Reducing cancer risk through better metabolic health

• Cancer represents one of the leading causes of claims in Life & Health Insurance across all lines of business. 
• In modern societies, the link between metabolic risks and cancer are common and is a growing health threat. 
• Scientific evidence supports associations between metabolic risks and many types of cancer. 
• These metabolic risks include high levels of insulin (insulin resistance) and type 2 diabetes, obesity (i.e. visceral adiposity) and physical inactivity.
• Cancer types with metabolic risk association include tumours of the endometrium (uterus), pancreas, colorectum, liver, biliary tract, kidney, bladder, oesophagus, breast, thyroid, brain, ovaries, and stomach. Recent evidence suggests that over 30 cancer types are affected. 
• Studies have shown a significantly lower risk for several of these cancers in individuals who perform regular and adequate physical exercise as well as in patients on insulin sensitising medication and after bariatric surgery. Diet associated with lower circulating insulin levels have been shown to reduce cancer risks in pre-clinical models. 
• This emphasises the enormous potential of nutritional patterns that reduce insulin levels and insulin resistance, gaining or keeping normal weight, and physical activity (which itself increases insulin sensitivity) in preventing or reducing the incidence of these cancers.

Cancer is a global health challenge as it represents a leading cause of morbidity and mortality. Each year, we face over 20 million new cancer cases and around 10 million cancer deaths worldwide. A recent study observed an overall increasing global trend (2010–2019, incidence +26%, cancer deaths +21%, respectively). This demonstrates a significant and growing burden of cancer. Considering cancer deaths attributable to modifiable risks globally, lung cancer was reported as the leading contributor followed by colorectal and oesophageal cancer in males, and cervical cancer, colorectal, and breast cancer in females. Malignancies are also one of leading causes of claims in Life &Health Insurance. Cancer-related claims impact multiple product lines, including critical illness, life and disability insurance (e.g. income protection), cancer products and health insurance. In large mortality portfolios (e.g. U.S.) and critical illness in general, cancer is number one cause of claim even ahead of cardiovascular diseases and other conditions. Although mental health and musculoskeletal-related claims play a major role in income protection policies, cancer is usually found in the list of top 3 or top 4 causes of claims (e.g. Australia, Germany). Analysis of Swiss Re claims data from the United Kingdom and Ireland (2019–2022) shows that cancer was the leading cause of claims in critical illness (59%; females: 73%, males: 46%) and term life (43%; females: 49%; males: 39%).

We observe a significant and growing burden of cancer worldwide.

Among the modifiable cancer risk factors, the wider group of metabolic risks including poor diet, physical inactivity, and metabolic disease such as insulin resistance, type 2 diabetes (T2D) and obesity have been on the rise. Many lines of scientific evidence ranging from animal and epidemiological studies to observational clinical data support associations between these risks and certain cancer types (Table 1). Another indicator is the common temporal trend for both conditions, with increasing rates of these risks and related cancers over time. An analysis of the Global Burden of Disease Study 2019 has identified metabolic risks as leading contributors to cancer deaths globally and are currently experiencing the largest relative increase among modifiable cancer risks.

Due to significant overlap (e.g. T2D and obesity), the differential effects of components of this group of risks are difficult to analyse and quantify as they may act independently, as confounders or modifiers. The mechanisms of this risk association are described below, and it appears that this is mainly driven by high fasting blood sugar, chronic hyperinsulinaemia (high blood levels of insulin) in conjunction with insulin resistance and visceral adiposity. These key factors likely independently and additively contribute to increased risk for certain cancers and their progression, while overall, hyperinsulinaemia and insulin resistance appear to be the most significant root mechanisms.

Many lines of scientific evidence support the association between metabolic risks and certain types of cancer. These conditions currently experience a significant increase among modifiable cancer risks.

