pro-inflammatory and pro-oxidative states, as well as motor functions and neurotransmission. A promising further use may derive from its effect on cardiometabolic health and neuroprotection. Current research, confined to animal studies, supports carnosine supple¬ment¬ation for preventing and treating obesity, DM2, CVD, and neurodegenerative diseases - by virtue of its anti-inflammatory, antioxidative, anti-glycating and chelating effects. Our team's novel pilot studies provide the first human cross-sectional and interventional metabolic data, and demonstrate relationships among carnosine, obesity, insulin resistance, and dyslipidaemia. Previous clinical trials also showed that supplementation of carnosine for 2-3 months improved cognitive performance in healthy individuals and patients with neurodegenerative diseases. However, none of them showed its effect in patient with type 2 diabetes and explored the effects of change in cardiometabolic outcomes on cognitive function.

Apart from its excellent side-effect profile, carnosine is cheap and safe (it is an over-the-counter dietary supplement), making it prima facie ideal for widespread, low cost use. Robust human research is now urgently needed to test the therapeutic potential of carnosine in improving cardiometabolic profile and cognitive function, and study the mechanisms involved.

Eligibility criteria: Inclusion Criteria:

* Age \>=18 or \<=70 years
* Weight change \< 5 kg in last 6 months
* HbA1c level \<= 8%
* Patients with prediabetes (Impaired glucose tolerance and impaired fasting glycaemia) or type 2 diabetes (diet controlled or on oral therapy)
* Patients will have to be on oral therapy for diabetes (without changes in treatment) at least for 3 months.
* Patients will be advised not to change their pre-existing therapy for diabetes and cardiovascular risk factors for the duration of the study if HbA1c is not above 8%
* No recent blood transfusion (3 months)
* No current intake of anti-inflammatory medications and supplements
* No significant kidney, cardiovascular, haematological, respiratory, gastrointestinal, or central nervous system disease, as well as no psychiatric disorders, no active cancer within the last five years; no presence of acute inflammation (by history, physical or laboratory examination)
* Pregnant or lactating

Exclusion Criteria:

* Age \<18 or \> 70 years
* HbA1c level of \>= 8%
* Weight change \> 5 kg in last 6 months
* Morbid obesity (body mass index \>40 kg/m2)
* Current smoking habit and high alcohol use
* Patients on insulin
* Taking anti-inflammatory medications or supplements
* Recent blood transfusion history
* Kidney (estimated glomerular filtration rate \< 30 ml/min), cardiovascular, haematological, respiratory, gastrointestinal, or central nervous system disease, as well as psychiatric disorder, active cancer within the last five years; presence of acute inflammation (by history, physical or laboratory examination)
* Pregnancy or lactation

Primary outcomes:
measure: Change in Oral Glucose Tolerance Test
timeFrame: baseline and 14 weeks
Secondary outcomes:
measure: Change in HbA1c
timeFrame: baseline and 14 weeks
measure: Change in lipid profile
timeFrame: baseline and 14 weeks
measure: Change in systolic and diastolic blood pressure
timeFrame: baseline and 14 weeks
measure: Change in arterial stiffness and central blood pressure
timeFrame: baseline and 14 weeks
measure: Change in markers of endothelial dysfunction
timeFrame: baseline and 14 weeks
measure: Change in heart rate variability
timeFrame: baseline and 14 weeks
measure: Change in interleukins
timeFrame: baseline and 14 weeks
measure: Change in tumour necrosis factor α
timeFrame: baseline and 14 weeks
measure: Change in macrophage migration inhibitory factor
timeFrame: baseline and 14 weeks
measure: Change in plasma C- reactive protein
timeFrame: baseline and 14 weeks
measure: Change in plasma and urinary advanced glycation end products
timeFrame: baseline and 14 weeks
measure: Change in plasma and urinary advanced lipoxidation end products
timeFrame: baseline and 14 weeks
measure: Change in general cognitive function
timeFrame: baseline and 14 weeks
Other outcomes:
measure: Change in liver stiffness and fat
timeFrame: baseline and 14 weeks
measure: Change in Serum and urine carnosine
timeFrame: baseline and 14 weeks
measure: Change in skeletal muscle fat and density
timeFrame: baseline and 14 weeks
measure: Change in body composition
timeFrame: baseline and 14 weeks
Locations:
city: Melbourne
country: Australia
facility: Monash Centre for Health Research and Implementation
state: Victoria
Study officials:
affiliation: Monash University
name: Barbora de courten, MD,PHD,MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baye E, Menon K, de Courten MP, Earnest A, Cameron J, de Courten B. Does supplementation with carnosine improve cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes? study protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open. 2017 Sep 1;7(9):e017691. doi: 10.1136/bmjopen-2017-017691.