Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Using technology to advance type 1 diabetes care among women during the reproductive years and in pregnancy Sarit Polsky, Dominique Giordano, Mary K Voelmle, Rachel Garcetti & Satish K Garg To cite this article: Sarit Polsky, Dominique Giordano, Mary K Voelmle, Rachel Garcetti & Satish K Garg (2016): Using technology to advance type 1 diabetes care among women during the reproductive years and in pregnancy, Postgraduate Medicine, DOI: 10.1080/00325481.2016.1159910 To link to this article: http://dx.doi.org/10.1080/00325481.2016.1159910
Accepted author version posted online: 27 Feb 2016.
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Article views: 1
View related articles
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [New York University]
Date: 01 March 2016, At: 04:43
Publisher: Taylor & Francis Journal: Postgraduate Medicine DOI: 10.1080/00325481.2016.1159910 Article Type: Review
Downloaded by [New York University] at 04:43 01 March 2016
Using technology to advance type 1 diabetes care among women during the reproductive years and in pregnancy
Sarit Polsky Barbara Davis Center for Diabetes 1775 AURORA COURT MAILSTOP A140 , AURORA, Colorado 80045 United States Dominique Giordano Barbara Davis Center for Diabetes AURORA, Colorado United States Mary K Voelmle Barbara Davis Center for Diabetes AURORA, Colorado United States Rachel Garcetti, Barbara Davis Center for Diabetes AURORA, Colorado United States Satish K Garg Barbara Davis Center for Diabetes AURORA, Colorado United States
Corresponding author: Sarit Polsky (email: [email protected])
Running Title: Technology to Advance Diabetes Care in Women
1
Abstract: The prevalence of diabetes is increasing globally. Technology to improve care among individuals with diabetes is constantly being developed. Women living with Type 1 Diabetes Mellitus (T1DM) have unique challenges affecting their glucose control relating to menstrual cycles, pregnancy, and menopause. The purpose of this review is to examine the literature related to the use of technology to help women with T1DM
Downloaded by [New York University] at 04:43 01 March 2016
manage their diabetes during the reproductive years, pregnancy, and beyond. Continuous subcutaneous insulin infusion (CSII) therapy can provider equivalent or better glucose control when compared with multiple daily injections (MDI), with less hypoglycemia, diabetic ketoacidosis, and weight gain. The CSII therapy has features that could help improve glucose control over the menstrual cycle, menopause, and pregnancy, although the most studied of these stages is pregnancy. Continuous glucose monitoring (CGM) can be combined with any insulin delivery system (MDI or CSII) to provide data on glucose values every few minutes and show glucose trends over time. CGM introduction can highlight glucose variability for women with T1DM, may be beneficial during pregnancy, and can reduce hypoglycemia. Sensor-augmented pump therapy and hybrid artificial pancreas (closed-loop) systems are promising tools that improve outcomes among individuals with diabetes. The use of modern technology to improve glucose and metabolic control among menopausal women with diabetes has not been well studied. Internet and phone-based technologies are emerging as important tools that may help with diabetes self-care for women living with diabetes.
2
Keywords: Type 1 diabetes mellitus, women, pregnancy, menopause, technology, insulin pump, continuous glucose monitor, telemedicine, artificial pancreas
Introduction: Diabetes prevalence is increasing globally and now accounts for 415 million diagnosed cases worldwide [1]. The management of Type 1 Diabetes Mellitus (T1DM) has
Downloaded by [New York University] at 04:43 01 March 2016
advanced over several decades with increasing use and better implementation of insulin pump therapy and continuous glucose monitoring [2, 3] and emerging internet tools for diabetes self-management. The prevalence of diabetes is rising worldwide because of increasing incident cases as well as improved survival among people with diabetes [4, 5]. Women face unique challenges with their diabetes care that include glycemic changes during the menstrual cycle [4, 6, 7], adjustments in insulin requirements during pregnancy up to three times pre-pregnancy doses [8, 9], significant alterations in insulin doses in the post-partum period [8, 10], and metabolic influences on glycemia during menopause [11]. As it is important to maintain glycemic control in order to prevent longterm complications of T1DM [12, 13], it is critical to assess all the tools currently available to help women regulate glycemia over the course of many years that have inherent obstacles. Despite the overall improved longevity among people with T1DM [14], recent reports suggest higher mortality rates and risk for vascular events in women with T1DM compared to men [15]. New technologies make it easier to monitor glucose and maintain optimal glycemic control in patients with T1DM. The use of modern technology to help women overcome challenges has been well studied in some areas, but remains undefined in others. The purpose of this review is to examine how 3
advanced technologies can help manage the care of women with T1DM as they transition through the reproductive health years, pregnancy, menopause, and beyond.
