Peer Review: Insulin Dosing After Bariatric Surgery

INSULIN DOSING AFTER BARIATRIC SURGERY: PREDICTABLE DOSE DECREASES?

AUTHORS

Katherine Hadsall, M.S. Kathryn Vollmer, Drake University College of Pharmacy and Health Sciences Natalie Ake, Drake University College of Pharmacy and Health Sciences Lynn Kassel, PharmD, BCPS, Associate Professor of Clinical Sciences, Drake University College of Pharmacy and Health Sciences,

Acute Care Pharmacist, MercyOne West Des Moines Medical Center Jamie Pitlick, PharmD, BCPS, BC-ADM, Associate Professor of Pharmacy Practice, Drake University College of Pharmacy and Health Sciences,

Clinical Pharmacist, MercyOne Diabetes and Endocrinology Center Michael Daly, PharmD, MSCI, BCPS, Associate Professor of Clinical Sciences, Drake University College of Pharmacy and Health Sciences,

Informatics Pharmacist, The Iowa Clinic Joel Rand, MPAS, PA-C, Des Moines Bariatric Surgery, MercyOne West Des Moines Medical Center Mark Smolik, MD, FACS, FASMBS, Medical Director Des Moines Bariatric Surgery, MercyOne West Des Moines Medical Center

Conflict of interest: The authors declare no conflict of interest.

A preliminary assessment of the project was presented at the 2019 ACCP Annual Meeting in New York, NY.

ABSTRACT

Introduction: The prevalence of obesity is increasing in the United States and worldwide, and obesity is associated with chronic diseases such as type 2 diabetes. Bariatric surgery, including procedures such as laparoscopic sleeve gastrectomy (LVSG) or Roux-en-Y (RYGB), represent one solution to reduce weight, hemoglobin A1c, and insulin doses in patients who are overweight or obese. However, the long-term data and predictability of decreasing insulin doses in the individuals who have received these surgeries is limited.

Methods: This was a retrospective study of individuals, ages 18-89 years with type 1 or 2 diabetes (n=39), who underwent LVSG or RYGB at MercyOne West Des Moines Medical Center and followed up at MercyOne Des Moines Endocrinology Care between March 1, 2012 and September 30, 2018. Descriptive statistics were used to analyze data.

Results: Of the 40 patients included, almost half (45% (n=18)) remained on insulin in the immediate post-op period. At 12-months post-op, 20% (n=8) of patients remained on insulin. Even though fewer patients were on insulin at 12-months post-op, the mean A1c increased from 7.01 ± 0.83 to 7.93 ± 1.42. On average, bariatric surgery reduced mean weight by 19.2% (or a mean of 24.6 kg) at 12-months post-op.

Conclusion: Bariatric surgery decreases weight and insulin requirements over 12 months in individuals with obesity and type 1 or 2 diabetes. However, insulin doses required were not predictable for the entire population.

Key Points: • Insulin doses often decrease following bariatric surgery, and can cure diabetes. • Insulin doses immediately drop following surgery and up to the 12-months after. • Glucose control, by A1c, returned to baseline within 12-months of surgery. • The time frame of insulin dose decreases are not predictable following LVSG or RYGB.

INTRODUCTION

Diabetes is currently the 7th leading cause of death in the United States, with the economic burden on the healthcare system costing an estimated $327 billion annually for diagnosed individuals1,2. The prevalence of diabetes continues to grow, due in part to the obesity epidemic3, as obesity is the leading risk factor for the development of type 2 diabetes mellitus4,5. Weight loss, as low as 5 to 15% of total weight, can help decrease the number of risk factors for the development of diabetes in individuals with obesity5 .

Bariatric surgery is recommended as a treatment option for type 2 diabetes in adults with a BMI greater than or equal to 40 kg/m2 and with a BMI 35.0 – 39.9 kg/m2 who do not achieve weight loss with non-surgical methods. Several studies have compared health outcomes in patients undergoing surgical versus non-surgical interventions. Two studies demonstrated that patients who underwent bariatric surgery had a higher remission rate of type 2 diabetes, greater reductions in A1c, and decreased body weight compared to patients receiving no surgical intervention6,7. The surgical group had a significant decrease in body weight that continued four years post-op, while the A1c decreased until two years post-op6 .

