Insulin glargine benefits patients with type 2 diabetes inadequately controlled on oral antidiabetic treatment: an observational study of everyday practice in 12,216 patients

AIMS: This observational study aimed to investigate the long-term efficacy and safety of adding insulin glargine (LANTUS((R))) to support oral antidiabetic (OAD) treatment in patients with type 2 diabetes in everyday practice. METHODS: A 9-month, open-label, multicentre, observational study, with an optional 20-month extension phase, in which add-on insulin glargine therapy was initiated in 12,216 patients with type 2 diabetes inadequately controlled on OADs. The insulin glargine dose was adjusted at the physician's discretion, reflecting everyday practice. The main outcome measures were changes in HbA(1c), fasting blood glucose (FBG), insulin dose and body mass index (BMI). RESULTS: At baseline, mean (+/- s.d.) age was 63.9 +/- 11.3 years; disease duration was >5 years in 47% of patients, 1-5 years in 39% of patients and <1 year in 10% of patients, while 4% of patients were newly diagnosed. Addition of insulin glargine to OAD therapy led to reductions in mean HbA(1c) (-1.5% from 8.7%) and FBG (-69 mg/dl from 202 mg/dl) levels after 3 months, which were maintained after 9 months [HbA(1c): -1.7%; FBG: -71 mg/dl (-3.9 mmol/l)] without an increase in BMI. Similar glycaemic control was observed after 20 months in the 2721 patients in the extension study. Adverse drug reactions were documented in 26 patients (0.2%). Of 47 adverse events documented, 19 were due to hypoglycaemia. CONCLUSIONS: In everyday practice, patients with type 2 diabetes who are inadequately controlled on OADs benefit from add-on basal insulin treatment with insulin glargine as they demonstrate improved glycaemic control without weight gain.     

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. Methods: Using the administrative databases of Saskatchewan Health, 12272 new users of oral antidiabetic therapy were identified between 1991 and 1996 and grouped according to cumulative insulin exposure based on total insulin dispensations per year: no exposure (reference group); low exposure (0 to <3); moderate exposure (3 to <12) and high exposure (≥12). Time‐varying multivariable Cox proportional hazards models were used to examine the relationship between insulin exposure and all‐cause, CV‐related and non‐vascular mortality after adjustment for demographics, medications and comorbidities. Results: Average age was 65 (s.d. 13.9) years, 45% were female, and mean follow‐up was 5.1 (s.d. 2.2) years. In total, 1443 (12%) subjects started insulin, and 2681 (22%) deaths occurred. The highest mortality rates were in the high exposure group; 95 deaths/1000 person‐years compared with 40 deaths/1000 person‐years in the no exposure group [unadjusted hazard ratio (HR): 2.32; 95% confidence interval (CI): 1.96–2.73]. After adjustment, we observed a graded risk of mortality associated with increasing exposure to insulin: low exposure [adjusted HR (aHR): 1.75; 95% CI: 1.24–2.47], moderate exposure (aHR: 2.18; 1.82–2.60) and high exposure (aHR: 2.79; 2.36–3.30); p = 0.005 for trend. Analyses restricted to CV‐related (p = 0.042 for trend) and non‐vascular (p = 0.004 for trend) mortality showed virtually identical results. Conclusions: We observed a significant and graded association between mortality risk and insulin exposure level in an inception cohort of patients with type 2 diabetes that persisted despite multivariable adjustment.     

High plasma glutamate and low glutamine-to-glutamate ratio are associated with type 2 diabetes: Case-cohort study within the PREDIMED trial

Background and aimsGlutamate, glutamine are involved in energy metabolism, and have been related to cardiometabolic disorders. However, their roles in the development of type-2 diabetes (T2D) remain unclear. The aim of this study was to examine the effects of Mediterranean diet on associations between glutamine, glutamate, glutamine-to-glutamate ratio, and risk of new-onset T2D in a Spanish population at high risk for cardiovascular disease (CVD).Methods and resultsThe present study was built within the PREDIMED trial using a case-cohort design including 892 participants with 251 incident T2D cases and 641 non-cases. Participants (mean age 66.3 years; female 62.8%) were non diabetic and at high risk for CVD at baseline. Plasma levels of glutamine and glutamate were measured at baseline and after 1-year of intervention. Higher glutamate levels at baseline were associated with increased risk of T2D with a hazard ratio (HR) of 2.78 (95% CI, 1.43–5.41, P for trend = 0.0002). In contrast, baseline levels of glutamine (HR: 0.64, 95% CI, 0.36–1.12; P for trend = 0.04) and glutamine-to-glutamate ratio (HR: 0.31, 95% CI, 0.16–0.57; P for trend = 0.0001) were inversely associated with T2D risk when comparing extreme quartiles. The two Mediterranean diets (MedDiet + EVOO and MedDiet + mixed nuts) did not alter levels of glutamine and glutamate after intervention for 1 year. However, MedDiet mitigated the positive association between higher baseline plasma glutamate and T2D risk (P for interaction = 0.01).ConclusionHigher levels of glutamate and lower levels of glutamine were associated with increased risk of T2D in a Spanish population at high risk for CVD. Mediterranean diet might mitigate the association between the imbalance of glutamine and glutamate and T2D risk.This trial is registered at http://www.controlled-trials.com, ISRCTN35739639.     