Continuous Subcutaneous Insulin Infusion: Continuous Subcutaneous Insulin Infusion (CSII) therapy can be used as an alternative to subcutaneous multiple daily insulin (MDI) injections in individuals with T1DM or
Downloaded by [New York University] at 04:43 01 March 2016
insulin-requiring Type 2 Diabetes Mellitus (T2DM). CSII therapy is effective, safe, and reduces hypoglycemia despite significant reductions in insulin doses [3]. In one survey with over 14,000 respondents from 5 countries in Europe and North America, individuals on CSII therapy reported improved glycemic control, satisfaction with this type of insulin delivery system, and quality of life [16]. A meta-analysis on randomized controlled trials found that compared to MDI therapy, CSII therapy was associated with an improvement in glycated hemoglobin (A1C) and better quality of life in individuals with T1DM [17]. Since the advent of CSII in the 1970s numerous technological advances have been made, such as the introduction of smaller, lighter, and smarter pumps [2]. The basic technology involves the administration of insulin through a catheter or cannula (plastic/steel) inserted in the subcutaneous tissue. In one type of CSII system, the catheter is attached to an external tube that connects it to the insulin pump containing an insulin reservoir. Another available CSII system has a cannula attached to a pod that contains a reservoir of insulin. Patients fill the reservoirs with insulin and change the infusion sets every 2 to 3 days [2] (see Table 1).
4
CSII technology has features that allow flexible insulin dosing for lifestyle changes that may be more difficult to control with MDI. CSII therapy uses rapid-acting insulin analogs to cover both basal and bolus insulin requirements. Rapid-acting insulin is continuously infused subcutaneously to cover basal insulin needs at pre-determined rates, and patients can bolus for meals or high blood glucose levels directly from the insulin pump. An insulin pump is usually programmed to have numerous basal rates infusing different
Downloaded by [New York University] at 04:43 01 March 2016
amounts of insulin throughout the day. This feature is commonly utilized to provide a lower basal rate of insulin overnight, a slightly higher rate in the early morning hours to account for a “Dawn” phenomenon [18], and intermediate rates for daytime use. An insulin pump can also be programmed to have different carbohydrate-to-insulin ratios for each meal, as well as multiple correction factors (sensitivities) and blood glucose targets for day and night. A patient can check a capillary blood glucose level with a glucose meter that can be manually or automatically entered to the pump and based on the carbohydrate amount s/he intends to consume, the insulin pump uses the preprogrammed settings to calculate the bolus amount of insulin needed to cover the meal and above-target glucose (if applicable). The patient can give the full calculated bolus or over-ride to give a different amount of insulin. Insulin boluses can be administered in fractions of a unit (for example, 5.3 units rather than 5 or 6 units). Advanced features of CSII therapy include the ability to provide “dual wave” or “square wave” boluses (a portion of the full meal bolus up front and the remainder over a designated amount of time) and to use a temporary basal rate that is decreased (such as to prevent hypoglycemia with physical activity) or increased (such as to prevent hyperglycemia from steroid use) for a short period of time. It is important to note two disadvantages of 5
CSII therapy: First, CSII therapy may increase the rate of diabetic ketoacidosis over MDI if insulin delivery is interrupted (such as from a clogged infusion set, infusion-site issue, or pump malfunction) [19, 20], however data supports the contrary [21, 22]. Thus, anyone using CSII should have a well-delineated back-up plan, should the insulin pump malfunction or fail (such as changing the infusion set, changing insulin, and promptly addressing insulin pump alarms for occlusions and no insulin delivery).
Downloaded by [New York University] at 04:43 01 March 2016
Second, the insulin pump and its supplies are more expensive than MDI therapy [20, 23].
Continuous Subcutaneous Insulin Therapy During the Reproductive Years: The glucose variability that occurs over a menstrual cycle [6, 7] could be one potential target for CSII therapy. Though few studies have directly measured glucose levels during menstrual cycles of women with T1DM, most women experience some impaired glucose control. Many women experience luteal phase hyperglycemia that remains consistent from cycle to cycle [6, 7]. To our knowledge, no studies have examined how CSII therapy could help alleviate the glycemic variability that occurs during menstrual cycles, though insulin pumps offer features that could be beneficial. First, one can program two different basal patterns that could be used during the follicular and luteal phases respectively for women with a consistent pattern of hyper- or hypoglycemia during one of these phases. Second, one could use a temporary basal setting to alter the infused insulin rate for the pre-menstrual period, wherein women often experience hyperglycemia, or during menses when some women experience hypoglycemia.
