Gijs W. D. Landman

Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16.

OBJECTIVE Several studies have suggested an association between specific diabetes treatment and cancer mortality. We studied the association between metformin use and cancer mortality in a prospectively followed cohort. RESEARCH DESIGN AND METHODS In 1998 and 1999, 1,353 patients with type 2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study in the Netherlands. Vital status was assessed in January 2009. Cancer mortality rate was evaluated using standardized mortality ratios (SMRs), and the association between metformin use and cancer mortality was evaluated with a Cox proportional hazards model, taking possible confounders into account. RESULTS Median follow-up time was 9.6 years, average age at baseline was 68 years, and average A1C was 7.5%. Of the patients, 570 died, of which 122 died of malignancies. The SMR for cancer mortality was 1.47 (95% CI 1.22–1.76). In patients taking metformin compared with patients not taking metformin at baseline, the adjusted hazard ratio (HR) for cancer mortality was 0.43 (95% CI 0.23–0.80), and the HR with every increase of 1 g of metformin was 0.58 (95% CI 0.36–0.93). CONCLUSIONS In general, patients with type 2 diabetes are at increased risk for cancer mortality. In our group, metformin use was associated with lower cancer mortality compared with nonuse of metformin. Although the design cannot provide a conclusion about causality, our results suggest a protective effect of metformin on cancer mortality.

Health-Related Quality of Life and Mortality in a General and Elderly Population of Patients With Type 2 Diabetes (ZODIAC-18)

OBJECTIVE Diabetes negatively impacts the health-related quality of life (HRQOL) of patients with type 2 diabetes. An earlier analysis showed HRQOL to be associated with mortality, which suggests that measuring HRQOL could have clinical implications. We studied the association between HRQOL and total and cardiovascular mortality in patients with type 2 diabetes during long-term follow-up and specifically focused on old age and sex differences. RESEARCH DESIGN AND METHODS HRQOL was measured in a prospectively followed cohort of 1,353 patients with type 2 diabetes using the RAND-36. Cox proportional hazard models were used to measure the independent effect of baseline HRQOL on mortality. RESULTS During a mean follow-up of 9.6 years, 570 (42%) patients died, 280 of whom died of cardiovascular disease (49%). The Physical Component Score (PCS) and the Mental Component Score (MCS) were inversely associated with total mortality, with hazard ratios of 0.988 (95% CI 0.983–0.993) and 0.990 (95% CI 0.985–0.995), respectively. A 10-point-higher score on the PCS and MCS decreased the risk for total mortality by 11 and 10%, respectively. An inverse relationship with mortality was also seen for men, women, and for patients aged >75 years. Mental health was significantly related to mortality in men but not in women. CONCLUSIONS Lower physical and mental HRQOL was associated with a higher total mortality and cardiovascular mortality in patients with type 2 diabetes; this is also the case when studying men and women and the elderly separately. The dimension mental health, related to depression and anxiety, was only associated with mortality in men, not in women.

Life Expectancy in a Large Cohort of Type 2 Diabetes Patients Treated in Primary Care (ZODIAC-10)

Background Most longitudinal studies showed increased relative mortality in individuals with type 2 diabetes mellitus until now. As a result of major changes in treatment regimes over the past years, with more stringent goals for metabolic control and cardiovascular risk management, improvement of life expectancy should be expected. In our study, we aimed to assess present-day life expectancy of type 2 diabetes patients in an ongoing cohort study. Methodology and Principal Findings We included 973 primary care type 2 diabetes patients in a prospective cohort study, who were all participating in a shared care project in The Netherlands. Vital status was assessed from May 2001 till May 2007. Main outcome measurement was life expectancy assessed by transforming actual survival time to standardised survival time allowing adjustment for the baseline mortality rate of the general population. At baseline, mean age was 66 years, mean HbA1c 7.0%. During a median follow-up of 5.4 years, 165 patients died (78 from cardiovascular causes), and 17 patients were lost to follow-up. There were no differences in life expectancy in subjects with type 2 diabetes compared to life expectancy in the general population. In multivariate Cox regression analyses, concentrating on the endpoints ‘all-cause’ and cardiovascular mortality, a history of cardiovascular disease: hazard ratio (HR) 1.71 (95% confidence interval (CI) 1.23–2.37), and HR 2.59 (95% CI 1.56–4.28); and albuminuria: HR 1.72 (95% CI 1.26–2.35), and HR 1.83 (95% CI 1.17–2.89), respectively, were significant predictors, whereas smoking, HbA1c, systolic blood pressure and diabetes duration were not. Conclusions This study shows a normal life expectancy in a cohort of subjects with type 2 diabetes patients in primary care when compared to the general population. A history of cardiovascular disease and albuminuria, however, increased the risk of a reduction of life expectancy. These results show that, in a shared care environment, a normal life expectancy is achievable in type 2 diabetes patients.

