Clinical effects, cardiovascular and renal outcomes associated with rapid-acting insulin analogs among individuals with type 2 diabetes: a nation-wide observational cohort study

BACKGROUND Rapid-acting insulin analogs (RAIs) have not been examined for long-term safety in randomized clinical trials. We performed a nationwide longitudinal cohort study among individuals with type 2 diabetes (T2DM) to address cardiovascular safety and mortality among users of lispro, aspart and glulisine insulins. METHODS We used four national registers, following patients previously not treated with RAI but with continuous use of RAIs in 2005-2014 up to 6.4 years, to examine HbA1c and weight, and the occurrence of severe hyperglycemia or hypoglycemia, renal failure, cardiovascular events or death. The treatment groups were compared using a weighted Cox proportional hazards model. RESULTS We included 17,620 patients, mean age slightly higher than 60 years, diabetes duration 9.9-11.7 years, mean BMI 30.5 kg/m2, HbA1c around 70 mmol/mol (8.6% NGSP), and 40.9-54.0% of the patients exhibiting eGFR <60 ml/min/1.73 m2 in the three groups. Around 95% of the patients also used another insulin, and 24.2-24.7% had a history of cardiovascular disease (CVD). Mean HbA1c and weight levels were stable and similar. Incidence rates of death were 234.4, 284.9 and 156.7 per 1000 person-years among users of lispro, aspart, and glulisine; incidence rates of all cardiovascular events were 668.4, 622.4, and 699.5 per 1000 person-years, respectively. There were no differences in mortality, CVD, renal failure or severe hypoglycemia or hyperglycemia, although a lower mortality risk in patients on glulisine compared with aspart, and lower risk of stroke in users of glulisine was suggested. The risk of severe hyperglycemia was higher with lispro than aspart, and lower of severe hypoglycemia than aspart or glulisine among the older age group. CONCLUSIONS Overall, there do not appear to be any major important differences in effects on hypoglycemia, hyperglycemia, weight or long-term safety between the three available RAIs among insulin-naive individuals with T2DM in clinical practice.