6
Continuous Subcutaneous Insulin Therapy Antepartum and Postpartum: Pregnancy and the postpartum period present unique challenges to optimizing glucose control in women with T1DM. The first trimester of pregnancy is most commonly affected by relative insulin sensitivity with a particularly high risk of nocturnal hypoglycemia [8, 10]. Beginning from 14 to 20 weeks of gestation, relative insulin resistance ensues as a result of increased placental-fetal glucose demands, maternal
Downloaded by [New York University] at 04:43 01 March 2016
and placental hormonal influences, and free fatty acid production [8, 9]. The cessation of placental hormonal influences immediately post-delivery will decrease insulin requirements by as much as ~40% (35-90%) of pre-pregnancy doses [8, 10, 24]. Insulin requirements remain low, even lower than pre-pregnancy, with continued breastfeeding [10, 24, 25]. Continued tight, well-controlled glucose levels throughout the pregnancy are important for preventing maternal and fetal complications [8, 26, 27]. As such, it is recommended that healthcare providers remain in frequent contact with women throughout gestation and the early postpartum period to adjust insulin doses as needed for each phase of the pregnancy.
Improved glycemic control prior to and during gestation with intensive insulin therapy has improved perinatal outcomes over several decades [23], as has the use of rapidacting insulin analogues [10]. While it is optimal to initiate CSII therapy prior to conception, women who have proper education and support can start using this technology during a pregnancy [28]. Insulin pump therapy has been shown to reduce the frequency of hypoglycemic episodes in pregnancy [28]. There is a paucity of outcomes data comparing CSII and MDI therapies in pregnancy, and most studies were 7
not randomized controlled trials. Although studies are lacking, CSII therapy is widely used among clinicians treating women with T1DM associated with pregnancy [23, 29]. The small studies that have been done report that CSII therapy has been found to be comparable to MDI in pregnancy with respect to metabolic glucose control, maternal outcomes, and fetal outcomes [20, 30].
Downloaded by [New York University] at 04:43 01 March 2016
There are several possible advantages of CSII therapy for selected women with T1DM who are pregnant. The frequent need to adjust insulin doses throughout the pregnancy can be accommodated easily with CSII therapy. In one study with women with wellcontrolled T1DM already on CSII therapy, insulin doses increased nearly threefold over the course of the pregnancy, with a much larger proportion of this increase being from bolus insulin than basal insulin [31]. The morning hours from 5 am to 9 am required the largest increases to basal and bolus insulin [31], thus having the flexibility to increase a basal rate at one particular time of day is an advantage of CSII therapy over MDI. In addition, as a woman may require multiple carbohydrate-to-insulin ratios that change frequently over several months, programming the ratios into an insulin pump can reduce the burden of having to remember each change.
Another potential benefit of CSII therapy in pregnancy is the ability to achieve a better A1C without significant hypoglycemia. In a recent Cochrane review of CSII versus MDI therapy of 23 randomized controlled trials in non-pregnant individuals, the average A1C was statistically significantly lower in the CSII groups by 0.3% with reductions in severe hypoglycemia [3]. A 2007 meta-analysis found that among small randomized controlled 8
trials of CSII versus MDI in pregnancy among women with T1DM and T2DM, the glycemic control was equivalent between groups with slightly more frequent hypoglycemia in the CSII group (22 vs 19%, respectively) [20]. Since then, a retrospective study at 10 Italian sites found an earlier and more robust improvement in A1C levels during gestation in a CSII group (n=100) without any increase in severe hypoglycemic events, compared to a MDI group using glargine (n=44) [32]. A large
Downloaded by [New York University] at 04:43 01 March 2016
retrospective observational study at 3 sites examined outcomes among pregnancies in women on MDI therapy (n=258) and on CSII therapy (n=129), and found that A1C was significantly lower among women using CSII therapy in multivariate analysis but rates of severe hypoglycemia were similar between groups [33]. Ringholm et al initiated an educational intervention to reduce severe hypoglycemia in pregnancy and found that while both MDI and CSII groups benefited, there was significantly less severe hypoglycemia in the CSII group [34]. There are several possible explanations for how CSII therapy decreases hypoglycemia. Basal rates can be reduced during the night-time hours, which could benefit women particularly in the first trimester when the nocturnal hypoglycemia risk is highest. A woman can prevent activity-related hypoglycemia by starting a temporary basal rate to reduce her basal insulin infusion over a predesignated time period. . . If a woman wants to correct a high glucose value with a bolus shortly after a previous bolus was already given, the insulin pump takes the active insulin on board into account and recommends a lower bolus amount, which can prevent hypoglycemia from insulin “stacking” (full boluses of rapid-acting insulin being given multiple times within the duration of action of the insulin, about 4 hours). In
9
summary, CSII therapy appears to improve glucose control without any increase in severe hypoglycemic episodes during pregnancy with T1DM.
