Lorraine L. Lipscombe

Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study

Objective To compare the risk of acute myocardial infarction, heart failure, and death in patients with type 2 diabetes treated with rosiglitazone and pioglitazone. Design Retrospective cohort study. Setting Ontario, Canada. Participants Outpatients aged 66 years and older who were started on rosiglitazone or pioglitazone between 1 April 2002 and 31 March 2008. Main outcome measure Composite of death or hospital admission for either acute myocardial infarction or heart failure. In a secondary analysis, each outcome was also examined individually. Results 39u2009736 patients who started on either pioglitazone or rosiglitazone were identified. During the six year study period, the composite outcome was reached in 895 (5.3%) of patients taking pioglitazone and 1563 (6.9%) of patients taking rosiglitazone. After extensive adjustment for demographic and clinical factors and drug doses, pioglitazone treated patients had a lower risk of developing the primary outcome than did patients treated with rosiglitazone (adjusted hazard ratio 0.83, 95% confidence interval 0.76 to 0.90). Secondary analyses revealed a lower risk of death (adjusted hazard ratio 0.86, 0.75 to 0.98) and heart failure (0.77, 0.69 to 0.87) with pioglitazone but no significant difference in the risk of acute myocardial infarction (0.95, 0.81 to 1.11). One additional composite outcome would be predicted to occur annually for every 93 patients treated with rosiglitazone rather than pioglitazone. Conclusions Among older patients with diabetes, pioglitazone is associated with a significantly lower risk of heart failure and death than is rosiglitazone. Given that rosiglitazone lacks a distinct clinical advantage over pioglitazone, continued use of rosiglitazone may not be justified.

Universal Drug Coverage and Socioeconomic Disparities in Major Diabetes Outcomes

OBJECTIVE Due in large part to effective pharmacotherapy, mortality rates have fallen substantially among those with diabetes; however, trends have been less favorable among those of lower socioeconomic status (SES), leading to a widening gap in mortality between rich and poor. We examined whether income disparities in diabetes-related morbidity or mortality decline after age 65 in a setting where much of health care is publicly funded yet universal drug coverage starts only at age 65. RESEARCH DESIGN AND METHODS We conducted a population-based retrospective cohort study using administrative health claims from Ontario, Canada. Adults with diabetes (N = 606,051) were followed from 1 April 2002 to 31 March 2008 for a composite outcome of death, nonfatal acute myocardial infarction (AMI), and nonfatal stroke. SES was based on neighborhood median household income levels from the 2001 Canadian Census. RESULTS SES was a strong predictor of death, nonfatal AMI, or nonfatal stroke among those <65 years of age (adjusted hazard ratio [HR] 1.51 [95% CI 1.45–1.56]) and exerted a lesser effect among those ≥65 years of age (1.12 [1.09–1.14]; P < 0.0001 for interaction), after adjusting for age, sex, baseline cardiovascular disease (CVD), diabetes duration, comorbidity, and health care utilization. SES gradients were consistent for all groups <65 years of age. Similar findings were noted for 1-year post-AMI mortality (<65 years of age, 1.33 [1.09–1.63]; ≥65 years of age, 1.09 [1.01–1.18]). CONCLUSIONS Observed SES differences in CVD burden diminish substantially after age 65 in our population with diabetes, which may be related to universal access to prescription drugs among seniors.

Diabetes and Breast Cancer among Women with BRCA1 and BRCA2 Mutations

Hyperinsulinemia and the metabolic syndrome are both risk factors for breast cancer. It is not clear if diabetes is associated with the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

Atypical antipsychotics and hyperglycemic emergencies: multicentre, retrospective cohort study of administrative data.