Fournier's gangrene in patients with type 2 diabetes using second-line antidiabetic medications

Cases of a rare but serious infection called Fournier's gangrene have been reported with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). To evaluate the safety signal in a population of patients with type 2 diabetes, we used administrative claims data from Horizon Blue Cross Blue Shield of New Jersey from 2014 through 2017 to estimate incidence rates of Fournier's gangrene or necrotizing fasciitis of the perineum among patients treated with a second-line antidiabetic drug. We found very low incidence rates of Fournier's gangrene or necrotizing fasciitis. While we found no indication of an increased risk among SGLT-2i users compared with similar patients treated with other second-line antidiabetic medications, the small number of events yielded wide confidence intervals.     

Sulphonylureas versus metformin and the risk of ventricular arrhythmias among people with type 2 diabetes: A population-based cohort study

Aim

To determine whether the use of sulphonylurea monotherapy, compared with metformin monotherapy, is associated with an increased risk of ventricular arrhythmia (VA) among patients initiating pharmacotherapy for type 2 diabetes.

Research Design and Methods

We conducted a population-based cohort study using electronic health data extracted from the UK's Clinical Practice Research Datalink Aurum. Using the active comparator, new-user cohort design, we compared rates of VA among patients aged 18 years or older using sulphonylurea monotherapy with those using metformin monotherapy as their initial pharmacological treatment for type 2 diabetes from April 1998 to December 2019. We used a Cox proportional hazards model with inverse probability of treatment weighting by propensity score to estimate the adjusted hazard ratio (aHR) and a corresponding bootstrap 95% confidence interval (CI) for VA with sulphonylurea monotherapy versus metformin monotherapy.

Results

The cohort included 92 638 new users of sulphonylurea and 506 882 new users of metformin. A total of 279 VA events occurred among sulphonylurea users (rate per 10 000 person-years: 25.5, 95% CI: 22.7 to 28.7) and 1537 VA events occurred among metformin users (rate per 10 000 person-years: 18.5, 95% CI: 17.6 to 19.5). Compared with metformin, sulphonylureas were associated with an increased risk of VA (aHR: 1.42, 95% CI: 1.18 to 1.69).

Conclusions

Sulphonylureas are associated with an increased risk of VA when used as first-line therapy for type 2 diabetes relative to metformin use. This increased risk should be considered when prescribing sulphonylureas as an initial treatment for type 2 diabetes.     

Liver fibrosis markers and all cause mortality in people with type 2 diabetes: A population based study (The Ayrshire Diabetes Outcomes Cohort (ADOC) Study)

Aims

To describe the distribution of the biomarker scores Fibrosis-4 (FIB4), nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), and aspartate aminotransferase to platelet ratio index (APRI), and the associations between risk categories and all-cause mortality.

Materials and Methods

This was a retrospective cohort study of 12 589 patients, with follow-up from January 2012 until November 2021. The cut-off points used to identify low risk were: FIB4 <1.3 if aged <65 years or <2.0 if aged ≥65 years; NFS < −1.455 if aged <65 years or <0.12 if aged ≥ 65 years; APRI <1 (independent of age). High-risk cut-off points were FIB4 >2.67, NFS >0.676 and APRI ≥1 (all independent of age). Multivariable Cox regression analysis was performed to assess the association between liver fibrosis scores and all-cause mortality.

Results

The mean ± standard deviation age was 65.2 ± 12.1 years, 54.5% were men and the median (interquartile range) diabetes duration was 5.8 (2.8–9.3) years. The prevalence of high-risk categories was 6.1% for FIB4, 23.5% for NFS and 1.6% for APRI. During a median follow-up of 9.8 years, 3925 patients (31.1%) died, resulting in a crude mortality rate of 40.4 per 1000 person-years. The overall adjusted all-cause mortality hazard ratios (95% confidence intervals [CIs]) in the high- compared with low-fibrosis-risk groups were 3.69 (1.95–2.75) for FIB4, 2.32 (2.88–4.70) for NFS, and 3.92 (2.88–5.34) for APRI. Stratified adjusted all-cause mortality hazard ratios for individuals under 65 years and people over 65 years of age at cohort entry were 3.89 (95% CI 2.99–5.05) and 1.44 (95% CI 1.28–1.61) for FIB4, 2.50 (95% CI 1.89–3.18) and 1.35 (95% CI 1.24–1.48) for NFS and 3.74 (95% CI 2.73–5.14) and 1.64 (95% CI 1.24–2.17) for APRI.

Conclusions

All three fibrosis risk scores were positively associated with all-cause mortality in people with type 2 diabetes, with higher relative risks in younger than older people. Effective interventions are required to minimize excess mortality in people at high risk of liver fibrosis.