Insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control.

BACKGROUND: It is unclear whether people with type 2 diabetes mellitus on insulin monotherapy who do not achieve adequate glycaemic control should continue insulin as monotherapy or can benefit from adding oral glucose-lowering agents to the insulin therapy. OBJECTIVES: To assess the effects of insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin monotherapy for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and reference lists of articles. The date of the last search was November 2015 for all databases. SELECTION CRITERIA: Randomised controlled clinical trials of at least two months' duration comparing insulin monotherapy with combinations of insulin with one or more oral glucose-lowering agent in people with type 2 diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated overall quality of the evidence using GRADE. We summarised data statistically if they were available, sufficiently similar and of sufficient quality. We performed statistical analyses according to the statistical guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We included 37 trials with 40 treatment comparisons involving 3227 participants. The duration of the interventions ranged from 2 to 12 months for parallel trials and two to four months for cross-over trials.The majority of trials had an unclear risk of bias in several risk of bias domains. Fourteen trials showed a high risk of bias, mainly for performance and detection bias. Insulin monotherapy, including once-daily long-acting, once-daily intermediate-acting, twice-daily premixed insulin, and basal-bolus regimens (multiple injections), was compared to insulin in combination with sulphonylureas (17 comparisons: glibenclamide = 11, glipizide = 2, tolazamide = 2, gliclazide = 1, glimepiride = 1), metformin (11 comparisons), pioglitazone (four comparisons), alpha-glucosidase inhibitors (four comparisons: acarbose = 3, miglitol = 1), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) (three comparisons: vildagliptin = 1, sitagliptin = 1, saxagliptin = 1) and the combination of metformin and glimepiride (one comparison). No trials assessed all-cause mortality, diabetes-related morbidity or health-related quality of life. Only one trial assessed patients' treatment satisfaction and showed no substantial differences between the addition of either glimepiride or metformin and glimepiride to insulin compared with insulin monotherapy.Insulin-sulphonylurea combination therapy (CT) compared with insulin monotherapy (IM) showed a MD in glycosylated haemoglobin A1c (HbA1c) of -1% (95% confidence interval (CI) -1.6 to -0.5); P < 0.01; 316 participants; 9 trials; low-quality evidence. Insulin-metformin CT compared with IM showed a MD in HbA1c of -0.9% (95% CI -1.2 to -0.5); P < 0.01; 698 participants; 9 trials; low-quality evidence. We could not pool the results of adding pioglitazone to insulin. Insulin combined with alpha-glucosidase inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.2); P < 0.01; 448 participants; 3 trials; low-quality evidence). Insulin combined with DPP-4 inhibitors compared with IM showed a MD in HbA1c of -0.4% (95% CI -0.5 to -0.4); P < 0.01; 265 participants; 2 trials; low quality evidence. In most trials the participants with CT needed less insulin, whereas insulin requirements increased or remained stable in participants with IM.We did not perform a meta-analysis for hypoglycaemic events because the included studies used different definitions.. In most trials the insulin-sulphonylurea combination resulted in a higher number of mild episodes of hypoglycaemia, compared to the IM group (range: 2.2 to 6.1 episodes per participant in CT versus 2.0 to 2.6 episodes per participant in IM; low-quality evidence). Pioglitazone CT also resulted in more mild to moderate hypoglycaemic episodes compared with IM (range 15 to 90 episodes versus 9 to 75 episodes, respectively; low-quality evidence. The trials that reported hypoglycaemic episodes in the other combinations found comparable numbers of mild to moderate hypoglycaemic events (low-quality evidence).The addition of sulphonylureas resulted in an additional weight gain of 0.4 kg to 1.9 kg versus -0.8 kg to 2.1 kg in the IM group (220 participants; 7 trials; low-quality evidence). Pioglitazone CT caused more weight gain compared to IM: MD 3.8 kg (95% CI 3.0 to 4.6); P < 0.01; 288 participants; 2 trials; low-quality evidence. Metformin CT was associated with weight loss: MD -2.1 kg (95% CI -3.2 to -1.1), P < 0.01; 615 participants; 7 trials; low-quality evidence). DPP-4 inhibitors CT showed weight gain of -0.7 to 1.3 kg versus 0.6 to 1.1 kg in the IM group (362 participants; 2 trials; low-quality evidence). Alpha-glucosidase CT compared to IM showed a MD of -0.5 kg (95% CI -1.2 to 0.3); P = 0.26; 241 participants; 2 trials; low-quality evidence.Users of metformin CT (range 7% to 67% versus 5% to 16%), and alpha-glucosidase inhibitors CT (14% to 75% versus 4% to 35%) experienced more gastro-intestinal adverse effects compared to participants on IM. Two trials reported a higher frequency of oedema with the use of pioglitazone CT (range: 16% to 18% versus 4% to 7% IM). AUTHORS' CONCLUSIONS: The addition of all oral glucose-lowering agents in people with type 2 diabetes and inadequate glycaemic control who are on insulin therapy has positive effects on glycaemic control and insulin requirements. The addition of sulphonylureas results in more hypoglycaemic events. Additional weight gain can only be avoided by adding metformin to insulin. Other well-known adverse effects of oral glucose-lowering agents have to be taken into account when prescribing oral glucose-lowering agents in addition to insulin therapy.

