John-Michael Gamble

Insulin use and increased risk of mortality in type 2 diabetes: a cohort study

Aim: To compare population‐based rates of all‐cause and cardiovascular (CV) mortality in newly treated patients with type 2 diabetes according to levels of insulin exposure.

Patterns of Care and Outcomes Differ for Urban Versus Rural Patients With Newly Diagnosed Heart Failure, Even in a Universal Healthcare System

Background— Access to medical care differs between urban and rural residents, but the magnitude of these differences and whether they affect outcomes are unknown. We aimed to determine whether outcomes differ for patients with incident heart failure (HF) by urban-rural status. Methods and Results— This cohort study used administrative data from Alberta, Canada. Patients with incident HF were identified from April 1, 1999, to December 31, 2005, and followed for 1-year. Multivariable logistic regression was used to assess differences in 1-year outcomes after initial HF diagnosis in patients living in rural versus urban settings. We identified 72 043 patients with incident HF (mean age, 72±14; male sex, 50%) of whom 12 173 (17%) died and 29 074 (39%) were hospitalized within 1 year. Although crude all-cause 1-year mortality rates were higher in urban than in rural residents (17.3% versus 15.6%, P<0.001), after adjustment for comorbidities, no significant differences were observed (adjusted odds ratio [aOR], 0.95; 95% CI, 0.90 to 1.00). However, sex-specific analyses indicated that urban men had a significantly lower risk of mortality than rural men (aOR, 0.89; 95% CI, 0.83 to 0.96). In contrast, no difference was observed between urban and rural women (aOR, 1.02; 95% CI, 0.94 to 1.10). Urban patients were more likely to have office-based physician visits in the first year after HF diagnosis (aOR, 1.09; 95% CI, 1.02 to 1.17) and exhibited lower rates of hospitalization (aOR, 0.71; 95% CI, 0.68 to 0.74) and emergency department visits (aOR, 0.62; 95% CI, 0.60 to 0.65) than rural patients. Conclusions— Even within a universal healthcare system, there are differences in outcomes after HF diagnosis based on location of residence. Urban patients with HF are more likely to receive outpatient care and less likely to be hospitalized or present to the emergency department in the first year after diagnosis than rural patients with HF.

Admission Hypoglycemia and Increased Mortality in Patients Hospitalized with Pneumonia

BACKGROUND The relationship between spontaneous admission hypoglycemia and mortality in patients hospitalized with community-acquired pneumonia is unclear. METHODS From 2000 to 2002, clinical data were prospectively collected on all patients with community-acquired pneumonia who were admitted to all 6 hospitals in Edmonton, Alberta, Canada. Patients with admission glucose greater than 6.1 mmol/L (n=1996) were excluded; the remaining patients were categorized as having admission hypoglycemia (<4.0 mmol/L [n=54]) or normoglycemia (4.0 to< or =6.1 mmol/L [n=902]). Multivariable Cox proportional hazards models were used to examine the relationship between hypoglycemia and all-cause mortality in-hospital, at 30 days, and at 1 year. RESULTS The mean age was 65 (standard deviation=20) years, 48% were female, 8% had diabetes, and 56% had severe pneumonia. Overall, admission hypoglycemia was present in 2% (54/2990) of the entire cohort and 6% of those with glucose of 6.1 mmol/L or less. Total deaths were 89 (9%) in-hospital, 96 (10%) at 30 days, and 247 (26%) at 1 year. In-hospital mortality was higher among patients with admission hypoglycemia (11 [20%] deaths) compared with those with normoglycemia (78 [9%]; adjusted hazards ratio [aHR] 2.96; 95% confidence interval [CI], 1.39-6.31; P=.005). An increased risk of mortality was observed at 30 days (11 [20%] vs 85 [10%]; aHR 2.89; 95% CI, 1.32-6.29) and remained elevated at 1 year (19 [35%] vs 228 [25%]; aHR1.80; 95% CI, 1.02-3.17). These results were not influenced by treatment for diabetes (P>.4 for interaction). CONCLUSION In a population-based sample of patients with community-acquired pneumonia, spontaneous admission hypoglycemia was independently associated with increased mortality during hospitalization that persisted to 1 year. Patients with hypoglycemia are an easily identified group that may warrant more intensive inpatient and postdischarge follow-up.