Metabolic syndrome (MetS) is composed of high fasting blood sugar, high blood pressure, obesity and elevated blood lipids (Figure 1). Besides its association with numerous non-communicable diseases such as cardiovascular conditions (e.g. heart attack), chronic liver disease (metabolic dysfunctionassociated steatotic liver disease – MASLD) or polycystic ovarian syndrome (PCOS), the role of MetS or its components as risk factors for certain common cancers has been increasingly acknowledged. In some cancer types, the risk differs between sexes, populations (e.g. ethnicity), or menopause status. For certain cancer types (pancreatic cancer, rectal cancer) stronger associations are seen in women. Furthermore, risk-association had been shown to be different depending on menopause, e.g. increased risk of colorectal cancer and malignant melanoma in pre-menopausal women, while an increased risk for breast and endometrial cancers was specifically identified in postmenopausal women.

Indicators of overweight and obesity such as BMI have been associated with increased risks for multiple cancers as well as mortality from those (Table 1). It had been common understanding that overweight and obesity are linked to just more than 10 different cancers. Recently presented study data of over 4 million individuals, however, revealed that over 30 cancer types may be affected. Additionally identified cancers included malignant melanoma, tumours of the pituitary and adrenal gland, head and neck as well as cervical cancer. According to this analysis, four out of ten cancer cases were linked to excess weight. 

Latest research suggests that the impact of metabolic ill-health on cancer risk is significantly greater than previously thought which has the potential to increase future cancer cases beyond current modeling.

Studies have demonstrated that individuals with blood markers positive for insulin resistance (c-peptide, insulin, proinsulin, HOMA-IR) had a greater risk of a variety of cancers including colorectal, breast, endometrial, liver, pancreatic, ovarian and stomach cancer, when compared with those having these markers within normal range. As insulin levels rise with increasing blood glucose, it is no surprise that chronically elevated glucose levels also lead to higher risks of these tumours including colorectal and pancreatic cancer. Interestingly, one study showed that overweight or obese individuals considered “metabolically healthy” (measured by C-peptide levels) were not at increased risk of colorectal cancer. On other investigations, hyperinsulinaemia (even in the absence of obesity) has been demonstrated to be linked to increased cancer-specific mortality. This also specifically holds true for breast cancer risk and recurrence, as well as fatal liver cancer.

A recently published European collaboration study analysed data of nearly 800 000 individuals that were followed for up to 40 years. While the study confirmed that a higher BMI increased the risk of cancer, the authors demonstrated that that metabolically unhealthy people (measured by blood glucose amongst others) were at increased risk irrespective of weight.

At an even later stage of insulin resistance, a diagnosis of T2D is linked to the risk of multiple cancers (Table 1). Interestingly, a lower risk for prostate cancer has been reported, which has been associated with metformin use and hormonal factors. One study conservatively estimated that 6% of all incident cancers were attributable to T2D and obesity with particularly high attribution in specific cancer types (e.g. liver cancer, 25%; endometrial cancer, 38%). A 25%-41% increased risk of cancer-related mortality has been published for T2D. In the context of decreasing cardiovascular death due to improved diagnosis and treatment in patients with T2D, a clear transition to cancer as leading contributor to diabetes-related death is currently observed.

It is important to look beyond simple markers such as BMI, but rather root indicators of metabolic health i.e. insulin resistance. This indicates the significance to address metabolic health holistically.

Diet is key to prevent insulin resistance and visceral adiposity from occurring, but nutrition goes beyond metabolic disease when considering the risk for cancer. The digestive tract (mouth, oesophagus, stomach, intestine, and colorectum) is particularly exposed to the components of food which may explain the association of certain diets and their components with cancer risks of these sites. One example is ultra-processed food (UPF) which represents industrial food formulations manufactured in a complex way using ingredients not usually found in kitchens and cosmetic additives. UPF-intake was shown to be associated with a higher risk of developing multiple cancers including those of the mouth, throat, oesophagus, and colorectum, but also pancreatic and ovarian cancer.

