Serum vitamin B12, distal symmetrical polyneuropathy and anaemia in type 2 diabetes: the Fremantle Diabetes Study Phase 2.

BACKGROUND: There are limited data relating to the effects of metformin-associated vitamin B12 deficiency on the risk of distal symmetrical polyneuropathy (DSPN) and megaloblastic anaemia in well-characterised community-based cohorts. AIMS: To assess inter-relationships between metformin therapy, vitamin B12 deficiency assessed using serum active B12 concentrations, and DSPN and anaemia in 1492 Fremantle Diabetes Study Phase 2 (FDS2) participants with type 2 diabetes. METHODS: Prevalence rates of vitamin B12 deficiency (total <80 pmol/L, active <23 pmol/L) and borderline deficiency (total ≥80 and ≤200 pmol/L, active ≥23 and ≤35 pmol/L) were determined using baseline sera. The relationship between vitamin B12 status and both DSPN and anaemia was assessed using multivariable analyses. RESULTS: Most FDS2 participants (94.4%) were vitamin B12 replete (total serum concentration >200 pmol/L, active >35 pmol/L), 2.0% were deficient (total <80 pmol/L, active <23 pmol/L) and the remainder (3.6%) borderline. Although metformin treatment increased the odds of deficiency (4.2%, 3.1% borderline) in a dose-dependent fashion (odds ratio (95% confidence interval) 39.4 (4.90-316) for >2000 mg daily compared with no treatment; P < 0.001), there was no significant association between vitamin B12 status and DSPN, anaemia (haemoglobin ≤130 g/L males, ≤120 g/L females), haemoglobin concentration or mean corpuscular volume (P ≥ 0.147). Metformin increased the likelihood of anaemia, especially at high doses, independent of vitamin B12 deficiency. CONCLUSIONS: Since nutritional sources likely attenuate metformin-associated vitamin B12 malabsorption and its clinical sequelae in developed countries such as Australia, there is no need for routine/opportunistic serum vitamin B12 screening in metformin-treated patients.

Temporal changes in glycaemic thresholds for treatment intensification in type 2 diabetes in an urban Australian setting: the Fremantle Diabetes Study.

BACKGROUND: Pharmacotherapy and supportive care for diabetes in Australia are improving, with potential beneficial effects on therapeutic procrastination. AIM: To determine whether glycaemic thresholds for therapeutic intensification in type 2 diabetes changed over the 15 years between phases of the community-based Fremantle Diabetes Study (FDS). METHODS: We studied 531 Phase 1 participants (mean age 62.4 years, 54.2% males, median diabetes duration 3.0 years) with valid data from baseline assessment and five subsequent annual reviews between 1993 and 2001 and 930 Phase 2 participants (mean age 65.3 years, 53.8% males, median diabetes duration 8.0 years) with valid data from baseline and two subsequent biennial reviews between 2008 and 2015. The main outcome measure was HbA1c at assessments before and after change in blood glucose-lowering therapy (average 6 months in Phase 1, 12 months in Phase 2). RESULTS: Ninety-seven participants in Phase 1 and 84 in Phase 2 progressed from diet-based management to oral hypoglycaemic agents (OHA) and 45 and 85 participants, respectively, progressed from diet/OHA to insulin. The median HbA1c was 7.5% (58 mmol/mol) and 6.9% (52 mmol/mol) before OHA initiation in Phases 1 and 2, respectively, and 9.1% (76 mmol/mol) and 7.8% (62 mmol/mol), respectively, before insulin initiation. There were median HbA1c falls of 0.3% (3 mmol/mol) and 1.5% (16 mmol/mol) after OHA and insulin initiation in Phase 1, but no statistically significant changes in Phase 2. CONCLUSIONS: HbA1c thresholds triggering treatment intensification fell between FDS phases, suggesting a more proactive approach to management of glycaemia over time.

Measurement and Clinical Utility of ßCTX in Serum and Plasma.