Of note, CSII therapy utilizes rapid-acting insulin analogues. Insulin Lispro and Aspart have been evaluated in pregnancy among women with pre-existing diabetes and gestational diabetes [35]. In one randomized controlled trial, Aspart use was compared
Downloaded by [New York University] at 04:43 01 March 2016
to regular human insulin in 322 pregnant women with T1DM [36]. Women in the Aspart group had significantly fewer episodes of severe hypoglycemia, lower post-prandial hyperglycemia, and comparable fetal outcomes [36, 37]. There are more studies on the use of insulin Lispro in pregnancy, although many are uncontrolled trials and retrospective reviews [35]. In most studies, Lispro appears safe with respect to maternal and fetal outcomes and may reduce maternal severe hypoglycemia [35]. One metaanalysis of women with pre-existing and gestational diabetes found that Lispro significantly decreased severe maternal hypoglycemia compared to regular or NPH insulin use, but increased the incidence of large for gestational age babies compared to regular insulin use [38]. There are no studies on the use of Glulisine in pregnancy. Of note, earlier prandial insulin bolusing is required in late gestation because of delayed glucose disposal that contributes to postprandial hyperglycemia in the third trimester [39]. Goudie et al also found that time-to-peak Aspart concentration was 1.6% slower with each week of pregnancy such that absorption was approximately 50% slower in the 38th week of gestation compared to the 8th [40].
Continuous Glucose Monitoring: 10
Continuous Glucose Monitor (CGM) Use: Continuous glucose monitor (CGM) systems contain sensors inserted into the interstitial fluid to continuously measure interstitial glucose values [41]. Patients change the sensor once a week. Many real time CGMs have the capability to sample interstitial glucose values every minute, though the glucose data are only shown every 5 minutes, transmit the values to a receiver for viewing, and thus provide glucose trends over time [41].
Downloaded by [New York University] at 04:43 01 March 2016
CGMs may improve glycemic control by better representing glucose trends as compared to self-monitoring of blood glucose (SMBG) [42]. CGM use lowers A1C without an increase in hypoglycemia [43-45]. In a study performed by the Juvenile Diabetes Research Foundation, A1C was significantly decreased in patients 25 years and older with the use of a CGM for 6 or more days per week. Furthermore, there was no significant increase in the number of hypoglycemic episodes [43]. Ludvigsson et al found that patients using a CGM had a 2-5 times better detection rate of hypoglycemia [12]. Pickup et al performed a meta-analysis of 6 randomized controlled trials and found that among 449 individuals with T1DM using CGM the mean overall reduction in A1C was 0.3% compared to 443 individuals using the same insulin delivery system but monitoring with SMBG, with the greatest effect being seen in individuals with the highest baseline A1C (estimated A1C reduction of 0.9%) and with more frequent sensor usage [44]. There was a 23% reduction in median exposure to hypoglycemia with the CGM use compared to the SMBG group [44]. Evidence supports the safe, effective, and beneficial use of CGMs to help in lowering A1C and preventing hypoglycemia. There are currently multiple CGM systems available around the world (see Table 2). Some CGM systems can use Bluetooth technology to wirelessly send data to Apple products 11
such as iPhones and iPods, while the Dexcom CGM also allows one to share data with family and friends who have compatible devices. CGM therapy can be used with any insulin pump or with MDI. Standardization of data presentation for patients and providers should be one of the top priorities such that use of new technology, both pumps and sensors, can be easily implemented with better health outcomes. As the CGM technology is expanding there are various ways it can be applied specifically to
Downloaded by [New York University] at 04:43 01 March 2016
women.
Continuous Glucose Monitor Use During the Reproductive Years: There is a paucity of studies that have directly evaluated glucose levels during the menstrual cycles of women with T1DM. In non-CGM studies, some women with T1DM exhibit a decrease in insulin sensitivity and increase in hyperglycemia during the luteal phase of the menstrual cycle [46, 47] and during menstruation there is a variable degree of impaired glucose control [48]. CGM studies examined the fluctuations in glucose over the menstrual cycle.
Goldner et al used CGMs to demonstrate a reproducible,
individually consistent, and significant increase in hyperglycemia during the luteal phase in 2 out of the 4 subjects [6]. In a study with 12 women with T1DM using CGMs, 9 women had consistent changes in insulin sensitivity in 2 out of the 3 menstrual cycles studied while 3 did not [49]. Barata et al conducted a study with 6 women with T1DM who wore CGM units for 72 hours for 5 days each during the early follicular and luteal phases. All 6 women had a reduced percentage of hypoglycemia and increased percentage of hyperglycemia in the luteal phase [7]. Hormones may in part account for these changes. Estrogen, which is higher in the luteal phase, has been associated with 12
decreased insulin sensitivity, while progesterone has been implicated in insulin resistance [6]. In addition glucose variability may change with advancing age [50, 51]. CGM can be a useful tool to identify glycemic patterns throughout the menstrual cycle and adjust insulin as needed for women with T1DM.