This is concerning, given the estimation of a study according to which over 70% of food in the United States may be ultraprocessed. Exposure to environmental cancer-causing substances includes those ingested by animal food sources as well. Many studies have looked into multiple dietary components, additives, and nutrients to explore possible associations with cancer risk. Examples include acrylamide, antioxidants, and artificial sweeteners. The results of those studies have always to be interpreted with caution as limitation of study methods and confounding factors need to be acknowledged.

A nutrient often believed to increase cancer risk is red meat, particularly when processed. The International Agency for Research on Cancer (IARC), an independent cancer agency, has stated that red meat consumption was “probably carcinogenic” because bias and confounding could not be ruled out. Different study outcomes highlight the limitation of nutritional, especially epidemiological observation studies that rely on association, and that are subject to these biases and confounders. A critical evaluation of the current evidence which was published in Nutrients in 2021 and concluded that the majority of the previously published systematic reviews and meta-analyses that examined the consumption of processed meat and the risk of cancer had severe methodological limitations. The authors stated that the “recommendation to reduce the consumption of processed meat and meat products (with the aim of lowering the risk of cancer) [...] seems to be based on evidence that is not methodologically strong.” In 2022 an article published in Nature Medicine titled “Health effects associated with consumption of unprocessed red meat: a Burden of Proof study” found “weak evidence of association between unprocessed red meat consumption and colorectal cancer (and) breast cancer.” The confounding, including the healthy user effect of associational studies implies that we cannot assume a causal link.

The underlying biological mechanisms of the multiple risk-associations described above are not fully understood. Several processes that interact with each other play a role. Risks, mechanisms, and susceptible tumour types are shown in Figure 2 and 3. For some of these risks, it is still not clear whether they act as carcinogen (factor that induces malignancy, e.g. by causing genetic changes, i.e., damage to DNA) or mitogen (factor that promotes cell proliferation and growth), or both. Although the scientific and medical literature suggests that the mitogenic potential, e.g. of insulin, appears to predominate, metabolic risks seem to be involved in several spots of cancer development and progression: malignant transformation and invasion, growth and survival, angiogenesis, metabolic reprogramming, treatment resistance.

Hyperinsulinaemia due to chronically elevated blood sugar levels and consecutive insulin resistance seems to play a central role. Insulin has significant anabolic effects and impacts metabolism, growth and proliferation through cell signalling and via higher availability of proteins that promote growth and proliferation such as insulin-like growth factor-1 (IGF-1). This is supported by evidence that shows an increased risk of colorectal adenomas and cancer as well as other certain tumour types such as breast, pancreas, liver, kidney, stomach, and lung cancer among T2D patients with chronic insulin therapy. Furthermore, the daily insulin dose is associated with cancer risk in patients with type 1 diabetes. Insulin also increases the bioavailability of oestrogen which is associated with breast cancer risk. Elevated blood sugar levels per se may cause DNA damage, increase oxidative stress, and stimulate the production of growth factors and AGEs (advanced glycation end products). AGEs can promote inflammation and tumour transformation of specific cells in our body (e.g. stomach, pancreas). Furthermore, overabundance of glucose is a natural promotor of tumour development and progression. It enhances cell growth and proliferation (Warburg effect) although cancers may use alternative fuel sources, too.

Obesity, especially excess visceral adipose tissue (VAT), is considered a low-grade inflammatory state and has several adverse local and systemic effects that impact the risk for several cancers, e.g. by overproduction of certain signalling molecules that play a role in malignant transformation and progression (Figure 3). These mechanisms include the impact on the vicious circle of insulin resistance, endoplasmic reticulum and mitochondrial stress, changes in circulating adipokines (specific fat hormones such as leptin and adiponectin which have impact on cell proliferation and differentiation, e.g. described in breast, endometrial and renal cancer), and especially chronic inflammation by secretion of pro-inflammatory hormones such as TNF-α or IL-6. A diet high in carbohydrates (higher glucose requiring higher insulin levels) also leads to chronic inflammation. Inflammation molecules stimulate cell cycling and carcinogenesis and are hyperactivated in a variety of tumours including colorectal and breast cancer. Oestrogens and inflammatory factors interact in the breast which is why inflammation contributes to hormone-dependent breast cancer progression. Another aspect in breast cancer is the cross-talk between adipokines and oestrogen. Other pathogenic mechanisms are driven by molecules of oxidative stress which seems to play an important role in renal cancer.