Bariatric surgeries are classified as either restrictive, malabsorptive, or a combination of both8. Two of the most common bariatric surgeries are Roux-en-Y Gastric Bypass (RYGB) and laparoscopic sleeve gastrectomy (LVSG). The RYGB is considered a mixed procedure because it restricts stomach volume and affects how nutrients are absorbed into the bloodstream. The RYGB alters the gastrointestinal tract, causing food to bypass most of the stomach and upper small intestine. This type of surgery has been shown to induce remission of type 2 diabetes mellitus

in 80% of patients, with an additional 15% receiving improvement in control9. The LVSG is a restrictive procedure as it solely decreases the stomach volume by removing a portion, thus increasing feelings of fullness8. Remission rates of type 2 diabetes mellitus are close to 60% with the LVSG9 .

These surgeries’ primary purpose is to reduce caloric intake, leading to weight loss and increased insulin sensitivity over the short and long term10. Both RYGB and LVSG result in similar weight loss over a 4-month time frame7. Reduction in A1c, weight loss, shortened duration of diabetes, and decreased insulin doses11 were associated with improved insulin sensitivity following bariatric surgery. Yan et al.12 demonstrated that nearly 85% (n=71) of patients with a duration of diabetes less than 9.5 years achieved complete remission within one year after RYGB. For patients with diabetes for longer than 9.5 years, only 36.7% (n=11) achieved complete remission.

Current literature on changes of insulin dosing post-op is limited and includes studies that only focus on short-term post-op (< 20 weeks). Middlebeek and colleagues13 found that RYGB rapidly decreased BMI, A1c, and insulin requirements in women with obesity and type 1 diabetes mellitus. In the study, insulin requirements were reduced by 38% in the 20 weeks following surgery. There is minimal evidence for the long-term effects that bariatric surgery has on insulin dosing. The purpose of this study is to determine if there is a predictable long-term decrease in patients’ insulin requirements during the 12 months following bariatric surgery.

METHODS

The Institutional Review Boards at MercyOne Medical Center and Drake University approved this retrospective cohort study. For this type of study, informed consent was not required and was waived by the IRBs involved. Subjects were identified utilizing information from MercyOne West Des Moines Medical Center and the Bariatric and Weight Loss Center. In total, 125 patients who had RYGB or LVSG surgery between March 1, 2012 and September 30, 2018 were identified from the surgical-reporting data. After cross-referencing with patients receiving care at MercyOne Des Moines Diabetes and Endocrinology Care, a total of 40 subjects were identified. One patient was excluded because insulin dosing could not be confirmed at any time point. Thirty-nine subjects were included in the final cohort for analysis. The patients were de-identified in data collection and reported in aggregate. Demographics were collected from medical records.

The study’s primary outcome was to determine the difference in total daily units of insulin between the pre-op and post-op time periods. To be included, follow-up appointments had to be within a 30-day window of 3-, 6-, and 12-months, respectively. For collecting data in patients utilizing continuous insulin pumps and insulin to carbohydrate ratios (ICR), the highest number in the range was recorded, as this was the maximum dose the patient could have received (e.g., ICR is 1:5 with a maximum amount of 75 units; therefore 75 units was utilized for data collection and analysis). Secondary outcomes included percent change in A1c and weight (in kilograms (kg)) at the prespecified time points. To determine the primary outcome, mean total insulin doses were calculated and compared pre-op to post-op. Insulin changes in patients remaining on insulin at 3-, 6-, and 12-months and immediately post-op were calculated. Mean percentage changes in A1c and weight from baseline were calculated to determine secondary outcomes. The last value carried forward method was used for missing data throughout the study.

RESULTS

The baseline characteristics of the study subjects (n=39) are included in Table 1. For the primary outcome, mean insulin doses decreased during the study period from 126.6 ± 67.5 units pre-op to 82.4 ± 57.4 units at 12-months post-op using the last value carried forward (Table 2). The decrease in insulin dose is even more robust at 12-months if only documented doses are used to calculate the mean (48 ± 43.4 units), as shown in Table 3.

While many patients, 82.4% (n=28 out of 34), remained on insulin on day 0 (the day of surgery), the number of patients remaining on insulin decreased throughout the hospital stay (Table 2). The day 3 data may be skewed by the number of patients (n=4) remaining eligible for insulin, as discharge frequently occurred on day 1 or 2 for these patients. Individual dose decreases throughout the immediate perioperative period can be seen in Table 3.

Weight decreased during the first 12-months following surgery with a mean weight loss of 18.6% from baseline (Table 4). This decrease in weight is maintained if only documented weights are used rather than the last value carried forward (19.1%). The A1c decreased by an average of 0.1% between pre-op and the 3-month follow-up. However, the A1c increased to 7.4% and 7.5% at 6- and 12-month post-op, respectively (Table 4).