OBJECTIVEnTo evaluate the relationship between initiation of atypical antipsychotic agents and the risk of hyperglycemic emergencies.nnnMETHODnWe conducted a multicentre retrospective cohort study using administrative health data from 7 Canadian provinces and the UK Clinical Practice Research Datalink. Hospitalizations for hyperglycemic emergencies (hyperglycemia, diabetic ketoacidosis, hyperosmolar hyperglycemic state) were compared between new users of risperidone (reference), and new users of olanzapine, other atypical antipsychotics, and typical antipsychotics. We used propensity scores with inverse probability of treatment weighting and proportional hazard models to estimate the site-specific hazard ratios of hyperglycemic emergencies in the year following drug initiation separately for adults under and over age 66 years. Site-level results were pooled using meta-analytic methods.nnnRESULTSnAmong 725,489 patients, 55% were aged 66+years; 5% of younger and 19% of older patients had pre-existing diabetes. Hyperglycemic emergencies were rare (1-2 per 1000 person years), but more frequent in patients with pre-existing diabetes (6-12 per 1000 person years). We did not find a significant difference in risk of hyperglycemic emergencies with initiation of olanzapine versus risperidone; however heterogeneity existed between sites. The risk of an event was significantly lower with other atypical (99% quetiapine) compared to risperidone use in older patients [adjusted hazard ratio, 95% confidence interval (CI): 0.69, 0.53-0.90].nnnCONCLUSIONSnRisk for hyperglycemic emergencies is low after initiation of antipsychotics, but patients with pre-existing diabetes may be at greater risk. The risk appeared lower with the use of quetiapine in older patients, but the clinical significance of the findings requires further study.

Pregnancy planning in women with pregestational diabetes.

Objectives.u2003Women with pregestational diabetes are advised to plan their pregnancies to optimize glycemia and reduce fetal complications. We evaluated the adequacy of pregnancy planning effort and medical planning in pregnant women with type 1 and type 2 diabetes. Methods.u2003This retrospective cohort study surveyed pregnant women with pregestational diabetes mellitus between 2006 and 2008 in Ontario, Canada. We evaluated three measures of pregnancy planning: pregnancy planning effort, medical planning based on prepregnancy glycemic control, and folic acid use. We compared women with type 1 and type 2 diabetes and explored predictors of pregnancy planning. Results.u2003Of the 163 women studied (89 type 1, 74 type 2 diabetes), 47% reported high pregnancy planning effort, 58% reported attempts to optimize glycemic control, and 56% took folic acid before pregnancy. Of those who reported high pregnancy planning, 20% did not medically plan their pregnancies. Rates were similar between women with type 1 and type 2 diabetes. The most important predictor of pregnancy planning was having discussed plans with their physician. Conclusions.u2003Our findings suggest that pregnancy planning is suboptimal in women with both type 1 and type 2 diabetes, highlighting a need to improve preconception counseling for all women with pregestational diabetes.

Association between Metformin Use and Mortality after Cervical Cancer in Older Women with Diabetes

Background: To examine the association between metformin use and mortality in patients with diabetes and cervical cancer. Methods: Using Ontario health databases, a retrospective, population-based cohort study was conducted in women with diabetes ≥ age 66 years diagnosed with cervical cancer between 1997 and 2010. The association between metformin exposure and cervical cancer–specific mortality was examined using Fine–Gray regression models, with noncancer death as a competing risk and cumulative metformin use as a time-varying exposure. The association with overall mortality was examined using Cox regression models. Results: Among the 181 women with diabetes and cervical cancer, there were 129 deaths, including 61 cervical cancer–specific deaths. The median follow-up was 5.8 years (interquartile range 4.2–9.6 years) for surviving patients. Cumulative dose of metformin after cervical cancer diagnosis was independently associated with a decreased risk of cervical cancer–specific mortality and overall mortality in a dose-dependent fashion [HR 0.79; 95% confidence interval (CI), 0.63–0.98; and HR 0.95; 95% CI, 0.90–0.996 per each additional 365 g of metformin use, respectively]. There was no significant association between cumulative use of other antidiabetic drugs and cervical cancer–specific mortality. Conclusion: This study suggests an association between cumulative metformin use after cervical cancer diagnosis and lower cervical cancer–specific and overall mortality among older women with diabetes. Impact: Cumulative dose of metformin use after cervical cancer diagnosis among older women with diabetes may be associated with a significant decrease in mortality. This finding has important implications if validated prospectively, as metformin is inexpensive and can be easily combined with standard treatment for cervical cancer. Cancer Epidemiol Biomarkers Prev; 25(3); 507–12. ©2015 AACR.

