Type 2 diabetes and cancers – what and why?

24th April 2022, Dr Chee L Khoo

There have many observational studies that have shown increased risks of a variety of cancers in patients with both type 1 and type 2 diabetes independent of body mass index (BMI). Cancer is also the second most common cause of death in patients with diabetes. Up to 18% of patients with cancers have diabetes. There is clearly a close link between diabetes and cancers. The underlying mechanisms of the link is not fully understood. Is it related to hyperglycaemia? Is there an association between the level of glycaemic control and these cancers?

The affected cancers

Studies have suggested that type 2 diabetes is associated with an increased risk of liver, pancreas, endometrium, colorectum, breast, and bladder cancers and a decreased risk of prostate cancer (1).  It is also possible, however, that some claimed associations could be caused by biases in the literature, in particular selective reporting biases favouring the publication of significant associations (2) and causing either false positives (3) or inflated estimates of association (4). 

Tsilidi K et al conducted an umbrella review of the evidence across meta-analyses of observational studies of type 2 diabetes with risk of developing or dying from any cancer (5). It’s kind of a meta-analysis of the meta-analyses of the observational studies on the subject.  Of the 27 meta-analyses, eventually only seven (26%) compiled evidence on more than 1000 cases, had significant summary associations at p ≤ 0.001 for both random and fixed effects calculations, and had neither evidence of small study effects nor evidence for excess significance.  Only breast, intrahepatic cholangiocarcinoma, colorectal, and endometrial cancer had robust evidence supporting the association of T2D and cancers.

So, the evidence linking T2D and various cancers is not that robust and all very conflicting. Trying to unravel the mechanisms of the link between T2D and cancers is even more complicated with many confounding factors involved. It could be to do with the direct effects of hyperglycaemia, insulin resistance, genetic risk, chronic inflammation or other associated metabolic abnormalities. Perhaps, a study of the effects of various levels of hyperglycaemia may help us shine some light on the matter. Is there an association between poor glycaemic control and cancers in patients with diabetes?

Rentsch C et al explored one of those possible links by studying the association between HbA1c and incidence of 16 site-specific cancers within UK Biobank (6). UK Biobank includes 502 536 men and women aged 40–69 years recruited between 2006 and 2010 from primary care practices in England, Scotland and Wales. Participants underwent a baseline assessment capturing sociodemographic and lifestyle factors, health status, and gave blood samples for biomarker measurement.

Baseline for this study was defined as the date of baseline assessment. Participants were considered at risk from 6 months after baseline to reduce the impact of reverse causality among cancers diagnosed shortly after baseline, whereby the undiagnosed cancer may have affected the baseline HbA1c measurement. Follow-up ended at the earliest of first record of any cancer or date of death.

The four most common cancers in the cohort were considered primary outcomes of interest, including prostate, breast, colorectal and lung. They also examined oesophageal, stomach, pancreatic cancer, melanoma, uterus, ovarian, kidney, bladder, central nervous system cancers, non-Hodgkin’s lymphoma, multiple myeloma, and leukemia.

HbA1c was categorised at standard clinical cut-off points for normal glycemia (<6%), prediabetes (6%–6.4%) and diabetes (≥6.5%), irrespective of diagnosed diabetes status at recruitment. Incidence rates for each cancer were estimated by HbA1c category and age standardized to the UK Biobank population.

The assessment

They investigated whether the effect of HbA1c on risk of cancer differed in a subgroup without smoking history, a key risk factor for many of the included cancer outcomes. Next, they assessed the potential for reverse causality by comparing the association between HbA1c and cancer incidence by time since study entry (0–6 months, 6 months–2 years, and 2+ years) for the primary outcomes. They then assessed changes in the association between HbA1c and risk of the primary cancer outcomes at each stage of confounder adjustment to identify which variables appeared to have greater impact on the observed results. Finally, they estimated the association between having a type 2 diabetes diagnosis at baseline and risk of cancer incidence, not adjusting for HbA1c, to determine if they could replicate established associations from multiple previous studies.

What did they find?

Of the 502 536 participants in the UK Biobank, 35 080 were excluded for having a history of cancer at the baseline assessment. A further 89 203 were excluded for having missing data on at least one of the covariates of interest, leaving a total of 378 253 participants eligible to contribute to analysis (figure 1). Of these, 349 825 (93%) had normal, 15 648 (4%) had prediabetes and 12 780 (3%) had diabetic levels of HbA1c at baseline. Individuals with higher HbA1c (prediabetic or diabetic) were observed to have higher median BMI, were less likely to do moderate or vigorous physical activity, were more deprived and more likely to be of non-white ethnicity compared with those with normal HbA1c.

Among 378 253 individuals with average follow-up of 7.1 years, 21 172 incident cancers occurred. They examined the associations between cancer risk and having a diagnosis of T2D at baseline and found positive associations with colorectal, pancreatic, uterine and bladder cancer, and a negative association with prostate cancer.

When they explored the associations of these cancers across the full glycaemic range, except for pancreatic cancer, they were not able to demonstrate any consistent link between higher HbA1c and risk for cancer that would support a hyperglycaemia associated mechanism for cancer risk.

The evidence for pancreatic cancer was strong. HbA1c was positively associated with pancreatic cancer, whereby low HbA1c was associated with lower cancer risk (HR 0.39) and high HbA1c was associated with elevated cancer risk (HR 1.55). There was also evidence that low HbA1c was associated with lower risk of uterine cancer (HR 0.52).

Interestingly, they found a novel inverse association between HbA1c and premenopausal breast cancer, whereby increased HbA1c was associated with decreased risk of cancer, that was not attributed to differences in demographic characteristics, BMI, or lifestyle factors. There have been previous suggestions that glucose-lowering therapies, particularly metformin, are associated with lower risk of breast cancer though concerns over bias were raised (7,8). Subsequent studies have found no such evidence (9). In this study, the effect from metformin was not found as the inverse association was present irrespective of whether the patients were on metformin.

There was a suggestion that increased HbA1c was associated with increased risk of stomach cancer but the numbers were low and potentially underpowered. Results from previous studies linking HbA1c to stomach cancers are conflicting (10,11).

In the most recent systematic review of associations ,4 between HbA1c and cancer risk included 19 studies the largest of which analysed 46 575 individuals with 634 .22 cancer events, no association between Hb1Ac and any of the cancers in this study was found (10).

In summary, in this study, there is a positive association between T2D and a number of cancers (colorectal, pancreatic, uterine and bladder cancer) but the association between HbA1c and cancers is only seen in pancreatic and uterine cancers. There was an inverse association with premenopausal breast cancer.

We looked at the glucose patterns in patients with T2D who developed pancreatic cancer last week.


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