We performed a retrospective cohort study, investigating the clinical outcomes including mortality and cardiovascular disease of sitagliptin compared with metformin monotherapies.
All patients receiving monotherapy with the dipeptidyl peptidase-IV inhibitors (DPP-IV) inhibitor sitagliptin between 1 January 2007 and 31 December 2011 were identified. All-cause mortality and a composite endpoint of stroke, acute myocardial infarction (AMI) and all-cause mortality associated with sitagliptin monotherapy were compared with metformin monotherapy. In addition, as an indicator of efficacy we analysed the hazard ratio of changing treatment.
A total of 84?756 patients were included in the analysis, 1228 (1.4%) received sitagliptin monotherapy whereas the remaining 83?528 (98.6%) patients received metformin monotherapy. Patients using metformin were younger than patients using sitagliptin (59.0?±?15.2 vs. 62.5?±?13.1) were less often male (51.6 vs. 54.2%) and had longer treatment duration with monotherapy (1.8?±?1.3 vs. 0.9?±?1.1?years). Compared with patients receiving metformin, patients using sitagliptin showed no statistically significant excess risks of all-cause mortality [hazard ratio, 1.25; 95% confidence interval (CI), 0.92-1.71; p?=?0.153] or the composite endpoint (hazard ratio, 1.22; 95% CI, 0.92-1.61; p?=?0.164). However, the use of sitagliptin monotherapy was associated with an increased likelihood of changing treatment (hazard ratio, 4.88; 95% CI, 4.46-5.35; p?
Studies of the risk of motor vehicle crash associated with diabetes have produced conflicting results.
To assess whether the use of anti-diabetic drugs among the elderly increases the risk of motor vehicle crash.
The computerized databases of the various universal insurance programs of Québec were linked to form a cohort of all 224,734 elderly drivers that was followed from 1990-1993. Using a nested case-control approach, all 5,579 drivers involved in an injurious crash (cases) and a random sample of 13,300 control subjects were identified. Exposure to anti-diabetic drugs was assessed in the year preceding the index date, namely the date of the crash for the cases and a randomly selected date during follow-up for the controls.
The adjusted rate ratio of an injurious crash was 1.4 (95% CI: 1.0-2.0) for current users of insulin monotherapy relative to non-users and 1.3 (95% CI: 1.0-1.7) for sulfonylurea and metformin combined. Monotherapy, using either a sulfonylurea or metformin, was not associated with an increased risk. There was a dose-response effect in subjects using high doses of combined oral therapy (RR 1.4; 95% CI: 1.0-2.0). For users of insulin monotherapy or of high doses of combined oral therapy, the increase corresponds to an excess rate of 32 crashes per 10,000 elderly drivers per year.
L Elderly drivers treated with insulin monotherapy or a combination of sulfonylurea and metformin, especially at high doses, have a small increased risk of injurious crashes. There is no increased risk associated with any regimen of oral monotherapy.
Data on cardiovascular risk associated with different types of antidiabetic treatments are sparse and conflicting. We examined the risk of hospitalisation with myocardial infarction (MI) among patients treated with sulfonylureas, metformin, insulin, any combination and no antidiabetic pharmacotherapy.
Using nationwide registries, we conducted a population-based nested case-control study among all patients with type 2 diabetes in Denmark and identified all patients hospitalised with a first-time MI and age- and gender-matched non-MI controls in the period 1996-2004. We estimated odds ratios (ORs) of MI according to type of antidiabetic treatment, adjusted for potential confounding factors using patients treated with sulfonylureas as the reference group.