Lower blood pressure associated with higher mortality in elderly diabetic patients (ZODIAC-12)

OBJECTIVE to investigate the relationship between blood pressure over time and mortality in elderly patients with type 2 diabetes mellitus (T2DM). DESIGN prospective observational cohort study. SETTING primary care, Zwolle, The Netherlands. SUBJECTS patients with T2DM aged 60 years and older (n = 881). The cohort was divided into two age categories: 60-75 years and older than 75 years. METHODS updated means for systolic, diastolic and pulse pressures were calculated after a median follow-up time of 9.8 years. These values were used as time-dependent covariates in a Cox proportional hazard model. Main outcome measures were all-cause and cardiovascular mortality. RESULTS all of the blood pressure measures were inversely related to all-cause mortality in elderly diabetic patients (>75 years). Furthermore, these relationships were specifically found in elderly patients treated with antihypertensive medication at baseline. A decrease of 10 mm Hg in systolic blood pressure, diastolic blood pressure and pulse pressure led to a mortality increase of 22% [95% confidence interval (95% CI): 13-31%], 30% [95% CI: 13%-46%] and 22% [95% CI: 11%-33%], respectively. In the low age group (60-75 years), no relationship was found between blood pressure and mortality. CONCLUSIONS blood pressure is a marker for mortality in elderly T2DM patients; however, the relationship is inverse.

The relationship between glycaemic control and mortality in patients with type 2 diabetes in general practice (ZODIAC-11).

BACKGROUND The relationship between the degree of glycaemic control and mortality remains an important topic of discussion. AIM This study aimed to investigate this relationship. DESIGN OF STUDY Prospective cohort study. SETTING Primary care. METHOD A total of 1145 patients with type 2 diabetes were enrolled in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) in 1998. Their survival status was recorded in September 2004. Mortality ratios were calculated using standardised mortality ratios (SMRs). Associations between haemoglobin A(1c) (HbA(1c)) levels and mortality were studied with a Cox proportional hazard model. HbA(1c) levels were studied as continuous and as categorical variables. RESULTS A total of 335 patients died after a median follow-up period of 5.8 years. The SMR (95% confidence interval [CI]) for total mortality was 1.86 (95% CI = 1.66 to 2.06) and 2.24 (95% CI = 1.91 to 2.61) for cardiovascular mortality. For each 1% increase in HbA(1c) there was a 21% increase in the hazard ratio for total mortality. When compared with the target HbA(1c) group (HbA(1c) 6.5-7%), the group with very poor glycaemic control (HbA1c >9%) had a hazard ratio of 2.21 (95% CI = 1.42 to 3.42) for total mortality. The group with normal glycaemic control (HbA(1c) <6.5%) had a hazard ratio of 1.00 (95% CI = 0.46 to 2.19) for total mortality. CONCLUSION HbA(1c) level was associated with mortality and this effect seemed largely attributable to patients who were in really poor glycaemic control. The absence of differences in mortality in the groups with lower HbA(1c) levels supports the position that there is no basis for continually decreasing the therapeutic target HbA(1c) level in patients with type 2 diabetes mellitus.

Safety and efficacy of gliclazide as treatment for type 2 diabetes: a systematic review and meta-analysis of randomized trials.

Objective and Design Gliclazide has been associated with a low risk of hypoglycemic episodes and beneficial long-term cardiovascular safety in observational cohorts. The aim of this study was to assess in a systematic review and meta-analysis of randomized controlled trials the safety and efficacy of gliclazide compared to other oral glucose-lowering agents (PROSPERO2013:CRD42013004156) Data Sources Medline, EMBASE, Clinicaltrials.gov, Trialregister.nl, Clinicaltrialsregister.eu and the Cochrane database. Selection Included were randomized studies of at least 12 weeks duration with the following outcomes: HbA1c change, incidence of severe hypoglycemia, weight change, cardiovascular events and/or mortality when comparing gliclazide with other oral blood glucose lowering drugs. Bias was assessed with the Cochrane risk of bias tool. The inverse variance random effects model was used. Results Nineteen trials were included; 3,083 patients treated with gliclazide and 3,155 patients treated with other oral blood glucose lowering drugs. There was a considerable amount of heterogeneity between and bias in studies. Compared to other glucose lowering agents except metformin, gliclazide was slightly more effective (−0.13% (95%CI: −0.25, −0.02, I2 55%)). One out of 2,387 gliclazide users experienced a severe hypoglycemic event, whilst also using insulin. There were 25 confirmed non-severe hypoglycemic events (2.2%) in 1,152 gliclazide users and 22 events (1.8%) in 1,163 patients in the comparator group (risk ratio 1.09 (95% CI: 0.20, 5.78, I2 77%)). Few studies reported differences in weight and none were designed to evaluate cardiovascular outcomes. Conclusions The methodological quality of randomized trials comparing gliclazide to other oral glucose lowering agents was poor and effect estimates on weight were limited by publication bias. The number of severe hypoglycemic episodes was extremely low, and gliclazide appears at least equally effective compared to other glucose lowering agents. None of the trials were designed for evaluating cardiovascular outcomes, which warrants attention in future randomized trials.