Continuous Glucose Monitor Use Antepartum and Postpartum:
Downloaded by [New York University] at 04:43 01 March 2016
CGM use can be beneficial in pregnancy. Currently the American Diabetes Association suggests that some high-risk pregnant women with T1DM use a CGM [52]. Pregnant women with T1DM and hemoglobin A1Cs
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Using technology to advance type 1 diabetes care among women during the reproductive years and in pregnancy Sarit Polsky, Dominique Giordano, Mary K Voelmle, Rachel Garcetti & Satish K Garg To cite this article: Sarit Polsky, Dominique Giordano, Mary K Voelmle, Rachel Garcetti & Satish K Garg (2016): Using technology to advance type 1 diabetes care among women during the reproductive years and in pregnancy, Postgraduate Medicine, DOI: 10.1080/00325481.2016.1159910 To link to this article: http://dx.doi.org/10.1080/00325481.2016.1159910
Accepted author version posted online: 27 Feb 2016.
Submit your article to this journal
Article views: 1
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [New York University]
Date: 01 March 2016, At: 04:43
Publisher: Taylor & Francis Journal: Postgraduate Medicine DOI: 10.1080/00325481.2016.1159910 Article Type: Review
Downloaded by [New York University] at 04:43 01 March 2016
Using technology to advance type 1 diabetes care among women during the reproductive years and in pregnancy
Sarit Polsky Barbara Davis Center for Diabetes 1775 AURORA COURT MAILSTOP A140 , AURORA, Colorado 80045 United States Dominique Giordano Barbara Davis Center for Diabetes AURORA, Colorado United States Mary K Voelmle Barbara Davis Center for Diabetes AURORA, Colorado United States Rachel Garcetti, Barbara Davis Center for Diabetes AURORA, Colorado United States Satish K Garg Barbara Davis Center for Diabetes AURORA, Colorado United States
Corresponding author: Sarit Polsky (email: [email protected])
Running Title: Technology to Advance Diabetes Care in Women
1
Abstract: The prevalence of diabetes is increasing globally. Technology to improve care among individuals with diabetes is constantly being developed. Women living with Type 1 Diabetes Mellitus (T1DM) have unique challenges affecting their glucose control relating to menstrual cycles, pregnancy, and menopause. The purpose of this review is to examine the literature related to the use of technology to help women with T1DM
Downloaded by [New York University] at 04:43 01 March 2016
manage their diabetes during the reproductive years, pregnancy, and beyond. Continuous subcutaneous insulin infusion (CSII) therapy can provider equivalent or better glucose control when compared with multiple daily injections (MDI), with less hypoglycemia, diabetic ketoacidosis, and weight gain. The CSII therapy has features that could help improve glucose control over the menstrual cycle, menopause, and pregnancy, although the most studied of these stages is pregnancy. Continuous glucose monitoring (CGM) can be combined with any insulin delivery system (MDI or CSII) to provide data on glucose values every few minutes and show glucose trends over time. CGM introduction can highlight glucose variability for women with T1DM, may be beneficial during pregnancy, and can reduce hypoglycemia. Sensor-augmented pump therapy and hybrid artificial pancreas (closed-loop) systems are promising tools that improve outcomes among individuals with diabetes. The use of modern technology to improve glucose and metabolic control among menopausal women with diabetes has not been well studied. Internet and phone-based technologies are emerging as important tools that may help with diabetes self-care for women living with diabetes.
2
Keywords: Type 1 diabetes mellitus, women, pregnancy, menopause, technology, insulin pump, continuous glucose monitor, telemedicine, artificial pancreas
Introduction: Diabetes prevalence is increasing globally and now accounts for 415 million diagnosed cases worldwide [1]. The management of Type 1 Diabetes Mellitus (T1DM) has
Downloaded by [New York University] at 04:43 01 March 2016
advanced over several decades with increasing use and better implementation of insulin pump therapy and continuous glucose monitoring [2, 3] and emerging internet tools for diabetes self-management. The prevalence of diabetes is rising worldwide because of increasing incident cases as well as improved survival among people with diabetes [4, 5]. Women face unique challenges with their diabetes care that include glycemic changes during the menstrual cycle [4, 6, 7], adjustments in insulin requirements during pregnancy up to three times pre-pregnancy doses [8, 9], significant alterations in insulin doses in the post-partum period [8, 10], and metabolic influences on glycemia during menopause [11]. As it is important to maintain glycemic control in order to prevent longterm complications of T1DM [12, 13], it is critical to assess all the tools currently available to help women regulate glycemia over the course of many years that have inherent obstacles. Despite the overall improved longevity among people with T1DM [14], recent reports suggest higher mortality rates and risk for vascular events in women with T1DM compared to men [15]. New technologies make it easier to monitor glucose and maintain optimal glycemic control in patients with T1DM. The use of modern technology to help women overcome challenges has been well studied in some areas, but remains undefined in others. The purpose of this review is to examine how 3
advanced technologies can help manage the care of women with T1DM as they transition through the reproductive health years, pregnancy, menopause, and beyond.