We see more cancers in younger people, in fact cancer types, that have been common in the elderly. The underlying reasons are not known, but a significant contribution of metabolic risks is plausible.

In modern societies, physical inactivity has reached pandemic dimensions. This is of particular interest as sufficient levels of regular physical exercise (as recommended in guidelines, e.g. 150 min per week of moderate activities such as walking or 75 min per week of vigorous activities, or a combination thereof) are associated with reduced risk for several cancers. For low levels, elevated risks for bladder, breast, colorectal, endometrial, oesophageal adenocarcinoma, renal, and stomach cancers have been reported (Table 1). In one systematic review, relative risk reductions (highest vs. lowest physical activity) ranged from roughly 10% to 20%. Regular muscular activity improves insulin sensitivity (thereby reducing insulin levels in the blood stream) and therewith metabolic health. It also decreases systemic inflammation and has further anti-tumour effects such as positive impact on anti-cancer immunity (e.g. by immune cell mobilisation) and gut microbiome diversity. Some scientific experts refer to regular physical activity as endogenous immunotherapy or immunosurveillance.

Cancer can develop at any age, but mostly affects individuals over the age of 50. The underlying paradigm is that cells in our body can get damaged over time (DNA damage), and as multiple of these ‘hits’ are necessary to develop cancer, the risk to be diagnosed with a tumour increases throughout lifetime. Another factor appears to be the decline of control functions including DNA repair mechanisms and the immune system.

An emerging issue, however, has been the rise of certain cancers in younger people, a phenomenon which is referred to as earlyonset cancer (EOC). Multiple studies have demonstrated an increase in cancer cases within age bands 20 to 50 since the 1990s with even ‘Millennials’ (those born 1981–1996) affected. One study found that global incidence of EOC has increased by 79% and the number of EOC-related deaths increased by 28% between 1990 and 2019. These cancers especially include tumour types typically seen in people older than 50 years, such as colorectal cancer. Others are ENT, renal, prostate and breast cancer. Recent data has shown an increase in pancreatic cancer diagnosis, especially in young women.

Causes and underlying mechanisms of rising EOC are not certain. Scientific experts believe that individual life-course exposures in combination with genetic susceptibility play a major role in the development, given the long latency periods of overall cancer development (gene-environment interaction). Looking at temporal trends of known cancer risks and the rise of cancer types associated with metabolic risks (e.g. colorectal, kidney, breast), the hypothesis that metabolic risks such as hyperinsulinaemia, visceral adiposity and physical inactivity as well as their combination significantly contribute to this development appear plausible, although other factors in discussion such as environmental pollution must not be ignored. A recent study using UK biobank data has shown that markers of accelerated ageing are more common in recent birth cohorts, and that these were linked to elevated risks of early-onset solid tumours especially lung, gastrointestinal, and uterine cancers. Glucose and c-reactive protein, a test indicating inflammation, were among the blood-based markers associated with biological age that were examined in this study.

The best cancer is the one that never develops. This is why primary prevention measures aim at lowering the risk of cancer ever occurring and try to address known and modifiable risk factors. As shown in several studies, a significant proportion (up to half) of cancer cases are avoidable if we effectively applied this knowledge, and this would dramatically decrease the burden of the disease, its treatment, and costs.

From a metabolic health viewpoint, the risk-associations described above indicate a significant potential benefit from controlling metabolic health components including strategies to address circulating insulin, visceral fat as well as physical inactivity. This indicates the potential of prevention through lifestyle modifications including diet and exercise, but also pharmacologic and surgical treatment options.