Metformin and breast cancer stage at diagnosis: a population-based study

PURPOSEnThe objective of the present study was to use a large, population-based cohort to examine the association between metformin and breast cancer stage at diagnosis while accounting for mammography differences.nnnMETHODSnWe used data from Ontario administrative health databases to identify women 68 years of age or older with diabetes and invasive breast cancer diagnosed from 1 January 2007 to 31 December 2012. Adjusted logistic regression models were used to compare breast cancer stage at diagnosis (stages i and ii vs. iii and iv) between the women exposed and not exposed to metformin. We also examined the association between metformin use and estrogen receptor status, tumour size, and lymph node status in the subset of women for whom those data were available.nnnRESULTSnWe identified 3125 women with diabetes and breast cancer; 1519 (48.6%) had been exposed to metformin before their cancer diagnosis. Median age at breast cancer diagnosis was 76 years (interquartile range: 72-82 years), and mean duration of diabetes was 8.8 ± 5.9 years. In multivariable analyses, metformin exposure was not associated with an earlier stage of breast cancer (odds ratio: 0.98; 95% confidence interval: 0.81 to 1.19). In secondary analyses, metformin exposure was not associated with estrogen receptor-positive breast cancer, tumours larger than 2 cm, or positive lymph nodes.nnnCONCLUSIONSnThis population-based study did not show an association between metformin use and breast cancer stage or tumour characteristics at diagnosis. Our study considered older women with long-standing diabetes, and therefore further studies in younger patients could be warranted.

HbA1c levels had low sensitivity but high specificity for screening for diabetes

Source Citation Olson DE, Rhee MK, Herrick K, et al. Screening for diabetes and pre-diabetes with proposed A1c-based diagnostic criteria. Diabetes Care. 2010;33:2184-9. 20639452

In type 1 diabetes, education with either insulin pumps or daily injections did not differ for HbA1c at 2 y

