A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study

Aims/hypothesis Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated. Methods LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used. Results We demonstrate that there is an association between NSHEs (2–11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2–11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]). Conclusions/interpretation The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs. Trial registration ClinicalTrials.gov (NCT01179048). Graphical abstract

Effect of a multitarget therapy with prednisolone, mycophenolate mofetil, and tacrolimus in a patient with type B insulin resistance syndrome complicated by lupus nephritis

ABSTRACT Type B insulin resistance syndrome (TBIR) is a rare autoimmune disease characterised by autoantibodies targeting insulin receptors. TBIR is often complicated by systemic lupus erythematosus (SLE). We describe the case of a 59-year-old Japanese man with TBIR complicated with lupus nephritis (LN), who presented with nephrotic syndrome and severe hypoglycaemia. Treatment with prednisolone (PSL), mycophenolate mofetil (MMF), and tacrolimus (TAC) resulted in improved SLE activity and glucose intolerance with the reduction of anti-insulin receptor autoantibodies. To the best of our knowledge, this is the first reported case of TBIR complicated with LN that was successfully treated using multitarget therapy with PSL, MMF, and TAC.

Metabolic control and hypoglycaemia in people with type 1 diabetes: insulin pump therapy vs. intensified insulin therapy in an unselected cohort in routine care

Aims The aim of this study was to compare individuals with type 1 diabetes with continuous subcutaneous insulin infusion (CSII) and intensified insulin therapy (ICT) in routine care regarding metabolic control and treatment satisfaction. Methods Individuals with type 1 diabetes (CSII n = 74; ICT n = 163) were analysed regarding metabolic control, frequency of hypoglycaemia and treatment satisfaction (DTSQs range 0–36). Results Individuals with CSII (duration of CSII: 14.1 ± 7.2 years) were younger (51.1 ± 15.8 vs. 56.2 ± 16.2 years, p = 0.023), had longer diabetes duration (28.7 ± 12.4 vs. 24.6 ± 14.3 years, p = 0.033), lower insulin dosage (0.6 ± 0.2 vs. 0.7 ± 0.4 IU/kg, p = 0.004), used more frequently short-acting analogue insulin (90.5% vs. 48.5%, p < 0.001) and flash/continuous glucose monitoring (50.0% vs. 31.9%, p = 0.009) than people with ICT. HbA1c was similar between CSII and ICT (7.1 ± 0.8%/54.4 ± 9.1 mmol/mol vs. 7.2 ± 1.0%/55.7 ± 10.9 mmol/mol, p = 0.353). Individuals with CSII had higher frequency of non-severe hypoglycaemia per week (in people with blood glucose monitoring: 1.9 ± 1.7 vs. 1.2 ± 1.6, p = 0.014; in people with flash/continuous glucose monitoring: 3.3 ± 2.2 vs. 2.1 ± 2.0, p = 0.006). Prevalence of polyneuropathy (18.9% vs. 38.0%, p = 0.004) and systolic blood pressure (138.0 ± 16.4 vs. 143.9 ± 17.1 mmHg, p = 0.014) was lower in CSII. Satisfaction with diabetes treatment (26.7 ± 7.3 vs. 26.0 ± 6.8, p = 0.600) did not differ between CSII and ICT. Conclusions CSII and ICT yielded comparable metabolic control and treatment satisfaction but CSII was associated with higher incidence of non-severe hypoglycaemia and lower insulin dosage.