Pilot studies that have shown diabetes remission by lifestyle modification (diet and exercise) would be expected to also result in a reduction of specific cancers and related mortality. Indeed, numerous investigations with therapeutic interventions for weight reduction and healthy lifestyle have been associated with a reduced cancer risk. Even after a cancer diagnosis, adherence to a healthy lifestyle has resulted in better outcomes such as reducing the risk of breast cancer recurrence with improved survival. A large study has observed that adherence to a diabetes risk reduction diet (DRRD) can reduce the risk of bladder cancer by over 20%. Among the dietary approaches, caloric restriction and limiting carbohydrate intake through a ketogenic diet (KD) have been analysed. KD has been shown to suppress tumour proliferation in certain cancers in pre-clinical (animal, laboratory and human) studies including glioblastoma (a very malignant form of brain cancer), prostate, colon, pancreatic, and breast cancer (Table 2). Admittedly, not all cancers responded positively to KD, and some did show an increased growth including kidney cancer and melanoma. These associations require further scientific investigation. Furthermore, it is not known whether these effects may be explained by lower levels of insulin or by circulating ketones, or both.

Metformin is an anti-diabetic drug which is known to increase insulin sensitivity (‘insulin sensitiser’) but also has other direct effects on cells and their environment. Numerous studies have indeed found an association of metformin use with reductions in cancer incidence and progression as well as cancer-related death, e.g. for colorectal tumours. This is of particular interest as T2D patients exposed to other drugs such as sulfonylureas and insulin prescribed by doctors show an increased cancer risk including cancer-related mortality when compared with metformin. Further potentially effective drugs may include a group of medications to reduce chronic inflammation such as anti-cytokine vaccines, inhibitors of proinflammatory signalling pathways, and antioxidants.

Another interesting aspect is looking at the long-term impact of bariatric surgery (e.g. sleeve gastrectomy, gastric bypass surgery) on cancer risks. Investigations have impressively demonstrated a significant reduction in the risk for all cancer types (28% risk reduction), but especially for obesity associated cancers (45% risk reduction). At a median time of 10.9 years, one study reported a 33% risk-reduction of cancer incidence suggesting that significant effects can be seen in a time range of few years. Cancer-related mortality reductions have also been reported, in meta-analyses of around 50%.

Given the risk associations described in this article, reducing these risks has enormous potential to reduce cancer-related claims in L&H insurance in a time span of few years after initiating effective strategies to improve lifestyle and metabolic health. This could be achieved by lowering the levels of circulating insulin – ideally by improved nutrition which is low cost and safe – and by maintaining normal weight in combination with physical activity. In the UK, Swiss Re is trialling the potentially beneficial impact of metabolic health initiatives on both its staff and a cohort of Income Protection disability claimants. The latter group are defined as having been absent from work for a minimum of 12 months and normal rehabilitation methods have failed. The Metabolic Health Rehab programme is provided by a collaboration partner (Combe Grove) and first positive results regarding return to work have already been seen. In the medium and longer term, these initiatives could have positive impact on cancer incidence reduction as well although larger interventions will be needed to show a statistical reduction. Analysis of Swiss Re claims data has shown that in women breast cancer was the leading cause of loss for both critical illness (51%) and term life (18%), followed by colorectal cancer (5%) in critical illness and lung (15%), colorectal (7%) and pancreatic (6%) in life. In men, the leading cancer types in critical illness were prostate (26%), colorectal (10%), and kidney cancer while tumours of the lung (16%), colorectum (9%), and pancreas (7%) were the leading cancers in life policies. In the context of this article, these data underpin the significant potential of improving metabolic risks especially in critical illness and life insurance portfolios with regard to cancer-related claim rates. It is important to acknowledge how these risks – especially nutrition including nutritional guidelines – impact metabolic health with respective non-obvious implications for life and health insurers.