Impact of guideline-concordant antibiotics and macrolide/β-lactam combinations in 3203 patients hospitalized with pneumonia: prospective cohort study

For patients hospitalized with pneumonia, guidelines provide empirical antibiotic recommendations and some studies suggest that macrolide/β-lactam combinations are preferable. We hypothesized that guideline-concordant regimens, particularly macrolide/β-lactams, would reduce mortality and ICU admissions. All patients hospitalized with pneumonia in Edmonton, Alberta, Canada, were managed according to a clinical pathway and enrolled in a population-based registry. Clinical data, Pneumonia Severity Index and treatments were collected. Guideline-concordant regimens were macrolides/β-lactams or respiratory fluoroquinolone monotherapy. The main outcome was in-hospital mortality. The study included 3203 patients and most had severe pneumonia (63% PSI Class IV-V). Three hundred and twenty-one (10.0%) patients died, 306 (9.6%) were admitted to the ICU and 570 (17.8%) achieved the composite of death or ICU admission. Most (n = 2506) patients received guideline-concordant antibiotics. Receipt of guideline-concordant antibiotics was not associated with a reduction in mortality alone (231 (9.2%) vs. 90 (12.9%); adjusted odds ratio (aOR), 0.82; 95% CI, 0.61-1.09; p 0.16), but was associated with decreased death or ICU admission (14.7% vs. 29.0%; aOR, 0.44; 95% CI, 0.36-0.54; p < 0.0001). Within guideline-concordant subgroups, there was no difference in mortality between macrolide/β-lactams and respiratory fluoroquinolone monotherapy (22 (8.3%) vs. 209 (9.3%); aOR, 1.09; 95% CI, 0.66-1.81; p 0.73) but macrolide/β-lactams were associated with increased odds of death or ICU admission (17.4% vs. 14.4%; aOR, 1.58; 95% CI, 1.09-2.27; p 0.01). In conclusion, guideline-concordant antibiotics were not associated with decreased mortality for patients hospitalized with pneumonia, but were associated with a decrease in the composite endpoint of death or ICU admission. Our findings do not support any clinical advantage of macrolide/β-lactam compared with respiratory fluoroquinolone monotherapy.

Stress Hyperglycemia and Newly Diagnosed Diabetes in 2124 Patients Hospitalized with Pneumonia

OBJECTIVE Our goal was to determine the association between random admission hyperglycemia and new diagnosis of diabetes after discharge in patients hospitalized with pneumonia. METHODS Clinical data, including the Pneumonia Severity Index, were prospectively collected on all 2124 patients without diabetes admitted with pneumonia to 6 hospitals in Edmonton, Alberta, Canada. Admission glucose was classified as: normal (4.0-6.0 mmol/L, reference group) versus mild (6.1-7.7 mmol/L), moderate (7.8-11.0 mmol/L), and severe (11.1-20.0 mmol/L) stress hyperglycemia. New diagnosis of diabetes over 5 years was ascertained using well-validated criteria within linked administrative databases. Multivariable Cox models were used, and sensitivity, specificity, and likelihood ratios were calculated. RESULTS Mean age was 68 years; 1091 (51%) were male, and 1418 (67%) had stress hyperglycemia. Over 5 years, 194 (14%) with stress hyperglycemia were diagnosed with diabetes. Compared with the 45 of 706 (6%) incidences of diabetes in normal glycemia patients (4.0-6.0 mmol/L), a strong graded increase in risk of new diabetes existed with increasing hyperglycemia: mild (59 of 841 [7%]; adjusted hazard ratio [aHR] 1.09; 95% confidence interval [CI], 0.74-1.61) versus moderate (86 of 473 [18%]; aHR 2.99; 95% CI, 2.07-4.31) versus severe (49 of 104 [47%]; aHR 11.43; 95% CI, 7.50-17.42). Among moderate-to-severe hyperglycemia (≥7.8 mmol/L) patients, the sensitivity, specificity, and positive and negative likelihood ratios for new diabetes were 57%, 77%, 2.1, and 0.6, respectively, with a number-needed-to-evaluate of 5 to detect one new case of diabetes. CONCLUSION Moderate-to-severe random hyperglycemia in pneumonia patients admitted to the hospital is strongly associated with new diagnosis of diabetes. Opportunistic evaluation for diabetes may be warranted in this group.

