FRONTIERS IN MEDICAL CASE REPORTS - Volume 2; Issue 2, (Mar-Apr, 2021)

Pages: 1-06

Date of Publication: 30-Mar-2021

Print Article   Download XML  Download PDF

Insulin Pump Therapy: Yesterday, Today and Tomorrow

Author: David Bell, Edison Goncalves

Category: Medical Case Reports

Abstract:

Historically, CSII therapy counteracted the peaking and short action of a long-acting human insulin through short-acting insulin in pumps obtaining stable and steady insulin levels between meals. As better short-acting insulins became available, the efficacy of CSII improved. Recently, the availability of long-acting and “peakless” insulins reduced the need for CSII. However, with the availability of accurate sensors utilized in a closed loop algorithm in combination with CSII has resulted in resurgence of CSII use. In the future the ability to utilize glucagon or even pramlintide infusions in combination with insulin infusion may result in even better glycemic control and greater use of CSII.

Keywords: Insulin Pumps, Long Acting Insulin, Short Acting Insulin, Compliance, Convenience, Basal Bolus Therapy

DOI URL: http://dx.doi.org/10.47746/FMCR.2021.2206

Full Text:

Yesterday

In the early 1980s two major events occurred which were to revolutionize insulin therapy in the type 1 diabetic patient. The first was that animal insulin was replaced with recombinant DNA human insulin and while this solved a supply problem, we were forced to utilize insulins that were inferior. The so-called long acting human insulins were not long acting, lasted less than 24 hours and most importantly showed excessively peaking. These insulins often peaked at times when short-acting insulins given as part of basal bolus therapy (BBT) were still active resulting in an increased frequency and severity of hypoglycemia (Bell, 2007).

The second significant event in the early 1980s was the general availability of Continuous Subcutaneous Insulin Infusion (CSII) or insulin pump therapy (Tamborlane et al., 1979). These insulin pumps only utilized short-acting insulin and as a result were able to maintain stable insulin levels between meals and when compared with BBT, the incidence and severity of hypoglycemia was decreased.

As enthusiasts in the 1980s, we were able to accumulate a large cadre of “pump patients” who we were able to study retrospectively. We were able to confirm that severe hypoglycemia was less frequent on CSII than on BBT and that a therapeutic HbA1c, unobtainable on BBT, could be obtained with CSII without the risk of severe hypoglycemia (Bell et al., 1988).

Subsequently, even better short-acting insulins than buffered human regular insulin that was the initial insulin used in CSS became available. These newer insulins (aspart and lispro) when used in CSII equally lowered the HbA1c and when compared with buffered human regular the lowering of the HbA1c was greater with both lispro and aspart. However, insulin aspart was the insulin that showed the lowest incidence of hypoglycemia and because of this became our preferred insulin for use with CSII (Bode et al., 2002). Subsequently, from one of our practices, we were able to show that compared with BBT, CSII utilizing lispro insulin over three years decreased the HbA1c from 8.4% to 7.7% (Bell and?Ovalle, 2000). Later continuous glucose monitoring (CGM) became available which further improved the efficacy of CSII and almost “closed the loop” (Grunberger et al., 2018).

Today

Thus, from the late 1990s, we recommended to all patients with type 1 diabetes that ideally, they should be treated with CSII, and since 2010 have advocated for the addition of CGM to CSII.

For patients who did not desire to be attached to two systems and who asked which system we would recommend we always recommended CSII with the exception of those who exercised a lot or who had manually intense occupations where we recommended CGM. This recommendation was changed with the availability of the COMISAIR study which showed that in type 1 diabetic patients the improvements in both HbA1c and the reductions in the frequency and severity of hypoglycemia was driven by CGM rather than by the route of insulin delivery (Soupal et al., 2016). This raised the question of whether BBT, in combination with CGM would decrease the need for the use of CSII in the type 1 diabetic subject.

In practice, we have always tried to give patients regular pump rests to preserve their ability to absorb subcutaneous insulin (Berg et al., 2018). Historically many have refused to participate in these pump rests and in those who did participate the vast majority returned to CSII either before or at the designated time of the completion of the pump rest. Their reasons for returning to CSII were almost invariably the deterioration in glycemic control and/or an increase in the frequency and severity of hypoglycemia that occurred with BBT.

However, with the availability of non-peaking ultra-long-acting insulins, particularly insulin degludec, with its low day-to-day variability in insulin levels, we began to see that many patients chose not to return to CSII because during these pump rests there was no change or even a positive change in both the HbA1c and the frequency and severity of hypoglycemia (Marso et al., 2017; Wysham et al., 2017). Recently, in an in house quality audit of these pump rest patients, we documented that of the last 20 patients embarking on a “pump rest” with degludec and aspart insulins utilized in BBT only one returned to CSII even though in that patient the HbA1c was lower with no severe hypoglycemia. Prior to the pump rest severe hypoglycemia was a major problem for this patient and resulted in a loss of driving privileges (Fig. 1).