Question In type 1 diabetes, does structured education (SEd) in flexible insulin treatment with either insulin-pump treatment or multiple daily injections (MDIs) improve glycemic control? Methods Design Cluster randomized controlled trial (Relative Effectiveness of Pumps over MDI and Structured Education [REPOSE] trial). Patients were assigned to 1 of 46 Dose Adjustment For Normal Eating (DAFNE) SEd courses; courses were randomized in pairs to insulin-pump treatment or MDIs. Current Controlled Trials ISRCTN61215213. Allocation {Concealed}*. Blinding Unblinded. Follow-up period 2 years. Setting 8 secondary care centers in England and Scotland, UK. Patients 317 adults (mean age 41 y, 60% men based on 267 patients attending an SEd course) who had type 1 diabetes mellitus for 1 year and clinical indications for, but no previous, SEd in insulin treatment. Exclusion criteria included need or strong preference for pump treatment, use of optimized MDIs and meeting National Institute for Health and Care Excellence criteria for pump treatment, or serious diabetes complications. Intervention Insulin-pump treatment with DAFNE SEd modified to include skills training on pump use (n =156) or MDIs with standard DAFNE SEd (n =161). 5 to 8 patients attended each 5-day SEd course, with a follow-up session at 6 to 8 weeks. Outcomes Primary outcomes were change in hemoglobin (Hb) A1c level in patients with baseline level 7.5% and proportion with HbA1c level 7.5%. Secondary outcomes included moderate or severe hypoglycemia and diabetic ketoacidosis (DKA); the latter was assessed using serious adverse event (SAE) reports. 248 patients were needed to detect a minimally important difference between groups of 0.5% for HbA1c level (80% power, 2-sided =0.05). Patient follow-up 78% of all patients and 93% of the 267 patients who attended SEd (n =267) (intention-to-treat analysis). Main results At 2 years, HbA1c level decreased across both groups (0.54%, 95% CI 0.38% to 0.69%) with no difference between groups in outcomes (Table). Groups did not differ for episodes of severe ({0.10 events/patient-y in each group}*, P =0.77) or moderate (2.6 vs 2.3 events/patient over 4 wk at 2 y, {P =0.99}*) hypoglycemia. {DKA SAEs occurred in 13% of patients in the insulin pump group vs 3.7% in the MDI group}*. Conclusion In adults with type 1 diabetes receiving structured education in flexible insulin treatment, insulin pumps and multiple daily injections did not differ for glycemic control at 2 years. Insulin pump vs multiple daily injections in patients with type 1 diabetes receiving structured education Outcomes Changes from baseline At 2 y Insulin pump Daily injections Mean difference (95% CI) HbA1c level 0.85% 0.42% 0.24% (0.53 to 0.05) Event rates RBI (CI) Patients with HbA1c level 7.5% 25% 23% 16% (32 to 81) HbA1c = hemoglobin A1c; other abbreviations defined in Glossary. RBI and CI calculated from daily injections event rate and odds ratio in article. Adjusted for study center, education course (cluster), and baseline HbA1c level. Based on 235 of 242 patients with baseline HbA1c level 7.5%. Commentary The past decade has seen major advances in type 1 diabetes management, with associated improvements in prognosis (1). Continuous subcutaneous insulin infusion pumps are one such advance. Advantages of these pumps over MDIs include more precise insulin delivery, automated bolus calculators, and ability to adjust basal insulin rates throughout the day. Disadvantages include higher cost and greater risk for metabolic decompensation with malfunction. Some evidence suggests that insulin pumps improve glucose control (2) and outcomes (3) compared with MDIs. However, these benefits may also be attributed to the enhanced diabetes care and self-management retraining that is given during the transition to insulin pumps. The REPOSE trial showed that, when all patients on MDIs received structured education, there was no additional benefit of switching to insulin-pump therapy for glycemic control, hypoglycemia rates, or quality of life. Effective self-management training may then be more important than the method of insulin administration in patients with type 1 diabetes. Some caveats should be considered. First, REPOSE only included patients without a clear indication or preference for pump treatment, who may have been less likely to use all of the pump features designed to optimize glycemic control. Therefore, these results cannot be applied to highly motivated patients who request pump treatment. Second, the risks for hypoglycemia and DKA with insulin pumps will be greatly reduced with such newer technologies as closed-loop systems that integrate continuous glucose monitoring with insulin administration. In the meantime, without clear added benefits of insulin pumps and their higher cost, complexity, and risk for DKA, we should focus on enhancing education rather than changing to pump treatment in patients with type 1 diabetes who are inadequately controlled on MDIs.

Insulin therapy among women with impaired glucose tolerance of pregnancy

aventisG. Vespasiani: Novo Nordisk, sanofi-aventis, Roche Diagnostics Employee: K. Admane: sanofi-aventis Commercially-sponsored research: L. Blonde: Amylin Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim Pharmaceutical, Bristol-Myers Squibb, Eli Lilly and Company, MannKind Corporation, Merck & Co., Inc., Novo Nordisk, Novartis Corporation, Pfizer Inc. and sanofi aventis Other substantive relationships: This study is sponsored by sanofi-aventis. P. Home and institutions with which he is associated receive funding for research, lecturing and health-care development activities from all major pharmaceutical companies active in diabetes, including sanofi-aventis.L. Blonde has recevied honoraria from Abbott, Amylin Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline, LifeScan, Merck & Co., Inc., Novartis Corporation, Novo Nordisk, Pfizer Inc. and sanofi aventis for acting as a speaker and consultant, and from BoehringerIngelheim Pharmaceutical and Hazlozyme for acting as a consultant.