this study was a single - center , retrospective chart review of patients prescribed u-500 insulin between 1 april 2009 and 1 february 2013 after evaluation by the nmvahcs endocrine service . the inclusion dates for chart review were chosen secondary to a u-500 insulin process change that occurred in march 2009 , which involved a mandatory appointment with a registered nurse / certified diabetes educator ( rn / cde ) for patient education before starting u-500 insulin therapy . this appointment entailed a review of insulin concentration and dosing based on units and milliliters for tuberculin syringe use . u-500 insulin could only be initiated by members of the endocrine service , who are responsible for selecting eligible candidates based on their adherence to previous insulin therapy , their high insulin demand ( total daily dose usually > 200 units / day ) , and their intolerance to or current use of an insulin sensitizer . additionally , u-500 insulin required a nonformulary request and review by a clinical pharmacist , who would approve the request after another assessment for medication adherence on the u-100 insulin regimen , appropriateness of u-500 insulin therapy and dose , and assurance of appropriate insulin education . a list of patients prescribed u-500 insulin after 1 april 2009 was generated using the veterans integrated service network data warehouse on a microsoft sql server ( microsoft ; redmond , wash . ) . patients were eligible for the study if they were evaluated by the endocrine service and converted from u-100 to u-500 insulin during the aforementioned inclusion dates with a minimum of one documented a1c measured 6 months before conversion and any subsequent a1c 2 months after conversion . additionally , patients must have received initial insulin education by the rn / cde and must have been followed by the nmvahcs endocrine service after conversion . the number of provider contacts was collected starting 3 months before the first a1c recorded before conversion ( baseline ) and through the date of the final a1c recorded after conversion . patient - provider contacts included in - person or telephone follow - up between patients and primary care physicians , endocrinologists , primary care nurses , or rn / cdes that involved the adjustment of medication therapy . the number of contacts was adjusted to reflect a rate of contacts per 30 days . patient characteristics collected included weight , comorbid conditions , ethnicity , age , duration of diabetes , and any changes in renal or hepatic function . total daily dose of insulin and number of injections were recorded at the time of conversion and at the time of the final a1c measurement . chart - documented objective ( < 70 mg / dl ) and subjective hypoglycemic episodes were recorded starting 3 months before conversion and until the final a1c measurement . similar to frequency of contacts , hypoglycemic episodes were also adjusted to reflect a per - month rate . it was expected that patients were adherent to u-100 insulin therapy because that is one of the eligibility criteria for u-500 insulin use . nevertheless , u-100 insulin adherence was evaluated along with u-500 adherence based on patients pharmacy record refill history . patients who refilled insulin on time 80% of the time during the study period were considered adherent . concomitant diabetes medications were recorded at the time of conversion to u-500 insulin and the most recent a1c . any patient who stopped u-500 insulin in favor of another insulin therapy for a reason other than hospital admission study approval was obtained through the university of new mexico institutional review board and the nmvahcs research and development committee . a wilcoxon signed rank test was used to account for outliers in changes in a1c and contact frequency . a spearman s rank correlation was applied to determine the presence of correlations between two variables . all statistical analyses were performed using the statistical analysis system ( sas institute , cary , n.c . ) . a wilcoxon signed rank test was used to account for outliers in changes in a1c and contact frequency . a spearman s rank correlation was applied to determine the presence of correlations between two variables . all statistical analyses were performed using the statistical analysis system ( sas institute , cary , n.c . ) . thirty - eight patients were prescribed u-500 insulin between 1 april 2009 and 1 february 2013 . twenty - five of these patients met the a1c inclusion criteria ; 13 patients did not meet inclusion criteria . one of the 25 was initiated on u-500 insulin by the endocrine service at nmvahcs but was followed at another va facility . this patient was included in the a1c analysis but was not included for the secondary outcome because the follow - up frequency could not be assessed . the only female patient in the study was the patient who was not followed by the nmvahcs endocrine service . therefore , the secondary outcome only includes data from male patients ( n = 24 ) . the average duration of diabetes was 16  8 years ( range 340 years ) . baseline patient demographics expressed as mean  standard deviation . as documented in computerized patient record system . the mean a1c level decreased from 9.4 to 8.7% ( p = 0.0343 ) during the median follow - up period of 13 months ( range 243 months ) . the mean frequency of provider contacts decreased from 2.8 to 1.7 per month ( p = 0.018 ) . statistical analysis using a wilcoxon signed rank test did not change the statistical significance of the change in a1c ( p = 0.0366 ) or contact frequency ( p = 0.0112 ) . there were no significant changes in the mean rate of hypoglycemic events or total daily dose of insulin before conversion compared with after conversion . the mean number of injections per day significantly decreased from 5.0 before conversion to 2.7 after conversion ( p < 0.0001 ) . a statistically significant change in weight was seen , with a mean increase of 12 lb ( p = 0.02 ) . no significant correlation was found between change in a1c and change in contact frequency or weight gain . the adherence rate decreased from 96% before conversion to 79% after conversion ( p = 0.046 ) . five patients converted back to u-100 insulin because of frequent hypoglycemia on u-500 insulin ( n = 2 ) or patient preference ( n = 3 ) . no changes in renal or hepatic function were noted in any patients . in terms of concomitant diabetes medications , only one patient was on another type of injectable medication at the time of the most recent a1c . six of fifteen patients on an oral agent at time of conversion remained on an oral agent at the time of the most recent a1c . no new oral agents were initiated in patients who were not on an oral agent at the time of conversion . in this retrospective study , a significant reduction in a1c was found in highly insulin - resistant veterans with type 2 diabetes who were converted from u-100 insulin to u-500 concentrated regular insulin and were not subject to a strict management protocol . although statistically significant , one may question the clinical significance of an a1c reduction that is < 1% given that a reduction of 1% has been well documented to be associated with a reduction in both micro- and macrovascular complications ( 12 ) . furthermore , previously published u-500 studies have shown a1c reductions of 1.0% ( 911 ) . the two studies that had reductions of 1.5% ( 9 ) and 1.7% ( 10 ) had shorter follow - up periods compared to our study ( 3 and 12 months , respectively ) . because our study did not have a maximum duration of follow - up , it is possible that some patients experienced a more significant reduction in a1c within the first year after conversion and then experienced a tapering off of that glycemic control benefit , possibly because of the progressive nature of diabetes , increasing insulin resistance , or lifestyle changes ( i.e. , diet and exercise ) . further evidence for this theory is one study that had a mean follow - up of 20 months and found only a 1.0% reduction in a1c ( 11 ) . additionally , the average duration of diabetes may dampen the glycemic effect of switching to u-500 insulin . the average duration of diabetes in our study ( 16  8 years ) was longer than in other published studies ( i.e. , quinn et al . , with a duration of 9.1  5.7 years and zeismer et al . , with a duration of 14  7 years ) ( 10,11 ) . because of the potential risk of hypoglycemia associated with u-500 insulin use , possible dosing errors related to its concentrated formulation , and additional follow - up from the endocrine service , it was anticipated that we would find at least a marginal increase in the frequency of contacts after conversion compared to before conversion . one reason may be that many patients had multiple appointments with primary care providers or the endocrine service before converting to u-500 insulin in an attempt to optimize their u-100 insulin regimen . second , one of the reasons for consideration for u-500 insulin is poor glycemic control , which may require more frequent follow - up from providers . because a significant improvement in glycemic control was seen after conversion to u-500 insulin , one could postulate that with better control comes a decreased need for frequent follow - up . third , another contributor to the finding of a decrease in follow - up frequency may have been underestimation of follow - up contacts after conversion . the number , duration , and causes of hospitalizations were not collected , although some patients were hospitalized during the study period . the number of contacts per month was not adjusted to account for time spent in an inpatient setting , thus potentially resulting in a reduction of the mean rate . to account for these confounders in a future study , similar time frames should be used to determine the per - month rate of contacts . a significant reduction in a1c without an increase in hypoglycemia or dose of insulin may indicate better utilization of injected insulin secondary to a more concentrated , lower - volume of injection solution . to further corroborate this , a significant increase in weight indicated better absorption of insulin . it is well established that insulin therapy can lead to weight gain . as found in quinn et al . ( 10 ) , there was a significant reduction in the number of injections per day . although not assessed in this study , reduced number of injections can potentially result in increased patient satisfaction and adherence . the reason for the reduction in adherence rate is likely a case of regression to the mean . because u-100 insulin medication adherence was evaluated by the endocrine service and a clinical pharmacist , it was expected that all patients were adherent to their previous diabetes regimen before converting to u-500 insulin . additionally , because adherence was determined by pharmacy database refill history , some patients may have been using u-500 vials for longer than the manufacturer s 31-day recommendation . as a result , reduced adherence may have been the result of a knowledge deficit regarding appropriate insulin handling . it is uncertain what impact reduced adherence had on a1c change . as with many retrospective studies , this study had some limitations . in addition , the study had a relatively small sample size , which consisted mostly of older men . the sample size likely would have been larger if patients prescribed u-500 insulin before 1 april 2009 were included . however , before this date , patients were not required to receive rn / cde education before starting u-500 insulin . we did not include these patients to maintain consistency in the education level of the patients included in the study . other limitations include the inability to fully and accurately assess patient adherence and to identify potential insulin self - adjustments . patients who were admitted to the hospital at any point during the study period may or may not have received u-500 insulin . finally , there was a wide range in insulin doses and in multiple clinician involvement , both of which may have influenced glycemic control . this study provides further evidence that u-500 insulin offers a significant a1c reduction even when follow - up contact is not structured or frequent . in addition , the frequency of documented hypoglycemia was not significantly increased in patients who converted from u-100 to u-500 insulin . better glycemic control , as represented by a1c , along with similar insulin doses and increased weight gain , provides further evidence that u-500 insulin may allow for better utilization of injected insulin than large volumes of u-100 insulin . we recommend that patients with type 2 diabetes who require 200 units / day of u-100 insulin and are adherent to , but not well - controlled on , their current insulin regimen , be considered for u-500 insulin therapy . we endorse a multidisciplinary approach involving rns , pharmacists , and cdes to support endocrinologists , primary care providers , and patients , as well as to select ideal candidates . patients should receive appropriate counseling on the basic differences between u-100 and u-500 insulin , know how to calculate and draw up doses to avoid medication errors , and demonstrate proper administration technique . as always , providers should assess patients willingness and ability to change insulin regimens and encourage self - care behaviors such as self - monitoring of blood glucose , eating a healthful diet , exercising , and adhering to medication regimens .
in brief this article describes a single - center , retrospective chart review to determine the glycemic effect of converting from u-100 to u-500 regular insulin in veterans with type 2 diabetes and the effect of this change , if any , on the frequency of provider contacts . 
 results showed that u-500 insulin improved glycemic control without significantly increasing the risk of hypoglycemia or total daily insulin dose , even when follow - up contacts with providers were not structured or frequent .