Figure 1: Schematic representation of Evolution Therapy of Type 1 Diabetes

Of the twenty patients who did not return to CSII the average age was 50.2 years (SD +12.9) with a range of 23 to 68 years. All had documented type 1 diabetes with an average duration 30.1 years (range 11 to 58 years, SD +12.6). Eleven had documented asymptomatic or mildly symptomatic distal symmetrical polyneuropathy, seven had retinopathy (three proliferative), five had ischemic heart disease, three had nephropathy and three had cataracts. The HbA1c on average dropped significantly (p= 0.002) by 0.71% from 8.19% (SD + 1.13) to 7.48% (SD +0.75) with the majority (thirteen of the 20 patients) achieving a lower HbA1c. There was also a non-significant weight gain from 199 to 201 pounds (p= 0.37) with 12 subjects gaining weight and eight subjects losing weight. Since all subjects were on continuous glucose monitoring while on and off CSII there were very few symptomatic hypoglycemic events.

Therefore, the efficacy of the combination of continuous glucose monitoring and long acting “peakless” insulins raises the question of whether the expense of CSII is presently justified in most type 1 diabetic patients. However, due to the emergence of “smart” insulin pumps which have the capability to be combined with rapidly improving continuous glucose monitoring systems effectively closing the loop are now increasing rather than decreasing the use of CSII. These pumps operate almost autonomously and effectively “close the loop” and are increasing rather than decreasing the use of CSII.

Tomorrow and The Near Future

Currently used and soon to be widely utilized, are the hybrid closed-loop systems with automated insulin delivery driven by CGM. The prototype system which became available in 2009 combined the Paradigm Revel insulin pump with continuous glucose monitoring and management software which had the capability to predict both hyperglycemia and hypoglycemia as long as thirty minutes before an event occurred which resulted in better glycemic control compared with BBT (Slover et al., 2012). An extension of this therapy was the addition of the ability to suspend insulin delivery based on low glucose levels. This was assessed in the ASPIRE study where the frequency of nocturnal hypoglycemia was reduced without a significant change in the HbA1c (Weiss et al., 2015). The ability to suspend insulin infusion with hypoglycemia was later augmented by the ability to increase basal insulin infusion when hyperglycemia occurred utilizing the MiniMed 670G which was approved in 2017 in the USA (Messer et al., 2018). However, currently with this system both patients and medical personnel are frustrated by the need for three daily calibrations which usually results in a lesser time “in range” and less time in the auto mode. In addition, the accuracy of the sensor utilized by this system is inferior to Dexcom (Kravarusic and Aleppo, 2020).

A more accurate sensor (the Dexcom G6) is utilized with a hybrid closed-loop algorithm in the T-Slim x2 insulin pump. This combination results in automated corrections of basal insulin to accommodate both hypoglycemia and hyperglycemia and safely and gradually intensifies overnight glycemic control. In addition, hypoglycemia is predicted with an alarm and calibration is not necessary (Brown et al., 2018).

In the near future the MiniMed 780G pump will be able to provide correction boluses, adjust for missed meals and allow for lower glucose targets. This system also extends the time in range resulting in a lower HbA1c (Duffus et al., 2020). Newer systems also hope to incorporate automatic mealtime insulin boluses. In addition, combinations of glucagon and insulin or pramlintide and insulin in pumps combined with continuous glucose monitoring are being developed (El-Khatib et al., 2017; Haidar et al., 2020).

Conclusions

CSII revolutionized insulin therapy by utilizing only short-acting insulin so that steady basal insulin levels were maintained between meals, lessening the frequency of hypoglycemia and lowering the HbA1c to levels that could not be obtained with BBT or other insulin therapies in the type 1 diabetic patient. With shorter-acting insulins the efficacy of CSII improved due to decreases in HbA1c and rate of hypoglycemia. However, with the availability of peakless long-acting insulins the advantage of CSII over BBT diminished. There has been a resurgence in the utilization of CSII due to the availability of systems where CSII is utilized in combination with CGM and closed loop algorithms so that hypoglycemia and hyperglycemia are corrected automatically by varying the basal insulin rate.

References:

Bell DS and Ovalle F. Improved glycemic control with use of continuous subcutaneous insulin infusion compared with multiple insulin injection therapy. Endocr Pract 2000; 6: 357-360.

Bell DS, Ackerson C, Cutter G, Clements RS Jr. Factors associated with discontinuation of continuous subcutaneous insulin infusion. Am J Med Sci 1988; 295: 23-28.

