Gillian Libby

New Users of Metformin Are at Low Risk of Incident Cancer A cohort study among people with type 2 diabetes

OBJECTIVE The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes. RESEARCH DESIGN AND METHODS In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994–2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression. RESULTS Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40–0.53). After adjusting for sex, age, BMI, A1C, deprivation, smoking, and other drug use, there was still a significantly reduced risk of cancer associated with metformin: 0.63 (0.53–0.75). CONCLUSIONS These results suggest that metformin use may be associated with a reduced risk of cancer. A randomized trial is needed to assess whether metformin is protective in a population at high risk for cancer.

Results from the first three rounds of the Scottish demonstration pilot of FOBT screening for colorectal cancer

Objectives: To assess the effects of the first three rounds of a pilot colorectal screening programme based on guaiac faecal occult blood testing (gFOBT) and their implications for a national population-based programme. Methods: A demonstration pilot programme was conducted in three Scottish NHS Boards. Residents aged between 50 and 69 years registered on the Community Health Index were included in the study. Results: In the first round, the uptake was 55.0%, the positivity rate was 2.07% and the cancer detection rate was 2.1/1000 screened. In the second round, these were 53.0%, 1.90% and 1.2/1000, respectively, and in the third round, 55.3%, 1.16% and 0.7/1000, respectively. In the first round, the positive predictive value of the gFOBT was 12.0% for cancer and 36.5% for adenoma; these fell to 7.0% and 30.3% in the second round and were maintained at 7.5% and 29.1% in the third round. The percentage of screen-detected cancers diagnosed at Dukes’ stage A was 49.2% in the first round, 40.1% in the second round and 36.3% in the third round. Conclusions: These results are compatible with those of previous randomised trials done in research settings, demonstrating that population-based colorectal cancer screening is feasible in Scotland and should lead to a comparable reduction in disease-specific mortality.

Mortality and hospitalization in patients after amputation: A comparison between patients with and without diabetes

OBJECTIVE—We sought to compare the risk of mortality and hospitalization between patients with and without diabetes following incident lower-extremity amputation (LEA). RESEARCH DESIGN AND METHODS—We performed a retrospective data-linkage review of all incident amputations between 1 January 1992 and 31 December 1995. Patients were categorized according to their diabetes status. Follow-up for mortality was until 1 January 2005 and until 31 March 1996 for hospitalization. RESULTS—Of 390 major-incident LEAs performed during the study period, 119 (30.5%) were in patients with diabetes and 271 (69.5%) were in nondiabetic subjects. The median time to death was 27.2 months in patients with diabetes compared with 46.7 months for patients without (P = 0.01). Diabetic subjects had a 55% greater risk of death than those without diabetes. The risk of developing congestive cardiac failure with diabetes was 2.26 (95% CI 1.12–4.57) and of further amputation was 1.95 (1.14–3.33) times that of a patient without diabetes after incident LEA. CONCLUSIONS—After LEA, patients with diabetes have an increased risk of death compared with nondiabetic patients. Efforts should be made to minimize these risks with aggressive treatment of cardiovascular risk factors and management of cardiac failure.

Pre-eclampsia and the later development of type 2 diabetes in mothers and their children: an intergenerational study from the Walker cohort.

Aims/hypothesisStudies have shown a relationship between pre-eclampsia and later coronary artery disease. This study investigated whether there is a relationship between pre-eclampsia and the development of type 2 diabetes in mothers and their babies and how this is affected by infant birthweight.Subjects and methodsThis was an intergenerational cohort study. The study population comprised 7,187 mothers who gave birth and 8,648 babies who were born in Dundee, Scotland between 1952 and 1958. Their later diabetic status was defined from 1980 to 2003 by linkage to population-based datasets.ResultsThere were 810 (11.3%) mothers with pre-eclampsia and 745 (10.4%) who subsequently developed type 2 diabetes. Logistic regression showed an increased risk of developing type 2 diabetes for mothers with pre-eclampsia, unadjusted odds ratio (OR) 1.37 (95% CI 1.10–1.71), p = 0.005. This relationship persisted after adjustment for infant birthweight, OR 1.40 (95% CI 1.12–1.75), p = 0.003. Of the babies born between 1952 and 1958, 221 (2.6%) had developed type 2 diabetes, 137 of them male (2.9% of male subjects in study population) and 84 female (2.2% of female subjects). The relationship between pre-eclampsia in the mother and the risk of type 2 diabetes in the offspring did not reach statistical significance, OR 1.38 (95% CI 0.90–2.10). Babies with birthweight in the lowest quintile (adjusted for sex, gestation and birth order) had an increased risk of developing type 2 diabetes, OR for lowest quintile vs highest quintile 1.84 (95% CI 1.24–2.72), p = 0.002.Conclusions/interpretationPre-eclampsia is associated with increased risk of developing type 2 diabetes in the mother, but birthweight is a more important determinant of future risk for the offspring.