Common Variants in the Type 2 Diabetes KCNQ1 Gene Are Associated with Impairments in Insulin Secretion During Hyperglycaemic Glucose Clamp

Background Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. Methodology The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. Principal Findings We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07–1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. Conclusions Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.

Device-Guided Breathing as Treatment for Hypertension in Type 2 Diabetes Mellitus A Randomized, Double-blind, Sham-Controlled Trial

IMPORTANCE Biofeedback with device-guided lowering of breathing frequency could be an alternate nonpharmacologic treatment option for hypertension. Evidence from trials with high methodologic quality is lacking. OBJECTIVE To evaluate the effects of device-guided lowering of breathing frequency on blood pressure in patients with type 2 diabetes mellitus and hypertension. DESIGN Single-center, double-blind, sham-controlled trial. SETTING A large nonacademic teaching hospital in the Netherlands. PARTICIPANTS Patients with type 2 diabetes mellitus and hypertension. INTERVENTION Fifteen-minute sessions with either the device that guides breathing through musical tones to a lower breathing frequency (aiming at <10 breaths/min) or a sham device (music without aiming at lowering of breathing frequency) for an 8-week study period. MAIN OUTCOMES AND MEASURES Systolic and diastolic blood pressure measured in the physicians office. RESULTS Forty-eight patients were randomized; 21 patients (88%) in the intervention group and 24 patients (100%) in the control group completed the study. There were no significant changes in systolic and diastolic blood pressure, with a difference in systolic blood pressure of 2.35 mm Hg (95% CI, -6.50 to 11.20) in favor of the control group and a difference in diastolic blood pressure of 2.25 mm Hg (95% CI, -2.16 to 6.67) in favor of the intervention group. Three patients in the intervention group experienced adverse events. CONCLUSIONS AND RELEVANCE This high methodologic quality study shows no significant effect of device-guided lowering of breathing frequency on office-measured blood pressure in patients with type 2 diabetes. On the basis of this study, together with results from all but one previous trial, device-guided lowering of breathing frequency does not appear to be a viable nonpharmacologic option for hypertension treatment.

CCR5Δ32 genotype is associated with outcome in type 2 diabetes mellitus

AIMS To test whether the genetic variant CCR5Delta32 in the CC-chemokine receptor 5, which is known to lead to CCR5 deficiency, is associated with mortality in type 2 diabetes patients. METHODS We examined the effect of presence or absence of the CCR5Delta32 on overall and cardiovascular mortality risk in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort, a type 2 diabetes patient cohort. RESULTS We studied 756 patients with a mean duration of follow-up of 5.4 (+/- 1.4) years. 194 patients died during follow up of which 83 were cardiovascular deaths. 144 subjects (19%) carried the CCR5Delta32 deletion. CCR5Delta32 carriers had an adjusted hazard ratio of 0.62 (95%CI: 0.40-0.96; p=0.03) for all-cause mortality and 0.63 (95%CI: 0.33-1.19; p=0.16) for cardiovascular mortality. CONCLUSIONS The presence of CCR5Delta32 is associated with better survival in type 2 diabetes patients. These data suggest that it is worthwhile to explore the protective potential of pharmacological blockade of CCR5 in type 2 diabetic patients.

Frailty and the relationship between blood pressure and mortality in elderly patients with type 2 diabetes (Zwolle Outpatient Diabetes project Integrating Available Care-34).

Objective: We aimed to investigate whether adjustment for frailty influences the relationship of blood pressure with mortality in elderly patients with type 2 diabetes mellitus (T2DM). Methods: Patients aged 60 years and older (n = 858) were selected from a prospective observational cohort study of primary care patients with T2DM. Frailty was defined as a score less than 80 on the subscale ‘physical functioning’ of the RAND-36 questionnaire. After median follow-up for 14 years, multivariate Cox regression analyses were performed to evaluate the association between blood pressure and (cardiovascular) mortality. Analyses were performed in strata according to the frailty level (‘physical functioning’ score <80 and ≥80) and were repeated for patients older than 75 years. Results: Frailty was highly prevalent in our study population; 629 out of 858 patients (73%) fulfilled the criterion. For patients aged at least 60 years, the hazard ratios (95% confidence interval) of a 10 mmHg increase in SBP and DBP for cardiovascular mortality in nonfrail patients were 1.38 (1.15–1.68%) and 1.60 (1.07–2.37%), respectively. No relationship was observed for frail patients. For the oldest frail elderly, the hazard ratios of SBP and DBP for all-cause mortality were 0.92 (0.87–0.98%) and 0.83 (0.73–0.93%), respectively. For the oldest nonfrail elderly, a positive relationship between SBP and all-cause mortality was observed. Conclusions: Frailty modifies the relationship between blood pressure and mortality in elderly patients with T2DM. Higher blood pressure was related to increased cardiovascular mortality in nonfrail patients, even in the oldest elderly, and to lower all-cause mortality in frail patients.