CONCLUSION

The mean total daily insulin doses decreased from the pre-op to postop period within a population that reflects current bariatric surgery patients in the United States. These results corroborate previous literature that LVSG and RYBG procedures decrease weight and insulin requirements, with some patients ultimately discontinuing insulin use. Middelbeek et al.13 found a 45.5% decrease in insulin from 59.7 ± 43.8 to 32.6 ± 20.9 units at the first post-surgical visit at 7.7 ± 5.8 weeks. This study yielded a decrease of 63% ± 27.1% for documented insulin doses at a similar point. Mean insulin doses continued to decrease throughout the year-long follow-up period.

This study analyzed both long-term insulin dosing in the first year after surgery and the immediate perioperative period. Most patients (82.4%, n=28) remained on insulin on post-op day 0, while 50% (n=2) of those still hospitalized continued insulin by post-op day 3, as shown in Table 2. This finding is most likely attributed to the significant reduction in caloric intake immediately post-op. Of note, not all patients remained hospitalized for three post-op days within the institution. There were five surgeries without documented immediate post-op insulin doses, as the health system had not utilized electronic medical records for medication administration recording during that time.

While A1c showed a slight improvement at 3-months post-op, it eventually increased above baseline by 12-months. This trend is similar to that seen in other literature13-18. The increase in A1c may be attributed to patient non-adherence to necessary medication and non-pharmacological therapy in the post-op period, a desire to no longer take medications for diabetes mellitus, or other factors that cannot be identified through retrospective analysis. In addition, the standard deviation was increased from pre-op to 3-, 6-, and 12-months post-op, which demonstrates that the level of variability increased, suggesting there were a few patients who skewed the increased A1c at the follow-up time periods. As expected, weight was shown to decrease from baseline at each follow-up period. However, this is expected given the known association between lack of insulin, rising A1c, and weight loss.

The present study’s findings are useful to patients and healthcare team members when discussing options for the treatment of diabetes. The study also looks at the consistency of long-term effects from the surgery, rather than short-term insulin dose requirements. Future studies could include patients using continuous glucose monitoring systems to monitor blood glucose levels, as this would monitor blood sugars with insulin doses in the perioperative time period. Additional studies are also needed to assess subjects more thoroughly with continuous insulin infusion pumps, limiting the potential inflation of insulin dosing in our research. To do this, researchers would need access to the insulin pump reports with actual pump settings and insulin use documented.

This study has several limitations. First, this is a small study of 39 subjects; therefore, generalizability to the whole population may be affected. Second, there was incomplete data due to inconsistencies in the follow-up period, as some patients did not follow up as instructed. Researchers utilized both last observation carried forward and all specified data points to demonstrate variation. Third, data were based on medical records inputted by prescribers. Still, some patients reported (within provider documentation) being non-adherent to therapy, so the actual insulin dose the patient was taking was unknown to the researchers. The insulin doses may not have been consistently documented within the medical record in the same manner by all the different providers; however, using the same documentation for data collection standardized the procedure for collecting data. Finally, the surgery team providing care during the study period was comprised of only one surgeon, further limiting the generalizability in practice but maintaining consistency within this study. The limitations are balanced out by the strengths of the studying including that the baseline characteristics of the study subjects were reflective of patients seeking bariatric surgery in the United States.

In conclusion, the results of this study demonstrate RYGB and LVSG consistently decrease insulin intake over a 12-month post-op time period, as well as immediately post-op. Additionally, weight decreased during the first 12-months following surgery. The A1c decreased between surgery and the 3-month follow-up time; however, on average, it increased to even higher than pre-op measurements at 6- and 12- months post-surgery.