A total of 10,616 type 2 diabetic cases hospitalised with MI and 90,697 type 2 diabetic non-MI controls were available for analysis. We found a lower risk of hospitalisation with MI among users of metformin (adjusted OR?=?0.86, 95%CI: 0.78-0.95), insulin (adjusted OR?=?0.92, 95%CI: 0.86-0.99) and among patients not receiving any antidiabetic pharmacotherapy (adjusted OR?=?0.75, 95%CI: 0.71-0.79) compared with users of sulfonylureas. Users of any combination had similar risk as users of sulfonylureas (adjusted OR?=?0.99, 95%CI: 0.92-1.06). We found no differences between individual sulfonylureas, and glycaemic control and lipid profile had only minor impact on the risk estimates in subanalyses including HbA(1c) , cholesterol and triglycerides.
Our findings provide some support for the hypothesis that sulfonylureas may be associated with an increased risk of hospitalisation with MI.
Division of Cardiac Surgery, Department of Surgery, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, Faculty of Medicine and Dentistry, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Adenosine triphosphate sensitive potassium (K(ATP)) channel activity is cardioprotective during ischaemia. One of the purported mechanisms for sulphonylurea adverse effects is through inhibition of these channels. The purpose of this study is to examine whether patients using K(ATP) channel inhibitors at the time of an acute coronary syndrome are at greater risk of death or heart failure (HF) than those not exposed.
Using linked administrative databases we identified all adults who had an acute coronary syndrome between April 2002 and October 2006 (n?=?21 023).
Within 30?days of acute coronary syndrome, 5.3% of our cohort died and 15.6% were diagnosed with HF. Individuals with diabetes exhibited significantly higher risk of death (adjusted OR: 1.20, 95% CI: 1.03-1.40) and death or HF (aOR: 1.73, 95% CI: 1.59-1.89) than individuals without diabetes. However, there was no significantly increased risk of death (aOR: 1.00, 95% CI: 0.76-1.33) or death/HF (aOR: 1.06, 95% CI: 0.89-1.26) in patients exposed to K(ATP) channel inhibitors versus patients not exposed to K(ATP) channel inhibitors prior to their acute coronary syndrome.
Diabetes is associated with an increased risk of death or HF within 30?days of an acute coronary syndrome. However, we did not find any excess risk of death or HF associated with use of K(ATP) channel inhibitors at the time of an acute coronary syndrome, raising doubts about the hypothesis that sulphonylureas inhibit the cardioprotective effects of myocardial K(ATP) channels.
As more studies report on patient preferences for diabetes treatment, identifying diabetes outcomes other than glycated hemoglobin (HbA1c) to describe effectiveness is warranted to understand patient-relevant, benefit-risk tradeoffs.
The aim of the study was to evaluate how preferences differ when effectiveness (glycemic control) is presented as long-term sequela (LTS) risk mitigation rather than an asymptomatic technical marker (HbA1c).
People with type 2 diabetes and using insulin (n = 3160) were randomly assigned to four self-administered, discrete-choice experiments that differed by their presentation of effectiveness. Epidemiologic reviews were conducted to ensure a close approximation of LTS risk relative to HbA1c levels. The relative importance of treatment benefit-risk characteristics and maximum acceptable risk tradeoffs was estimated using an error-component logit model. Log-likelihood ratio tests were used to compare parameter vectors.
In total, 1031 people responded to the survey. Significantly more severe hypoglycemic events were accepted for a health improvement in terms of LTS mitigation versus HbA1c improvement (0.7 events per year; 95% confidence interval [CI]: 0.4-1.0 vs. 0.2 events per year 95% CI: -0.02 to 0.5) and avoidance of treatment-related heart attack risk (1.4 severe hypoglycemic events per year; 95% CI: 0.8-1.9 vs. 1 event per year; 95% CI: 0.6-1.3). This finding is supported by a log-likelihood test that rejected at the 0.05 level that respondent preference structures are similar across the different experimental arms of the discrete-choice experiment.
We found evidence that benefit descriptions influence elicited preferences for the benefit-risk characteristics of injectable diabetes treatment. These findings argue for using carefully defined effectiveness measures to accurately take account of the patient perspective in benefit-risk assessments.