Biochemical markers of bone turnover (BTM) are released during bone remodeling and can be measured in blood or urine as noninvasive surrogate markers for the bone remodeling rate. The C-terminal cross-linked telopeptide of type I collagen (ßCTX) is released during bone resorption and is specific to bone tissue. Assays have been developed to measure ßCTX in blood and in urine; most current use of ßCTX measurement for research and in clinical practice is performed on a blood sample. Method-specific differences for serum and plasma ßCTX have led to initiatives to standardize or harmonize ßCTX commercial assays. ßCTX demonstrates significant biological variation due to circadian rhythm and effect of food which can be minimized by standardized sample collection in the fasting state in the morning. While ßCTX predicts fracture risk independent of bone mineral density, lack of data has precluded its inclusion in fracture risk calculators. The changes seen in ßCTX with antiresorptive therapies have been well characterized and this has led to its widespread use for monitoring therapy in osteoporosis. However, more fracture-based data on appropriate treatment goals for monitoring need to be developed. Evidence is lacking for the use of ßCTX in managing "drug holidays" of bisphosphonate treatment in osteoporosis or risk stratifying those at increased risk of developing osteonecrosis of the jaw. ßCTX is useful as an adjunct to imaging techniques for the diagnosis of Paget's disease of bone and for monitoring therapy and detecting recurrence. ßCTX also shows promise in the management of metastatic bone disease.

Continuing disparities in cardiovascular risk factors and complications between aboriginal and Anglo-Celt Australians with type 2 diabetes: the Fremantle Diabetes Study.

OBJECTIVE: To determine whether disparities in the nature and management of type 2 diabetes persist between Aboriginal and the majority Anglo-Celt patients in an urban Australian community. RESEARCH DESIGN AND METHODS: Baseline data from the observational Fremantle Diabetes Study collected from 1993 to 1996 (phase I) and from 2008 to 2011 (phase II) were analyzed. Patients characterized as Aboriginal or Anglo-Celt by self-report and supporting data underwent comprehensive assessment, including questionnaires, examination, and biochemical testing in a single laboratory. Generalized linear modeling with age/sex adjustment was used to examine differences in changes in variables in the two groups between phases I and II. RESULTS: The indigenous participants were younger at entry and at diabetes diagnosis than the Anglo-Celt participants in both phases. They were also less likely to be educated beyond primary level and were more likely to be smokers. HbA(1c) decreased in both groups over time (Aboriginal median 9.6% [interquartile range 7.8-10.7%] to 8.4% [6.6-10.6%] vs. Anglo-Celt median 7.1% [6.2-8.4%] to 6.7% [6.2-7.5%]), but the gap persisted (P = 0.65 for difference between phases I and II by ethnic group). Aboriginal patients were more likely to have microvascular disease in both phases. The prevalence of peripheral arterial disease (ankle-brachial index ≤0.90 or lower-extremity amputation) increased in Aboriginal but decreased in Anglo-Celt participants (15.8-29.7 vs. 30.7-21.5%; P = 0.055). CONCLUSIONS: Diabetes management has improved for Aboriginal and Anglo-Celt Australian patients, but disparities in cardiovascular risk factors and complications persist.

Helicobacter pylori cytotoxin-associated gene-A antibodies do not predict complications or death in type 2 diabetes: the Fremantle Diabetes Study.

OBJECTIVES: There is cross-sectional evidence that CagA antigen produced by Helicobacter pylori is associated with coronary heart disease, stroke, atrial fibrillation (AF) and microalbuminuria, but no large-scale longitudinal studies have been conducted in diabetic patients. We aimed to determine whether cytotoxin-associated gene-A (CagA) seropositivity is independently associated with important vascular outcomes in type 2 diabetes. METHODS: We studied 1179 type 2 patients from a well characterized community-based cohort who had available sera from baseline assessment between 1993 and 1996, and follow-up for incident events to end-June 2007. H. pylori IgG and CagA antibodies at baseline were measured by validated ELISA. Multiple logistic/linear regression analysis and Cox proportional hazards modelling were used to determine independent baseline associates of prevalent and incident complications, respectively, including H. pylori/CagA serostatus. RESULTS: At baseline, 62.0% of patients were H. pylori seropositive and 37.7% were both H. pylori and CagA seropositive. CagA seropositivity was not independently associated with prevalent coronary heart disease (CHD), cerebrovascular disease (CVD), peripheral arterial disease or AF at baseline (P > 0.41), but there was a significant inverse association with ln(urinary albumin:creatinine) (P = 0.033). There were no independent associations between CagA seropositivity and incident CHD/CVD or progression to microalbuminuria (P > 0.20). During follow-up, 480 patients (40.7%) died, 246 (50.2%) from cardiovascular causes. After adjustment for other variables,CagA seropositivity was weakly protective against cardiovascular death (P = 0.024). CONCLUSION: CagA seropositivity is not a risk factor for chronic vascular complications of type 2 diabetes. Assay of CagA antibodies does not contribute significantly to clinical management outside gastroenterological indications.