References: 1. Statistics About Diabetes [article online], 2018. Available from http://www.diabetes. org/diabetes-basics/statistics/. Accessed 19 November 2020 2. Diabetes [article online], 2020 Available from https://www.who.int/news-room/factsheets/detail/diabetes Accessed 19 November 2020 3. Adult Obesity Facts [article online], 2020. Available from https://www.cdc.gov/ obesity/data/adult.html Accessed 19 November 2020 4. Barnes AS. The epidemic of obesity and diabetes: Trends and Treatments. Tex Heart Inst J 2011;38(2): 142-144 5. Obesity in America [article online], 2018. Available from https://asmbs.org/resources/obesity-in-america. Accessed 19 November 2020 6. Wu G, Cai B, Yu F, Fang Z, Fu X-L, Zhou H-S, et al. Meta-analysis of bariatric surgery versus non-surgical treatment for type 2 diabetes mellitus. Oncotarget. 2016; 7(52):87511-87522. DOI: 10.18632/oncotarget.11961 7. Douglas IJ, Bhaskaran K, Batterham RL, Smeeth L. Bariatric Surgery in the United Kingdom: a cohort study of weight loss and clinical outcomes in routine clinical care. PLoS Med 2015;12(12). DOI: 10.1371/journal.pmed.1001925 8. Koliaki C, Liatis S, le Roux CW, Kokkinos A. The role of bariatric surgery to treat diabetes: current challenges and perspectives. BMC Endocrine Disorders 2017; 17(50). DOI: 10.1186/s12902-017-0202-6 9. Surgery for Diabetes [article online], 2019 Available from https://asmbs.org/patients/ surgery-for-diabetes. Accessed on 19 November 2020 10. Bradley D, Magkos F, Klein S. Effects of bariatric surgery on glucose homeostasis and type 2 diabetes. Gastroenterology 2012;143(4): 897-912. DOI: 10.1053/j.

gatro.2012.07.114 11. Ramos-Levi AM, Sanchez-Pernaute A, Marcuello C, Galindo M, Calle-Pascual AL, et al. Glucose variability after bariatric surgery: is prediction of diabetes remission possible? Obes Surg 2017;27(12):3341-3343. DOI: 10.1007/s11695-017-2960-7 12. Yan W, Bai R, Li Y, Xu J, Zhong Z, Xing Y, et al. Analysis of predictors of type 2 diabetes mellitus remission after Roux-en-Y gastric bypass in 101 Chinese patients. Obes

Surg 2019; 29:1867-73. DOI: 10.1007/s11695-019-03783-x 13. Middelbeek RJW, James-Todd T, Patti ME, Brown FM. Short-term insulin requirements following gastric bypass surgery in severely obese women with type I diabetes.

Obes Surg 2014;24:1442-1446. DOI: 10.1007/s11695-014-1228-8 14. Kirwan JP, Aminian A, Kashyap SR, Burguera B, Brethauer SA, Schauer PR. Bariatric surgery in obese patients with type 1 diabetes. Diabetes Care 2016; 39(6): 941-948.

DOI: 10.2337/dc15-2732 15. De Block CE, De Leeuw IH, Van Gaal LF. Impact of overweight on chronic microvascular complications in type 1 diabetic patients. Diabetes Care 2005;28:1649–1655.

DOI: 10.2337/diacare.28.7.1649 16. Fernández-soto ML, Martín-Leyva A, González-Jiménez A, Garcia-Rubio J, Cozar-

Ibanex A, Zamora-Camacho FJ, et al. Remission of type 2 diabetes mellitus after bariatric surgery - comparison between procedures. Endokrynol Pol 2017;68(1):1825. DOI: 10.5603/EP.2017.0004 17. Barry RG, Amiri FA, Gress TW, Nease DB, Canterbury TD. Laparoscopic vertical sleeve gastrectomy: A 5-year veterans affairs review. Medicine (Baltimore). 2017;96(35):e7508. DOI: 10.1097/MD.0000000000007508 18. Cruijsen M, Koehestani P, Huttjes S, Leenders K, Janssen I, de Boer H. Perioperative glycaemic control in insulin-treated type 2 diabetes patients undergoing gastric bypass surgery. Neth J Med 2014; 72(4):202-9

Table 1. Baseline Characteristics

Age, years (mean ± standard deviation, range) 53.8 ± 9.9 (24 – 72) Female (n, %) 22 (56.4) Previous Weight Loss Surgery (n, %) No 38 (97.4)

Yes

Type of Surgery (n, %) LVSG 1 (2.6)

35 (89.7)

RYGB

Type of Diabetes (n, %) Type 1 diabetes mellitus Type 2 diabetes mellitus Duration of Diabetes (n, %) 0-9 years 10-20 years ≥ 21 years Comorbidities (n, %) Cardiovascular Disease 4 (10.3)

3 (7.7)

36 (92.3)

6 (16.2) 18 (48.6) 13 (35.1)

35 (89.7)

PCOS

Psychiatric Disorders Neuropathic Pain General Pain 1 (2.6) 15 (38.5) 6 (15.4) 11 (28.2)

Thyroid Disorders 9 (23.1)

LVSG = Laparoscopic Vertical Sleeve Gastrectomy, PCOS = Polycystic Ovarian Syndrome, RYGB = Roux-en-Y Gastric Bypass