Blood glucose concentration and risk of pancreatic cancer
A systematic review and meta-analysis
Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis. BMJ 2015;349:g7371 doi:10.1136/bmj.g7371 by Wei-Chih Liao and colleagues
Objective—To evaluate potential linear and non-linear dose-response relations between blood glucose and risk of pancreatic cancer.
Design—Systematic review and dose-response meta-analysis of prospective observational studies.
Data sources—Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction.
Eligibility criteria—Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality.
Data extraction and synthesis—Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations.
Results—Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer.
Conclusions—Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer.
Why do the study?
The incidence and mortality of pancreatic adenocarcinoma is rising. In the United Kingdom, it is fourth leading cause of cancer death. Regrettably, at presentation, typically with painful obstructive jaundice, most pancreatic tumours have already invaded the adjacent superior mesenteric vessels, and are considered unsuitable for surgery. As a consequence, the median five year survival rate is less than 5%.
Type 2 diabetes, like smoking and Helicobacter pylori infection, is an established risk factor for pancreatic cancer. In rodent models, hyperglycaemia and secondary hyperinsulinaemia promote proliferation and the invasive potential of pancreatic cancer cells, in part through the increased bioavailability of insulin-like growth factor. 
The link between prediabetes, which affects about 8% of the world’s population and pancreatic cancer, is less clear. Some studies have reported a positive association, whereas others have found none.
The authors of this study sought to identify, on the basis of current literature, whether there is an association between prediabetes and the risk of pancreatic cancer. In particular, they aimed to determine if there is a blood glucose concentration dose-response relation with an increased risk of pancreatic cancer.
What did the authors do?
The authors completed a systematic review and meta-analysis. A systematic review is an exhaustive summary of the current literature on a specific research question. Meta-analysis is a mathematical synthesis of the results of two or more primary studies that dealt with the same hypothesis in a similar way. By pooling the results of clinical studies, meta-analyses increase the power of existing statistical analyses and overcome the problem of individual trials being too small to reliably detect outcomes.
Two authors independently searched the PubMed and Scopus medical research databases using specific keywords to identify articles published before November 2013, which examined the association between blood glucose concentrations and pancreatic cancer. No language restrictions were set.
They included prospective evaluations of blood glucose and the risk of pancreatic cancer. Because pancreatic cancer is known to induce diabetes, retrospective and cross sectional studies were excluded (reverse causality).
Data abstraction, in this case using a standardised electronic database, involves extracting the data of interest from each of the studies, in a format that allows them to be combined in a meaningful statistical analysis. Study quality was assessed using the Newcastle-Ottawa scale.
In this study, the authors extracted specific data including:
- Author, country of origin, publication year
- Study design, sample size, inception of cohort, duration of follow-up
- Mean age, gender (%)
- Adjustment for covariates
- Methods of measurement/categorisation of serum blood glucose
- Fasting or calculated fasting blood glucose concentrations
- Rate ratio of the incidence or mortality of pancreatic cancer
In practice, the designs of clinical studies incorporated into a meta-analysis are rarely identical. In this study, the authors used the I and Cochran’s Q statistics, which indicate the amount of variance in a meta-analysis that can be attributable to study heterogeneity.
The primary outcome was the rate ratio of the incidence of/or mortality from pancreatic cancer (pancreatic cancer incidence almost equals mortality). A rate ratio compares the rates of disease in two groups that differ by demographic characteristics or exposure history; in this case, high or low blood glucose concentration. The rate for the group of primary interest is divided by the rate for a comparison group.
Using multivariate analyses, comparisons between participants with “high” and “low” blood glucose concentrations were undertaken to look for associations with pancreatic cancer.
Moreover, the authors conducted a further multivariate analysis to test whether there was dose-response association between glucose concentration and the risk of pancreatic cancer.
Pancreatic cancer will induce diabetes in 40% of patients. To control for reverse causality the authors undertook a sensitivity analysis. In brief, rate ratios in the diabetic range were excluded from this secondary analysis. By excluding glucose categories in the diabetes range, the authors could see if increases within the prediabetic ranges of fasting blood glucose alone (>5.6 mmol/L but <7.0 mmol/L) would have an effect on the rate ratio of developing pancreatic cancer.
What did they find?
The authors identified 2769 potentially relevant articles. After screening of their titles and abstracts, 2748 articles were excluded, leaving 21 for detailed analysis. Once the full manuscripts had been read a further 12 were excluded: five did not have blood glucose concentration as an exposure; one was a retrospective study; four were duplicate studies; one did not have blood glucose concentration and numbers of cases reported; and one was not a primary research study.