Effect of gender, age and deprivation on key performance indicators in a FOBT-based colorectal screening programme

Objectives To assess the effect of gender, age and deprivation on key performance indicators in a colorectal cancer screening programme. Setting Between March 2000 and May 2006 a demonstration pilot of biennial guaiac faecal occult blood test (gFOBT) colorectal screening was carried out in North-East Scotland for all individuals aged 50-69 years. Methods The relevant populations were subdivided, by gender, into four age groups and into five deprivation categories according to the Scottish Index of Multiple Deprivation (SIMD), and key performance indicators analysed within these groups. Results In all rounds, uptake of the gFOBT increased with age (P < 0.001), decreased with increasing deprivation in both genders (P < 0.001), and was consistently higher in women than in men in all age and all SIMD groups. In addition, increasing deprivation was negatively associated with uptake of colonoscopy in men with a positive gFOBT (P < 0.001) although this effect was not observed in women. Positivity rates increased with age (P< 0.001) and increasing deprivation (P > 0.001) in both genders in all rounds, although they were higher in men than in women for all age and SIMD categories. Cancer detection rates increased with age (P < 0.001), were higher in men than in women in all age and SIMD categories, but were not consistently related to deprivation. In both genders, the positive predictive value (PPV) for cancer increased with age (P < 0.001) and decreased with increasing deprivation (P < 0.001) in all rounds and was consistently higher in men than in women in all age and SIMD categories. Conclusions In this population-based colorectal screening programme gender, age, and deprivation had marked effects on key performance indicators, and this has implications both for the evaluation of screening programmes and for strategies designed to reduce inequalities.

The impact of population-based faecal occult blood test screening on colorectal cancer mortality: a matched cohort study

Background:Randomised trials show reduced colorectal cancer (CRC) mortality with faecal occult blood testing (FOBT). This outcome is now examined in a routine, population-based, screening programme.Methods:Three biennial rounds of the UK CRC screening pilot were completed in Scotland (2000–2007) before the roll out of a national programme. All residents (50–69 years) in the three pilot Health Boards were invited for screening. They received a FOBT test by post to complete at home and return for analysis. Positive tests were followed up with colonoscopy. Controls, selected from non-pilot Health Boards, were matched by age, gender, and deprivation and assigned the invitation date of matched invitee. Follow-up was from invitation date to 31 December 2009 or date of death if earlier.Results:There were 379 655 people in each group (median age 55.6 years, 51.6% male). Participation was 60.6%. There were 961 (0.25%) CRC deaths in invitees, 1056 (0.28%) in controls, rate ratio (RR) 0.90 (95% confidence interval (CI) 0.83–0.99) overall and 0.73 (95% CI 0.65–0.82) for participants. Non-participants had increased CRC mortality compared with controls, RR 1.21 (95% CI 1.06–1.38).Conclusion:There was a 10% relative reduction in CRC mortality in a routine screening programme, rising to 27% in participants.