BACKGROUND: Biphasic insulin aspart 30 (BIAsp 30 [30% soluble, rapid-acting insulin aspart and 70% protamine-bound insulin aspart], NovoLog Mix 70/30, Novo Nordisk, Bagsvaerd, Denmark), a premixed insulin analogue, addresses both the prandial and basal aspects of glucose regulation when used once or twice daily in patients with type 1 or type 2 diabetes. It provides overall glycemic control similar to biphasic human insulin 30 (BHI 30, 30% human insulin and 70% neutral protamine Hagedorn [NPH] insulin) in patients with type 1 or type 2 diabetes. OBJECTIVE: The aim of this review was to evaluate the safety profile associated with BIAsp 30 in patients with type 1 or type 2 diabetes versus that of comparator insulin products, including BHI 30 and biphasic insulin lispro 25 (Mix 25 [25% biphasic insulin lispro and 75% protaminated lispro], Humalog Mix 75/25, Eli Lilly and Company, Indianapolis, Indiana), together with the basal insulins, including NPH insulin and insulin glargine (Lantus, Sanofi-Aventis Pharmaceuticals, Paris, France). METHODS: Data from human clinical studies published in peer-reviewed journals or as conference proceedings that reported safety results in patients with type 1 or type 2 diabetes who were treated with BIAsp 30 versus comparator insulins were evaluated. To locate the appropriate articles, a MEDLINE search was performed for all years up to February 2005, using the following key words: biphasic insulin aspart, BIAsp 30, biphasic insulin, and premixed insulin. Additional papers were identified by examining the reference lists in these papers as well as our own personal reference files. Results from 17 publications were analyzed. The analysis included >2600 patients with type 2 diabetes (mean [range] age, 58 [36-70] years; duration of diabetes, 11.8 [9-17] years; and baseline glycosylated hemoglobin [HbA1c], 8.6% [7.5%-9.9%]). It also included 104 patients with type 1 diabetes (mean [range] age, 44.5 [30-58] years; duration of diabetes, 16 [2-30] years; and baseline HbA1c, 8.4% [7.2%-10.4%]). RESULTS: Hypoglycemia occurred in 43% to 57% of patients receiving BIAsp 30 versus 32% to 57% of patients receiving BHI 30 and 28% of patients receiving NPH insulin. Major hypoglycemic events were uncommon in most studies; but when they did occur, they were reported less frequently in patients receiving BIAsp 30 (2%-8% of patients) than in patients receiving BHI 30 (2%-14% of patients). Furthermore, patients treated with BIAsp 30 were at lower risk of experiencing minor nocturnal hypoglycemia than patients receiving comparator insulin; in 1 study, the relative risk (BIAsp 30 vs BHI 30) was calculated to be 0.63 (95% CI, 0.37 to 1.09). The adverse event (AE) profile, weight gain during treatment, and formation of cross-reactive antibodies were not different between BIAsp 30 and BHI 30. AEs were reported in 36% to 90% of patients receiving BIAsp 30, 38% to 88% of patients receiving BHI 30, and 51% of patients receiving Mix 25. The use of oral antidiabetic drugs in combination with BIAsp 30 did not alter the safety profile of BIAsp 30. CONCLUSION: The flexible and convenient treatment regimen offered by BIAsp 30, together with its ability to improve postprandial glucose control, is associated with a safety profile comparable to that of BHI 30 and NPH insulin, with a lower risk of major and nocturnal hypoglycemic events.
Cancer is more frequent among diabetes patients, but it is unknown how this excess varies with duration of diabetes and insulin use. The aim of this study was to analyse disease data to examine this issue further.
We linked the Danish National Diabetes Register and Cancer Registry and performed a cohort analysis of the entire Danish population by diabetes status, duration of diabetes and insulin use, comparing cancer incidence rates in diabetic patients with the non-diabetic population for the 15 year period 1995-2009, using Poisson regression with natural splines to describe the variation by duration.