Continuous Subcutaneous Insulin Infusion: Continuous Subcutaneous Insulin Infusion (CSII) therapy can be used as an alternative to subcutaneous multiple daily insulin (MDI) injections in individuals with T1DM or
Downloaded by [New York University] at 04:43 01 March 2016
insulin-requiring Type 2 Diabetes Mellitus (T2DM). CSII therapy is effective, safe, and reduces hypoglycemia despite significant reductions in insulin doses [3]. In one survey with over 14,000 respondents from 5 countries in Europe and North America, individuals on CSII therapy reported improved glycemic control, satisfaction with this type of insulin delivery system, and quality of life [16]. A meta-analysis on randomized controlled trials found that compared to MDI therapy, CSII therapy was associated with an improvement in glycated hemoglobin (A1C) and better quality of life in individuals with T1DM [17]. Since the advent of CSII in the 1970s numerous technological advances have been made, such as the introduction of smaller, lighter, and smarter pumps [2]. The basic technology involves the administration of insulin through a catheter or cannula (plastic/steel) inserted in the subcutaneous tissue. In one type of CSII system, the catheter is attached to an external tube that connects it to the insulin pump containing an insulin reservoir. Another available CSII system has a cannula attached to a pod that contains a reservoir of insulin. Patients fill the reservoirs with insulin and change the infusion sets every 2 to 3 days [2] (see Table 1).
4
CSII technology has features that allow flexible insulin dosing for lifestyle changes that may be more difficult to control with MDI. CSII therapy uses rapid-acting insulin analogs to cover both basal and bolus insulin requirements. Rapid-acting insulin is continuously infused subcutaneously to cover basal insulin needs at pre-determined rates, and patients can bolus for meals or high blood glucose levels directly from the insulin pump. An insulin pump is usually programmed to have numerous basal rates infusing different
Downloaded by [New York University] at 04:43 01 March 2016
amounts of insulin throughout the day. This feature is commonly utilized to provide a lower basal rate of insulin overnight, a slightly higher rate in the early morning hours to account for a “Dawn” phenomenon [18], and intermediate rates for daytime use. An insulin pump can also be programmed to have different carbohydrate-to-insulin ratios for each meal, as well as multiple correction factors (sensitivities) and blood glucose targets for day and night. A patient can check a capillary blood glucose level with a glucose meter that can be manually or automatically entered to the pump and based on the carbohydrate amount s/he intends to consume, the insulin pump uses the preprogrammed settings to calculate the bolus amount of insulin needed to cover the meal and above-target glucose (if applicable). The patient can give the full calculated bolus or over-ride to give a different amount of insulin. Insulin boluses can be administered in fractions of a unit (for example, 5.3 units rather than 5 or 6 units). Advanced features of CSII therapy include the ability to provide “dual wave” or “square wave” boluses (a portion of the full meal bolus up front and the remainder over a designated amount of time) and to use a temporary basal rate that is decreased (such as to prevent hypoglycemia with physical activity) or increased (such as to prevent hyperglycemia from steroid use) for a short period of time. It is important to note two disadvantages of 5
CSII therapy: First, CSII therapy may increase the rate of diabetic ketoacidosis over MDI if insulin delivery is interrupted (such as from a clogged infusion set, infusion-site issue, or pump malfunction) [19, 20], however data supports the contrary [21, 22]. Thus, anyone using CSII should have a well-delineated back-up plan, should the insulin pump malfunction or fail (such as changing the infusion set, changing insulin, and promptly addressing insulin pump alarms for occlusions and no insulin delivery).
Downloaded by [New York University] at 04:43 01 March 2016
Second, the insulin pump and its supplies are more expensive than MDI therapy [20, 23].
Continuous Subcutaneous Insulin Therapy During the Reproductive Years: The glucose variability that occurs over a menstrual cycle [6, 7] could be one potential target for CSII therapy. Though few studies have directly measured glucose levels during menstrual cycles of women with T1DM, most women experience some impaired glucose control. Many women experience luteal phase hyperglycemia that remains consistent from cycle to cycle [6, 7]. To our knowledge, no studies have examined how CSII therapy could help alleviate the glycemic variability that occurs during menstrual cycles, though insulin pumps offer features that could be beneficial. First, one can program two different basal patterns that could be used during the follicular and luteal phases respectively for women with a consistent pattern of hyper- or hypoglycemia during one of these phases. Second, one could use a temporary basal setting to alter the infused insulin rate for the pre-menstrual period, wherein women often experience hyperglycemia, or during menses when some women experience hypoglycemia.