Pre-notification increases uptake of colorectal cancer screening in all demographic groups: a randomized controlled trial

Objectives To assess whether pre-notification is effective in increasing uptake of colorectal cancer screening for all demographic groups. Setting Scottish national colorectal cancer screening programme. Methods Males and females aged 50-74 years received a faecal occult blood test by post to complete at home. They were randomized to receive in addition: the pre-notification letter, the pre-notification letter + information booklet, or the usual invitation. Overall, 59,953 subjects were included in the trial between 13/04/09 and 29/05/09 and followed to 27/11/09. Pre-notification letters were posted two weeks ahead of the screening test kit. Uptake was defined as the return of a screening test and chi-squared tests compared uptake between the trial arms. Logistic regression assessed the impact of the letter and letter + booklet on uptake independently of gender, age, deprivation and screening round. Results Uptake was higher with both the letter (59.0%) and the letter + booklet (58.5%) compared with the usual invitation (53.9%, p < 0.0001). This increased uptake was seen for males, females, all age groups and all deprivation categories including least deprived females (letter 69.9%, usual invitation 66.6%) and most deprived males (42.6% vs. 36.1%), the groups with the highest and lowest levels of uptake respectively in the pilot screening rounds conducted prior to the roll out of the programme. Uptake with the pre-notification letter compared with the usual invitation was higher both unadjusted and adjusted for demographic factors (odds ratio 1.24, 95% CI 1.193-1.294). Conclusions Pre-notification is an effective method of increasing uptake in colorectal cancer screening for both genders and all age and deprivation groups.

Clinical outcomes using a faecal immunochemical test for haemoglobin as a first-line test in a national programme constrained by colonoscopy capacity

Introduction Because of their many advantages, faecal immunochemical tests (FIT) are superseding traditional guaiac-based faecal occult blood tests in bowel screening programmes. Methods A quantitative FIT was adopted for use in two evaluation National Health Service (NHS) Boards in Scotland using a cut-off faecal haemoglobin concentration chosen to give a positivity rate equivalent to that achieved in the Scottish Bowel Screening Programme. Uptake and clinical outcomes were compared with results obtained contemporaneously in two other similar NHS Boards and before and after the evaluation in the two evaluation NHS Boards. Results During the evaluation, uptake was 58.5%. This was higher than in the same NHS Boards both before and after the evaluation, higher than in the other two NHS Boards and higher than the 53.7% achieved overall in Scotland. The overall positivity rate was higher in men than in women and increased with age in both genders. Positive predictive values for cancer (4.8%), high-risk adenoma (23.3%), all adenoma (38.2%) and all neoplasia (43.0%) in the two test NHS Boards were similar in all groups. Conclusions In summary, this evaluation of the FIT supports the introduction of FIT as a first-line test, even when colonoscopy capacity is limited.

Use of a faecal immunochemical test narrows current gaps in uptake for sex, age and deprivation in a bowel cancer screening programme

Objectives To investigate the characteristics of participants screened for bowel cancer using a faecal immunochemical test for haemoglobin (FIT). Setting Scottish Bowel Screening Programme. Methods 65909 men and women in two NHS Boards, aged 50 to 74, were invited to participate in an evaluation of FIT as a first-line test. Uptake was calculated by sex, age in quintiles, and deprivation in quintiles, and compared with a group who had completed a guaiac faecal occult blood test (gFOBT) and for whom details of sex, age and deprivation were well documented. Results FIT kits from 38672 participants were tested. The overall uptake of 58.7% was significantly higher than the 53.9% for gFOBT (p < 0.0001). Uptakes in the two NHS Boards were 57.6% and 54.4% for men and 63.2% and 59.1% for women, higher than the 49.5% and 58.1% completing gFOBT. Uptake was higher for FIT than gFOBT in all age and deprivation quintiles for both men and women in both NHS Boards. The difference in uptake fell with age for men but rose for women; the increase in uptake was greater for men than women. Uptake fell as deprivation decreased for both sexes, and was similar in both NHS Boards. Conclusions Use of FIT increases uptake over gFOBT, and the greatest increases are seen in men, younger participants, and more deprived individuals, groups for which an increase in uptake is likely to be beneficial. The results support a move to FIT as a first-line screening test for those countries still using gFOBT.

Obstetric management of a woman's first delivery and the implications for pelvic floor surgery in later life

Objective  To determine the influence of intrapartum care during a first delivery on the risk of pelvic floor surgery in later life.