Thereafter, nine prospective studies were included in the meta-analysis, including 2408 cases of pancreatic cancer. All studies had a prospective design; six were cohort, one was case cohort, and two were nested case-control. They studied populations living in a range of geographical areas: two in North America, four in Europe, three in Asia, one in Australia, and one in New Zealand. All were published in the past 15 years and patients were studied from as early as 1963 and as late as 2005. Duration of follow-up ranged from 5.3 years to 25 years (see table).
|Study||Region||Design||Mean age (years)||Women (%)||Baseline||Duration of follow-up (year)||Adjusted variables|
|Gapstur, 200021||North America||Cohort||39.9||42.6||1963-73||25 (mean)||Age, race, smoking, BMI|
|Batty, 200422||Europe||Cohort||51.5||0||1967-70||25||Age, smoking, BMI, physical activity, etc|
|Stolzenberg-Solomon, 200520||Europe||Case cohort||57.2||0||1985-88||13.8 (median)||Age, smoking, BMI|
|Jee, 200525||Asia||Cohort||46.9||36.1||1992-95||10||Age, age2, smoking, alcohol|
|Ansary-Moghaddam, 2006*19||Asia, Australia/New Zealand||Cohort||46.3||35.3||1961-99||6.8 (median)||Age, sex, study, smoking, BMI|
|Inoue, 200923||Asia||Cohort||55.8||65.6||1990-94||10.2 (mean)||Age, area, smoking, alcohol, cholesterol|
|Johansen, 2010†26||Europe||Cohort||Male 43.9||—||1972-2005||12.8 (mean)||Smoking, BMI, age|
|Female 44.1||49.9||1972-2005||11.3 (mean)|
|Grote, 201124||Europe||Nested case-control||58 (cases), 58 (control)||51.7 (cases), 51.7 (control)||1992-2000||5.3 (mean)||Smoking, BMI, matched for date, sex, age, food, drink, centre|
|Wolpin, 2013‡43||North America||Nested case-control||63.1 (cases), 62.5 (control)||71.5 (cases), 70.7 (control)||1976-98||12.2-25.3 (median)||Cohort, smoking, BMI, fasting time, age, race, sex|
The pooled rate ratio of pancreatic cancer for the highest fasting blood glucose (ranging from >5.4 to 14.2 as the cut-off) versus the lowest category of fasting blood glucose (ranging from <4.1 to <5.6 as the cut-off) was 1.83 (95% confidence interval, 1.50 to 2.24). This included participants who were in both the prediabetes (cut-off fasting blood glucose >5.6 mmol/L) and diabetes (cut-off fasting blood glucose >7.0 mmol/L). This calculation, however, had significant heterogeneity (I=52.4%, P=0.026), suggesting that the positive association reported herein may have been biased by differences in individual study design. Full explanation of heterogeneity and measuring inconsistencies in meta-analysis is out of the scope of the article, but a useful resource is available online.
Eight studies were included in the dose-response meta-analysis; one study reported blood glucose categories (high and low) only and was therefore excluded. As seen in the figure, a positive dose-response relation between fasting blood glucose concentration and the rate of pancreatic cancer was observed. The pooled rate ratio was 1.14 (1.06 to 1.24) per 0.56 mmol/L increase in fasting blood glucose concentration. In other words the rate of pancreatic cancer increases linearly by 14% with every 0.56 mmol/L increase in fasting blood glucose across the diabetic and non-diabetic range of blood sugars. No significant heterogeneity across studies was observed (I = 26.8%, P=0.21). 1
When rate ratios with an assigned fasting blood glucose concentration over 7.0 mmol/L were excluded, the pooled rate ratio was 1.15 (1.05 to 1.27, P=0.003). Therefore, blood glucose concentrations in the prediabetes range alone were associated with an increased risk of pancreatic cancer.
Strengths and limitations
When looking at the individual studies, the association between prediabetes and pancreatic cancer was significant in one, non-significant in four, mixed in three, and unclear in one study. By pooling the studies into a systematic review, the authors have increased the patient dataset and statistical power and precision of the data estimates overall.
The authors hypothesised that the individual studies may have had conflicting results for a number of reasons, including the way in which individual study authors categorised high versus low blood glucose concentrations, the definitions used for prediabetes and diabetes and the recruitment of small numbers of patients with pancreatic cancer in the prediabetes population.
What does the study mean?
The rate of pancreatic cancer increases linearly with worsening hyperglycaemia throughout prediabetes and diabetes.
A notable increasing incidence of pancreatic cancer globally has been attributed to the rapid increase in prediabetes/diabetes, the latter now affecting 14.2% of the world’s population.
One way to combat this risk may be implementation of lifestyle changes to improve glucose metabolism; previous randomised trials have shown that counselling on weight loss, diet, and physical activity for individuals with prediabetes could decrease fasting blood glucose concentrations and reduce the risk of progression to type 2 diabetes by 60%. Neil Chanchlani, foundation year two doctor1, James Goodhand, specialist registrar in gastroenterology2
1Colchester General Hospital, UK , 2Barts Health NHS Trust, Newham University Hospital, London, UK
Correspondence to: firstname.lastname@example.org
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.
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Cite this as: Student BMJ 2015;23:h969