Risk of acute coronary events associated with glyburide compared with gliclazide use in patients with type 2 diabetes: a nested case-control study.

Sulfonylureas might increase the risk of adverse cardiovascular events; however, emerging evidence suggests there may be important differences amongst these drugs. Some, like glyburide, inhibit KATP channels in the heart and pancreas, while others, like gliclazide, are more likely to selectively inhibit KATP channels in the pancreas. We hypothesized that the risk of acute coronary syndrome (ACS) events would be higher in patients using glyburide compared with gliclazide.

Analysis of drug coverage before and after the implementation of Canada's Common Drug Review

Background: Canada’s Common Drug Review was implemented to provide publicly funded drug plans (provincial and federal) with a transparent, rigorous and consistent approach for assessing the clinical effectiveness and cost-effectiveness of new drugs. We compared uptake of drug coverage across jurisdictions before and after the implementation of the Common Drug Review. Methods: Using the IMS Brogan formulary acceptance: monitoring and evaluation database, we identified new drug products in Canada five years before and five years after the first recommendation was made by the Common Drug Review. For each jurisdiction, we compared the proportion of drugs listed, the median time-to-listing and the agreement between the listing decisions of the drug plans and the recommendations of the Common Drug Review. Results: We identified 198 new drugs approved for use in Canada between May 26, 1999, and May 27, 2009, of which 53 had a recommendation from the Common Drug Review. The proportion of drugs listed decreased after the introduction of the Common Drug Review for all participating drug plans (81.1% to 71.3% overall [p ≤ 0.01 for all plans, with the exceptions of Ontario and Quebec [p = 0.07]). The change in median time-to-listing between the periods before and after the Common Drug Review varied by jurisdiction, ranging from a decrease of 691 days to an increase of 250 days. The change in median time-to-listing was not statistically significant for most jurisdictions, with the exceptions of Saskatchewan (increased, Mann–Whitney U test p = 0.01) and New Brunswick, Prince Edward Island, and Newfoundland and Labrador (all decreased, Mann–Whitney U test p < 0.01). Interpretation: There was a decline in the proportion of new drugs listed after the introduction of the Common Drug Review for both participating and nonparticipating jurisdictions. The introduction of the review was associated with a decreased time-to-listing for certain smaller provinces.

Incretin‐based medications for type 2 diabetes: an overview of reviews

To summarize evidence from and assess the quality of published systematic reviews evaluating the safety, efficacy and effectiveness of incretin‐based medications used in the treatment of type 2 diabetes.