6
Continuous Subcutaneous Insulin Therapy Antepartum and Postpartum: Pregnancy and the postpartum period present unique challenges to optimizing glucose control in women with T1DM. The first trimester of pregnancy is most commonly affected by relative insulin sensitivity with a particularly high risk of nocturnal hypoglycemia [8, 10]. Beginning from 14 to 20 weeks of gestation, relative insulin resistance ensues as a result of increased placental-fetal glucose demands, maternal
Downloaded by [New York University] at 04:43 01 March 2016
and placental hormonal influences, and free fatty acid production [8, 9]. The cessation of placental hormonal influences immediately post-delivery will decrease insulin requirements by as much as ~40% (35-90%) of pre-pregnancy doses [8, 10, 24]. Insulin requirements remain low, even lower than pre-pregnancy, with continued breastfeeding [10, 24, 25]. Continued tight, well-controlled glucose levels throughout the pregnancy are important for preventing maternal and fetal complications [8, 26, 27]. As such, it is recommended that healthcare providers remain in frequent contact with women throughout gestation and the early postpartum period to adjust insulin doses as needed for each phase of the pregnancy.
Improved glycemic control prior to and during gestation with intensive insulin therapy has improved perinatal outcomes over several decades [23], as has the use of rapidacting insulin analogues [10]. While it is optimal to initiate CSII therapy prior to conception, women who have proper education and support can start using this technology during a pregnancy [28]. Insulin pump therapy has been shown to reduce the frequency of hypoglycemic episodes in pregnancy [28]. There is a paucity of outcomes data comparing CSII and MDI therapies in pregnancy, and most studies were 7
not randomized controlled trials. Although studies are lacking, CSII therapy is widely used among clinicians treating women with T1DM associated with pregnancy [23, 29]. The small studies that have been done report that CSII therapy has been found to be comparable to MDI in pregnancy with respect to metabolic glucose control, maternal outcomes, and fetal outcomes [20, 30].
Downloaded by [New York University] at 04:43 01 March 2016
There are several possible advantages of CSII therapy for selected women with T1DM who are pregnant. The frequent need to adjust insulin doses throughout the pregnancy can be accommodated easily with CSII therapy. In one study with women with wellcontrolled T1DM already on CSII therapy, insulin doses increased nearly threefold over the course of the pregnancy, with a much larger proportion of this increase being from bolus insulin than basal insulin [31]. The morning hours from 5 am to 9 am required the largest increases to basal and bolus insulin [31], thus having the flexibility to increase a basal rate at one particular time of day is an advantage of CSII therapy over MDI. In addition, as a woman may require multiple carbohydrate-to-insulin ratios that change frequently over several months, programming the ratios into an insulin pump can reduce the burden of having to remember each change.
Another potential benefit of CSII therapy in pregnancy is the ability to achieve a better A1C without significant hypoglycemia. In a recent Cochrane review of CSII versus MDI therapy of 23 randomized controlled trials in non-pregnant individuals, the average A1C was statistically significantly lower in the CSII groups by 0.3% with reductions in severe hypoglycemia [3]. A 2007 meta-analysis found that among small randomized controlled 8
trials of CSII versus MDI in pregnancy among women with T1DM and T2DM, the glycemic control was equivalent between groups with slightly more frequent hypoglycemia in the CSII group (22 vs 19%, respectively) [20]. Since then, a retrospective study at 10 Italian sites found an earlier and more robust improvement in A1C levels during gestation in a CSII group (n=100) without any increase in severe hypoglycemic events, compared to a MDI group using glargine (n=44) [32]. A large
Downloaded by [New York University] at 04:43 01 March 2016
retrospective observational study at 3 sites examined outcomes among pregnancies in women on MDI therapy (n=258) and on CSII therapy (n=129), and found that A1C was significantly lower among women using CSII therapy in multivariate analysis but rates of severe hypoglycemia were similar between groups [33]. Ringholm et al initiated an educational intervention to reduce severe hypoglycemia in pregnancy and found that while both MDI and CSII groups benefited, there was significantly less severe hypoglycemia in the CSII group [34]. There are several possible explanations for how CSII therapy decreases hypoglycemia. Basal rates can be reduced during the night-time hours, which could benefit women particularly in the first trimester when the nocturnal hypoglycemia risk is highest. A woman can prevent activity-related hypoglycemia by starting a temporary basal rate to reduce her basal insulin infusion over a predesignated time period. . . If a woman wants to correct a high glucose value with a bolus shortly after a previous bolus was already given, the insulin pump takes the active insulin on board into account and recommends a lower bolus amount, which can prevent hypoglycemia from insulin “stacking” (full boluses of rapid-acting insulin being given multiple times within the duration of action of the insulin, about 4 hours). In
9
summary, CSII therapy appears to improve glucose control without any increase in severe hypoglycemic episodes during pregnancy with T1DM.