High vaccination rates for seasonal and pandemic (A/H1N1) influenza among healthcare workers in Dutch general practice.

In previous years, the influenza vaccination rate among Dutch general practitioners (GPs) was low (36% during the 2007/2008 season). Since 2008, yearly influenza vaccination has been actively recommended for GPs in The Netherlands. Moreover, in 2009 the Dutch government urged healthcare workers to receive additional vaccination against the pandemic influenza (A/H1N1). The effects of these recommendations are unknown. In February 2010, a questionnaire was mailed to random samples of GPs (n=810) and GP-trainees (n=300). Vaccination rates were determined and motives and barriers for vaccination were assessed. The response rates for GPs and GP-trainees were 83% and 90%, respectively. In total, 63% of the GPs were vaccinated against seasonal influenza and 85% against pandemic (A/H1N1) influenza. For GP-trainees, these percentages were 47% and 77%, respectively. With regard to the medical staff working in the respondents' practices, 60% received the seasonal and 76% the pandemic (A/H1N1) influenza vaccine. Reducing the risk of transmitting the virus to vulnerable patients and the individual's personal protection were the most frequently reported motives for vaccination. Having no medical indication for influenza vaccination and the conviction of being protected against influenza because of frequent professional exposure to the virus were the most frequently mentioned reasons for not being vaccinated. In conclusion, the seasonal influenza vaccination rate among Dutch GPs has risen considerably since the previous survey and the vaccination rate against pandemic (A/H1N1) influenza was very high. Moreover, Dutch GPs were convinced that influenza vaccination will reduce the risk of transmitting the virus to their patients.

Influenza immunization of Dutch general practitioners: vaccination rate and attitudes towards vaccination.

With effect from the 2008/2009 season, yearly influenza immunization will be recommended to all Dutch general practitioners (GPs). For successful implementation of this recommendation, knowledge about the current vaccination rate and attitudes towards vaccination is necessary. In February 2008, a questionnaire was mailed to a random sample (n=730) of practicing GPs. Vaccination rate was determined and the factors associated with not being vaccinated were assessed using multivariate logistic regression. Reasons for being vaccinated or not were also recorded. Of the 730 questionnaires sent out, 698 (96%) were completed and returned. In total, 248 GPs (36%) had been immunized against influenza. Independent factors related to not being vaccinated were female gender and age <40 years. Having no medical indication for an influenza vaccination and the conviction that one is protected against influenza because of frequent professional exposure to the virus were the most frequently reported reasons for not being vaccinated. The most frequently reported motives for being vaccinated were personal protection against influenza and a lower risk of transmitting the virus to patients. Education of GPs about the effects of vaccination may be needed to ensure their compliance to the current recommendation of yearly influenza immunization.