Article
Burnt Out ? The Phenomenon of Type 2 Diabetes Mellitus in End-Stage Renal Disease
In patients with T2DM and ESRD, insulin is the antidiabetic medication of choice with a hemoglobin A1c target of 6 to 8%, using fructosamine...
Strengths and Limitations
This study has several limitations. Data about hospitalizations for congestive heart failure, amputations, progression of diabetic retinopathy, neuropathy, and nephropathy were not collected for this analysis. As both groups of subjects were relatively small, statistical power to assess outcomes is a concern. Retrospective chart reviews may also be affected by incomplete data collections and multiple biases. No data were available for other hypoglycemic episodes, especially to calculate the rate of the more common forms of hypoglycemia. The period of data analyzed spanned only about 15 months. A longer, longitudinal assessment of the differences between these 2 groups may yield more differences, and clearer results and conclusions. Moreover, the data set had aged before publication of this report; however, the authors think that the analysis and information remain highly clinically relevant. The uncommon use of U-500, and prominence as a “special case” insulin may also lead to a detection bias for severe hypoglycemia in the U-500 group. In contrast, lapses in documentation of hypoglycemia in subjects using U-100 could have occurred. Finally, the differences in total daily dose and body weight among groups were significant and may reflect on important physiologic differences between the 2 groups that may affect the reproducibility of our results.
Nevertheless, this study had notable strengths. Comparing U-500 insulin users with similar subjects using U-100 over a period of time provides head-to-head data with potentially important clinical utility. Also, we collected and analyzed a sizable number of clinically important variables, including cardiovascular risk factors, the occurrence of new cardiovascular events, and prevalence of renal disease. The use of linear regression and multivariate analysis using multiple models also strengthened the results. Previous studies compared the outcomes in subjects using U-500 insulin with only their historical selves.8,13-16,18,19,22-25 Therefore, these studies analyzed the data for preconversion and postconversion of U-500 only and consistently favored U-500. This design in a retrospective study cannot eliminate the selection and/or intervention biases, as the subjects of study had inevitably “failed” prior therapies. Similarly, there is no prospective clinical trial data comparing patients on U-500 with patients on high doses of U-100 insulin. Finally, the patients in our study had high rates of comorbidities, which may have increased the applicability of our results to those of “real-life” patients in the community. To our knowledge, no other study has attempted a similar study design approach either prospectively or retrospectively.
Conclusions
In this population of elderly veterans with severely insulin-resistant T2DM, with a high incidence of CKD and ASCVD, U-500 insulin was associated with significantly greater reductions in Hb A1C than U-100 insulin-based regimens, while requiring fewer injections. No difference was noted in the incidence of new ASCVD events. More studies are needed to assess whether U-500 may increase the risk of severe hypoglycemic episodes.
Acknowledgments
The authors recognize the invaluable help provided by the editorial staff of University of South Florida IMpact, the Intramural Review to Support Research and Scientific Publication, and especially to Richard F. Lockey, MD, who has mentored us in this beautiful journey of scientific writing and for his editorial assistance. A portion of this study preliminary data was presented as an abstract at ENDO 2013, The Endocrine Society Annual meeting in San Francisco, CA, June 15-18, 2013.
Appendix. Severe Hypoglycemic Events
Subject 1: U-500 user, 61-year-old African American male. Hypoglycemia occurred during fasting and was associated with a seizure-like event 9 months after transition to concentrated insulin. He was taken by ambulance to a local hospital. No additional data were obtained. Hb A1C was 8.2% in the month before the episode (lowest of the studied period) and increased to 9.1% in the last segment of the study.
Subject 2: U-500 user, 57-year-old white male. The severe hypoglycemic episode occurred approximately 8 months after transition. His Hb A1C was 5.6% around the time of the event, the lowest of the studied period, and increased to 6.8% over the next 4 months. No other data were available.
Subject 3: U-500 user, 67-year-old white male. The event occurred at home in the morning while fasting, 3 months after transition. He was assisted by his family. Hb A1C was 7.1% 10 weeks after the event and was 7% at the end of the studied period. He had a history of CKD and PVD.
Subject 4: U-500 user, 68-year-old white male. He presented with altered consciousness, hypoglycemia, and elevated troponin levels, which was later confirmed as a non-ST elevation myocardial infarction (NSTEMI), 7 months after transition. Hb A1C during the events was 7.1% and was followed by a 9.3% level 9 weeks later. He had history of CKD and PVD.
Subject 5: U-500 user, 67-year-old white man. Hypoglycemia occurred 6 months after transition to U-500. Hb A1C was 8.4% 2 months prior, and was followed by a 7% during the admission for severe hypoglycemia. 3 months later, his HbA1c rose to 8.2%. He had an extensive history of CAD and had a NSTEMI during the study period.
Subject 6: U-100 user, 65-year-old white man. He was found unconscious in the morning while fasting, 6 months after his first clinic visit. He had CKD and advanced ASCVD with prior CAD, PVD, and CVA. He had also had a recent CVA that had affected his movement and cognition.