Of note, CSII therapy utilizes rapid-acting insulin analogues. Insulin Lispro and Aspart have been evaluated in pregnancy among women with pre-existing diabetes and gestational diabetes [35]. In one randomized controlled trial, Aspart use was compared
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to regular human insulin in 322 pregnant women with T1DM [36]. Women in the Aspart group had significantly fewer episodes of severe hypoglycemia, lower post-prandial hyperglycemia, and comparable fetal outcomes [36, 37]. There are more studies on the use of insulin Lispro in pregnancy, although many are uncontrolled trials and retrospective reviews [35]. In most studies, Lispro appears safe with respect to maternal and fetal outcomes and may reduce maternal severe hypoglycemia [35]. One metaanalysis of women with pre-existing and gestational diabetes found that Lispro significantly decreased severe maternal hypoglycemia compared to regular or NPH insulin use, but increased the incidence of large for gestational age babies compared to regular insulin use [38]. There are no studies on the use of Glulisine in pregnancy. Of note, earlier prandial insulin bolusing is required in late gestation because of delayed glucose disposal that contributes to postprandial hyperglycemia in the third trimester [39]. Goudie et al also found that time-to-peak Aspart concentration was 1.6% slower with each week of pregnancy such that absorption was approximately 50% slower in the 38th week of gestation compared to the 8th [40].
Continuous Glucose Monitoring: 10
Continuous Glucose Monitor (CGM) Use: Continuous glucose monitor (CGM) systems contain sensors inserted into the interstitial fluid to continuously measure interstitial glucose values [41]. Patients change the sensor once a week. Many real time CGMs have the capability to sample interstitial glucose values every minute, though the glucose data are only shown every 5 minutes, transmit the values to a receiver for viewing, and thus provide glucose trends over time [41].
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CGMs may improve glycemic control by better representing glucose trends as compared to self-monitoring of blood glucose (SMBG) [42]. CGM use lowers A1C without an increase in hypoglycemia [43-45]. In a study performed by the Juvenile Diabetes Research Foundation, A1C was significantly decreased in patients 25 years and older with the use of a CGM for 6 or more days per week. Furthermore, there was no significant increase in the number of hypoglycemic episodes [43]. Ludvigsson et al found that patients using a CGM had a 2-5 times better detection rate of hypoglycemia [12]. Pickup et al performed a meta-analysis of 6 randomized controlled trials and found that among 449 individuals with T1DM using CGM the mean overall reduction in A1C was 0.3% compared to 443 individuals using the same insulin delivery system but monitoring with SMBG, with the greatest effect being seen in individuals with the highest baseline A1C (estimated A1C reduction of 0.9%) and with more frequent sensor usage [44]. There was a 23% reduction in median exposure to hypoglycemia with the CGM use compared to the SMBG group [44]. Evidence supports the safe, effective, and beneficial use of CGMs to help in lowering A1C and preventing hypoglycemia. There are currently multiple CGM systems available around the world (see Table 2). Some CGM systems can use Bluetooth technology to wirelessly send data to Apple products 11
such as iPhones and iPods, while the Dexcom CGM also allows one to share data with family and friends who have compatible devices. CGM therapy can be used with any insulin pump or with MDI. Standardization of data presentation for patients and providers should be one of the top priorities such that use of new technology, both pumps and sensors, can be easily implemented with better health outcomes. As the CGM technology is expanding there are various ways it can be applied specifically to
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women.
Continuous Glucose Monitor Use During the Reproductive Years: There is a paucity of studies that have directly evaluated glucose levels during the menstrual cycles of women with T1DM. In non-CGM studies, some women with T1DM exhibit a decrease in insulin sensitivity and increase in hyperglycemia during the luteal phase of the menstrual cycle [46, 47] and during menstruation there is a variable degree of impaired glucose control [48]. CGM studies examined the fluctuations in glucose over the menstrual cycle.
Goldner et al used CGMs to demonstrate a reproducible,
individually consistent, and significant increase in hyperglycemia during the luteal phase in 2 out of the 4 subjects [6]. In a study with 12 women with T1DM using CGMs, 9 women had consistent changes in insulin sensitivity in 2 out of the 3 menstrual cycles studied while 3 did not [49]. Barata et al conducted a study with 6 women with T1DM who wore CGM units for 72 hours for 5 days each during the early follicular and luteal phases. All 6 women had a reduced percentage of hypoglycemia and increased percentage of hyperglycemia in the luteal phase [7]. Hormones may in part account for these changes. Estrogen, which is higher in the luteal phase, has been associated with 12
decreased insulin sensitivity, while progesterone has been implicated in insulin resistance [6]. In addition glucose variability may change with advancing age [50, 51]. CGM can be a useful tool to identify glycemic patterns throughout the menstrual cycle and adjust insulin as needed for women with T1DM.
Continuous Glucose Monitor Use Antepartum and Postpartum:
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CGM use can be beneficial in pregnancy. Currently the American Diabetes Association suggests that some high-risk pregnant women with T1DM use a CGM [52]. Pregnant women with T1DM and hemoglobin A1Cs
