Underneath the lost kilos – using MRI-based body and muscle composition measurements to understand weight loss in clinical trials

Excess weight or body fat, often termed obesity, is a growing healthcare problem with mounting demands for new treatment options. There is a lot of drug development activity and interest in this field following recent approvals and trial successes. However, the market is becoming increasingly competitive, and drug developers are needing evidence that goes beyond absolute or relative weight loss to demonstrate the source of the weight loss, other organ benefits, and to differentiate their drugs from those of their competitors.

Many drugs are currently in development for the treatment of obesity, with the goal of inducing long-term weight loss. While weight loss in absolute (kg) and relative (% of body weight) terms are typically the primary endpoints in clinical trials, they give limited insights regarding drug efficacy and body composition changes. Some of the motivations for seeking additional information regarding weight loss in clinical trials are, for example:

  • Demonstrating the source of the weight loss: if it is expected that the treatment could induce changes in weight beyond adipose tissue (e.g. change in lean tissue), demonstrating where the weight loss is coming from can be important. For example, if there is muscle gain coinciding with the weight loss, this might not be captured by looking only at weight loss (kg or % body weight). As different types of adipose tissue can have different health implications, the redistribution of fat could be of interest to investigate.
  • Showing signs of efficacy from a holistic perspective: the drugs in development for obesity are also demonstrating other effects across a variety of end organs, both in relation to and independently of the weight loss. Measuring weight loss alone will not elucidate these effects.

 

Capturing weight loss and body composition in clinical trials

There are many methods for measuring weight loss and body composition in clinical trials, each with its advantages and disadvantages (See Figure 1). Of the currently available methods, using Magnetic Resonance Imaging (MRI) enables precise and comprehensive measurements of the source of the weight loss and other body composition changes.

Figure 1: Currently available methods for measuring weight loss in clinical trials

Using MRI to get a precise and comprehensive measurement of body composition

With MRI, we can separate fat and lean tissue by measuring visceral (VAT), subcutaneous adipose tissue (SAT) and adipose tissue-free mass (ATFM) from whole-body images. This can help to understand where the weight loss is coming from, also sometimes referred as the 'quality' of the weight loss. MRI can also be used to look into more specific ectopic fat depots in and around e.g. the liver, kidney, muscle, heart, and pancreas, as well as other effects linked to metabolic disease. It has been suggested that ectopic fat acts as an inflammatory milieu in metabolic disease and there can also be mechanical effects.

MRI-based detailed assessment of muscle volume and composition

Beyond VAT and SAT, imaging can also be used to make more advanced body composition assessments looking specifically at muscle composition. When applied to muscle compartments, individually segmenting each muscle component enables assessment of:

  • Muscle volume: the muscle volume either including or excluding the intramuscular fat component.
  • Intramuscular fat: the muscle fat content expressed either as a volume or as the muscle fat fraction. Made up by a combination of intra- and extra myocellular lipids.
  • Intermuscular fat: the fat around the muscles, beneath the deep fascial layer.

Assessing muscle composition, and more specifically measuring muscle fat, is important for several reasons. For example, it helps to ensure that loss of muscle fat is not interpreted as loss of muscle volume. It is also important to make sure that conservation of muscle volume is not interpreted as lack of weight loss efficacy. Going one step further, it is possible to separate the intramuscular fat deposition into its intra- and extramyocellular components, the two being associated with distinct metabolic implications. Studying these will require the use of spectroscopic techniques (Magnetic Resonance Spectroscopy; MRS) and will primarily be an option in studies limited to few imaging sites.

Figure 3: (Left) Individually segmented thigh muscles, (Right) intramuscular, intermuscular, and subcutaneous fat of the same subject
“We can tailor body and muscle composition protocols depending on research needs, and combine whole-body assessments with detailed looks into specific tissues of interest”
Edvin Johansson Senior MR Imaging Director

Integrating MRI body and muscle composition endpoints into clinical trials

Integrating MRI body and muscle composition endpoints into a clinical trial will give you more information about the weight loss and the effects of the drug. Earlier and more specific markers of efficacy can inform decision making or differentiation. Protocols can be designed to combine body composition measurements with other biomarkers to look at end organ effects.

Figure 4: Integrating an imaging protocol to include body and muscle composition measures with other organ effects