We found 20,032 cancer cases among patients not using insulin and 2,794 cancer cases among diabetic patients using insulin. The cancer incidence rate ratio among non-insulin users relative to the non-diabetic population decreased from over 2 at diagnosis to 1.15 after 2 years of diabetes duration. The cancer incidence rate ratio was higher among patients using insulin, decreasing from 5 at the start of insulin treatment to about 1.3 [corrected] after 5 years of insulin use. Among non-insulin users, cancers of the stomach, colorectum, liver, pancreas, lung, corpus uteri, kidney and brain, and lymphomas were elevated. Among insulin users the rate ratio of prostate cancer was decreasing by duration whereas we found higher risk of cancer of the stomach, lung, liver, pancreas and kidney. Breast cancer incidence rates were not affected by either diabetes or insulin use.
The observed duration effects suggest that both increased surveillance for cancer in the first years after diagnosis of diabetes, and reverse causation, where undiagnosed cancers increase the likelihood of diabetes diagnosis, play a role. For longer durations, a combination of common causes for diabetes and cancer, as well as the effects of diabetes and insulin exposure per se, may play a role in the association between diabetes and some cancers.
Insulin glargine was the first long-acting human insulin analogue to be authorised in the European Union, in the early 2000s, for the treatment of diabetes mellitus. It has about a 6-fold increase in affinity for the insulinlike growth factor 1 (EGF-1) receptor compared with natural human insulin, which may stimulate tumour development. Four European epidemiological studies published in 2009 examined the risk of cancer in diabetic patients treated with insulin glargine. One of these studies, conducted in Germany, showed a statistically significant dose-dependent increase in the risk of cancer. Two other studies, one in Scotland and the other in Sweden, showed an increase in the risk of breast cancer. The fourth study, conducted in the UK, showed a lower risk of cancer in patients on metformin. This evidence is inconclusive, notably because these studies did not take confounding factors into account. Nevertheless, the results tend to be similar and consistent with certain pharmacological mechanisms. In practice, pending more solid evidence, these epidemiological results should be taken into account when weighing the risk-benefit balance of insulin therapy for diabetic patients, on a case by case basis, depending on the type of diabetes, patient history, life expectancy, and the possible practical advantages of insulin glargine.
The aim of this study was to examine the relationship between use of metformin and sulfonylurea and mortality in new users of these agents.
Saskatchewan Health databases were used to examine population-based mortality rates for new users of oral antidiabetic agents. Individuals with prescriptions for sulfonylurea or metformin in 1991-1996 and no use in the year prior were identified as new users. Prescription records were prospectively followed for 1-9 years; subjects with any insulin use were excluded. Causes of death were identified based on ICD-9 codes in an electronic vital statistics database. Multivariate logistic regression and survival analyses were used to assess the differences in mortality between drug cohorts, after adjusting for potential confounding variables.
The total study sample comprised 12,272 new users of oral antidiabetic agents; the average length of follow-up was 5.1 (SD 2.2) years. In subjects with at least 1 year of drug exposure and no insulin use, mortality rates were 750/3,033 (24.7%) for those receiving sulfonylurea monotherapy, 159/1,150 (13.8%) for those receiving metformin monotherapy, and 635/4,683 (13.6%) for those receiving combination therapy over an average 5.1 (SD 2.2) years of follow-up. The adjusted odds ratio (OR) for all-cause mortality for metformin monotherapy was 0.60 (95% CI 0.49-0.74) compared with sulfonylurea monotherapy. Sulfonylurea plus metformin combination therapy was also associated with reduced all-cause mortality (OR 0.66, 95% CI 0.58-0.75). Reduced cardiovascular-related mortality rates were also observed in metformin users compared with sulfonylurea monotherapy users.
Metformin therapy, alone or in combination with sulfonylurea, was associated with reduced all-cause and cardiovascular mortality compared with sulfonylurea monotherapy among new users of these agents.