Insulin dose and Mortality
Gerti Tashko, MD
Your Comprehensive Endocrinologist | Board Certified in Lipidology, Hypertension, and Obesity
The findings of this cohort study suggest that a higher insulin dose is a manifestation rather than cause of increased cardiovascular disease and death in patients with diabetes. About 6,000 adults were followed for 3 years. Individuals on high amounts of insulin may require a more aggressive cardiovascular attention and intervention.
GT
The Lancet: Diabetes and Endocrinology:
Original cohort Study
January 2017
Background: Existing studies have shown conflicting evidence regarding the safety of exogenous insulin therapy in patients with type 2 diabetes. In particular, observational studies have reported an increased risk of death and cardiovascular disease among users of higher versus lower doses of insulin. We aimed to quantify the association between increasing dosage of insulin exposure and death and cardiovascular events, while taking into account time-dependent confounding and mediation that might have biased previous studies.
Methods: We did a cohort study using primary care records from the UK-based Clinical Practice Research Datalink (CPRD). New users of metformin monotherapy were identified in the period between Jan 1, 2001 - Dec 31, 2012. We then identified those in this group with a new prescription for insulin. Insulin exposure was categorised into groups according to the mean dose (units) per day within 180-day time segments throughout each patient's follow-up. Relative differences in mortality and major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, cardiovascular-related mortality) were assessed using conventional multivariable Cox proportional hazards models. Marginal structural models were then applied to reduce bias introduced by the time-dependent confounders affected by previous treatment.
Findings: We identified 165,308 adults with type 2 diabetes in the CPRD database. After applying our exclusion criteria, 6,072 (mean age 60 years, 54% men, mean HbA1c 8·5%, and median follow-up 3.1 years were new add-on insulin users and were included in the study cohort; 3599 were new add-on insulin users and were included in the subcohort linked to hospital records and death certificate information.
Crude mortality rates were comparable between insulin dose groups; <25 units/day (46 per 1000 person-years), 25-50 units/day (39 per 1000 person-years), 50-75 units/day (27 per 1000 person-years), 75-100 units/day (34 per 1000 person-years), and at least 100 units/day (32 per 1000 person-years; p>0·05 for all; mean rate of 31 deaths per 1000 person-years [95% CI 29–33]). With adjustment for baseline covariates, mortality rates were higher for increasing insulin doses compared to reference group of <25 units/day; 25 to <50 units per day, hazard ratio (HR) 1.41 [95% CI 1·12–1·78]; 50 to <75 units per day, 1.37 [1·04–1·80]; 75 to <100 units per day, 1.85 [1·35–2·53]; and at least 100 units per day, 2.16 [1·58–2·93]. After applying marginal structural models, insulin dose was not associated with mortality in any group (p>0·1 for all).
Interpretation: In conventional multivariable regression analysis, higher insulin doses are associated with increased mortality after adjustment for baseline covariates. However, this effect seems to be confounded by time-dependent factors such as insulin exposure, glycaemic control, bodyweight gain, and the occurrence of cardiovascular and hypoglycaemic events. This study provides reassurance of the overall safety of insulin use in the treatment of type 2 diabetes and contributes to our understanding of the contrasting conclusions from non-randomised and randomised studies regarding dose-dependent effects of insulin on cardiovascular events and mortality.
Funding: Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and the Newfoundland and Labrador Research and Development Corporation.
Consultant Physician GPSI Diabetes
8yThis message so needs to gotten out to providers. So many are withholding escalation of insulin due to the belief that it is causing CV disease.
Your Comprehensive Endocrinologist | Board Certified in Lipidology, Hypertension, and Obesity
8ySwelling is usually due to fluid retention, since insulin is an anabolic hormone. If any inflammation, it could be from weight gain.
Coordinator, WESTMED Diabetes Education Program
8yIt was always my understanding that insulin causes an inflammatory response especially at high doses. patients have stated that their joints and hands and feet swell at high doses