Bell DS. Insulin therapy in diabetes mellitus: how can the currently available injectable insulins be most prudently and efficaciously utilised? Drugs 2007; 67: 1813-1827.

Berg AK, Nørgaard K, Thyssen JP, Zachariae C, Hommel E, Rytter K, Svensson J. Skin Problems Associated with Insulin Pumps and Sensors in Adults with Type 1 Diabetes: A Cross-Sectional Study. Diabetes Technol Ther 2018; 20: 475-482.

Bode B, Weinstein R, Bell D, McGill J, Nadeau D, Raskin P, Davidson J, Henry R, Huang WC, Reinhardt RR. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care 2002; 25: 439-444.

Brown S, Raghinaru D, Emory E, Kovatchev B. First Look at Control-IQ: A New-Generation Automated Insulin Delivery System. Diabetes Care 2018; 41: 2634-2636.

Duffus SH, Ta'ani ZA, Slaughter JC, Niswender KD, Gregory JM. Increased proportion of time in hybrid closed-loop "Auto Mode" is associated with improved glycaemic control for adolescent and young patients with adult type 1 diabetes using the MiniMed 670G insulin pump. Diabetes Obes Metab 2020; 22: 688-693.

El-Khatib FH, Balliro C, Hillard MA, Magyar KL, Ekhlaspour L, Sinha M, Mondesir D, Esmaeili A, Hartigan C, Thompson MJ, Malkani S, Lock JP, Harlan DM, Clinton P, Frank E, Wilson DM, DeSalvo D, Norlander L, Ly T, Buckingham BA, Diner J, Dezube M, Young LA, Goley A, Kirkman MS, Buse JB, Zheng H, Selagamsetty RR, Damiano ER, Russell SJ. Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial. Lancet 2017; 389: 369-380.

Grunberger G, Handelsman Y, Bloomgarden ZT, Fonseca VA, Garber AJ, Haas RA, Roberts VL, Umpierrez GE. American Association of Clinical Endocrinologists and American College of Endocrinology 2018 position on integration of insulin pumps and continuous glucose monitoring in patients with diabetes mellitus. Endocr Pract 2018; 24: 302-308.

Haidar A, Tsoukas MA, Bernier-Twardy S, Yale JF, Rutkowski J, Bossy A, Pytka E, El Fathi A, Strauss N, Legault L. A Novel Dual-Hormone Insulin-and-Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial. Diabetes Care 2020; 43: 597-606.

Kravarusic and Aleppo G. Diabetes Technology Use in Adults with Type 1 and Type 2 Diabetes. Endocrinol Metab Clin North Am 2020; 49: 37-55.

Marso SP, McGuire DK, Zinman B, Poulter NR, Emerson SS, Pieber TR, Pratley RE, Haahr PM, Lange M, Brown-Frandsen K, Moses A, Skibsted S, Kvist K, Buse JB. DEVOTE Study Group. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med 2017; 377: 723-732.

Messer LH, Forlenza GP, Sherr JL, Wadwa RP, Buckingham BA, Weinzimer SA, Maahs DM, Slover RH. Optimizing Hybrid Closed-Loop Therapy in Adolescents and Emerging Adults Using the MiniMed 670G System. Diabetes Care 2018; 41: 789-796.

Slover RH, Welsh JB, Criego A, Weinzimer SA, Willi SM, Wood MA, Tamborlane WV. Effectiveness of sensor-augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study. Pediatr Diabetes 2012; 13: 6-11.

Šoupal J, Petruželková L, Fleka M, Pelcl T, Matoulek M, Da?ková M, Škrha J, Svaina Š, Prázný M. Comparison of Different Treatment Modalities for Type 1 Diabetes, Including Sensor-Augmented Insulin Regimens, in 52 Weeks of Follow-Up: A COMISAIR Study. Diabetes Technol Ther 2016; 18: 532-538.

Tamborlane WV, Sherwin RS, Genel M, Felig P. Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump. N Engl J Med 1979; 300: 573-578.

Weiss R, Garg SK, Bergenstal RM, Klonoff DC, Bode BW, Bailey TS, Thrasher J, Schwartz F, Welsh JB, Kaufman FR. ASPIRE In-Home Study Group. Predictors of Hypoglycemia in the ASPIRE In-Home Study and Effects of Automatic Suspension of Insulin Delivery. J Diabetes Sci Technol 2015; 9: 1016-1020.

Wysham C, Bhargava A, Chaykin L, de la Rosa R, Handelsman Y, Troelsen LN, Kvist K, Norwood P. Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 2 Diabetes: The SWITCH 2 Randomized Clinical Trial. JAMA 2017; 318: 45-56.