Use Patterns of Antidiabetic Regimens by Patients with Type 2 Diabetes

OBJECTIVE To describe the use patterns of metformin-based antidiabetic regimens in patients with type 2 diabetes and to identify predictors of initiating metformin monotherapy. METHODS By using administrative databases from Alberta, Canada, we identified all metformin users ages 65 years and older between 1998 and 2010. Rates of metformin use, either alone or in combination with other antidiabetic drugs, were evaluated at 6-month intervals. All rates were direct age- and sex-standardized using the 2006 Alberta census. Trends over time were assessed using Joinpoint regression software (National Cancer Institute, USA). In addition, a cohort of new users of antidiabetic drugs was identified and multivariable logistic regression models were constructed to identify independent predictors of receiving initial treatment with metformin monotherapy. RESULTS Metformin monotherapy became the most common metformin-based regimen (508 of 1000 persons in 2010). Sulfonylureas were the most prevalent add-on drug to metformin; however, their use significantly decreased from 548 of 1000 in 1998 to 182 of 1000 persons in 2010 (67% reduction; p<0.001), with more patients using newer drugs, mainly thiazolidinediones (103 of 1000 persons in 2007). Combination therapy of metformin with glinides or insulin also significantly increased during the same period. Compared with patients starting sulfonylurea monotherapy, patients starting metformin monotherapy were younger, had fewer cardiovascular complications and lower healthcare use rates. CONCLUSIONS In accordance with the clinical practice guidelines, patients with type 2 diabetes manage hyperglycemia mainly with metformin monotherapy and sulfonylureas are the most common add-on therapy. Older age and the presence of nephropathy, liver disease or congestive heart failure were important predictors for starting sulfonylurea monotherapy rather than metformin monotherapy.

Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study

BACKGROUND Existing studies have shown conflicting evidence regarding the safety of exogenous insulin therapy in patients with type 2 diabetes. In particular, observational studies have reported an increased risk of death and cardiovascular disease among users of higher versus lower doses of insulin. We aimed to quantify the association between increasing dosage of insulin exposure and death and cardiovascular events, while taking into account time-dependent confounding and mediation that might have biased previous studies. METHODS We did a cohort study using primary care records from the UK-based Clinical Practice Research Datalink (CPRD). New users of metformin monotherapy were identified in the period between Jan 1, 2001, and Dec 31, 2012. We then identified those in this group with a new prescription for insulin. Insulin exposure was categorised into groups according to the mean dose (units) per day within 180-day time segments throughout each patients follow-up. Relative differences in mortality and major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, cardiovascular-related mortality) were assessed using conventional multivariable Cox proportional hazards models. Marginal structural models were then applied to reduce bias introduced by the time-dependent confounders affected by previous treatment. FINDINGS We identified 165 308 adults with type 2 diabetes in the CPRD database. After applying our exclusion criteria, 6072 (mean age 60 years [SD 12·5], 3281 [54%] men, mean HbA1c 8·5% [SD 1·75], and median follow-up 3·1 years [IQR 1·7-5·3) were new add-on insulin users and were included in the study cohort; 3599 were new add-on insulin users and were included in the subcohort linked to hospital records and death certificate information. Crude mortality rates were comparable between insulin dose groups; <25 units per day (46 per 1000 person-years), 25 to <50 units per day (39 per 1000 person-years), 50 to <75 units per day (27 per 1000 person-years), 75 to <100 units per day (34 per 1000 person-years), and at least 100 units per day (32 per 1000 person-years; p>0·05 for all; mean rate of 31 deaths per 1000 person-years [95% CI 29-33]). With adjustment for baseline covariates, mortality rates were higher for increasing insulin doses: less than 25 units per day [reference group]; 25 to <50 units per day, hazard ratio (HR) 1·41 [95% CI 1·12-1·78]; 50 to <75 units per day, 1·37 [1·04-1·80]; 75 to <100 units per day, 1·85 [1·35-2·53]; and at least 100 units per day, 2·16 [1·58-2·93]. After applying marginal structural models, insulin dose was not associated with mortality in any group (p>0·1 for all). INTERPRETATION In conventional multivariable regression analysis, higher insulin doses are associated with increased mortality after adjustment for baseline covariates. However, this effect seems to be confounded by time-dependent factors such as insulin exposure, glycaemic control, bodyweight gain, and the occurrence of cardiovascular and hypoglycaemic events. This study provides reassurance of the overall safety of insulin use in the treatment of type 2 diabetes and contributes to our understanding of the contrasting conclusions from non-randomised and randomised studies regarding dose-dependent effects of insulin on cardiovascular events and mortality. FUNDING Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the Newfoundland and Labrador Research and Development Corporation.