Background An increase in newly diagnosed type 1 diabetes (T1D) has been posited during the COVID-19 pandemic, but data are conflicting. We aimed to determine trends in newly diagnosed T1D and severity of presentation at diagnosis for pediatric and adolescent patients during COVID-19 (2020) as compared to the previous year (2019) in a multi-center analysis across the United States. Methods This retrospective study from seven centers in the T1D Exchange Quality Improvement Collaborative (T1DX-QI) included data on new onset T1D diagnosis and proportion in DKA at diagnosis from January 1 to December 31, 2020, compared to the prior year. Chi-square tests were used to compare differences in patient characteristics during the pandemic period compared to the prior year. Results Across seven sites, there were 1399 newly diagnosed T1D patients in 2020, compared to 1277 in 2019 (p = 0.007). A greater proportion of newly diagnosed patients presented in DKA in 2020 compared to 2019 (599/1399(42.8%) vs. 493/1277(38.6%), p = 0.02), with a higher proportion presenting with severe DKA (p = 0.01) as characterized by a pH <7.1 and/or bicarbonate of <5 mmol/L. Monthly data trends demonstrated a higher number of new T1D diagnoses over the spring and summer months (March to September) of 2020 compared to 2019 (p < 0.001). Conclusions We found an increase in newly diagnosed T1D and a greater proportion presenting in DKA at diagnosis during the COVID-19 pandemic compared to the prior year. Future longitudinal studies are needed to confirm these findings with population level data and determine the long-term impact of COVID-19 on diabetes trends.

Hypoglycemia is an obstacle in achieving optimal glycemic control for patients with type 1 diabetes (T1D). Automated insulin delivery (i.e., closed-loop systems) has the potential to reduce hypoglycemia. The first step in creating a closed-loop system is suspending insulin delivery when sensor glucose values are below the prespecified threshold, technology known as low glucose suspend (LGS). LGS systems reduce the severity and duration of hypoglycemia in patients with T1D. Future research has focused on suspending insulin delivery in anticipation of hypoglycemia (prediction) and improving automated insulin delivery to further reduce hypo- and hyperglycemia and thus improving quality of life.

ket.A biosimilar of Sanofi's popular insulin Lantus was approved for use in the European Union in 2014 but was initially delayed for 2 more years by a lawsuit in the United States. 6Now that the biosimilar product, Basaglar, has finally hit the market, its price is only minimally lower than the original brand. 7 The same insulin pen that retails for $140 in the United States costs less than $15 in Germany and Canada. 8 The US insurance system-private and public-does not cut people with chronic disease a break but instead tends to penalize them.People with type 1 diabetes are people who drew a short straw in the disease lottery.Most other developed countries have concluded that their citizens should therefore not be subject to copays or high deductibles."If you have a chronic disease, you shouldn't be burdened by the cost," York F. Zöllner, a professor of health economics at Hamburg University of Applied Sciences, told me in an interview for the New York Times before explaining the German approach, in which out-of-pocket contributions for insulin are less than $100 per year. 9Until very recently, the disease foundations (JDRF and the American Diabetes Association among them), as well as many diabetes patient groups, did not protest much as the prices rose, in part likely because so many receive funding from pharmaceutical companies.Extreme prices can lead to extreme solutions.A 29-year-old student in Missouri with diabetes whom I interviewed for my book 10 told me that she would only consider doctoral programs outside of the United States."My one goal in life has been to move to Europe so I don't have to pay these staggering prices just to survive," she said.But others-that 25%-will quietly skimp on their insulin, taking less than they need but more, perhaps, than they can really afford.Some of them will die.

Background: The majority of therapies have generally targeted fasting glucose control, and current mealtime insulin therapies have longer time action profiles than that of endogenously secreted insulin. The primary purpose of this study was to assess both glucose time-in-range (TIR: 70-180mg/dL) and postprandial glucose excursions (PPGE) in 1-4h using a real-time continuous glucose monitor (CGM) with Technosphere insulin (TI) versus insulin aspart in patients with type 1 diabetes (T1DM) on multiple daily injections (MDI). Research Design and Methods: This pilot, investigator-led, collaborative, open-label, multicenter, clinical research trial enrolled 60 patients with T1DM with HbA1c levels 6.5% and 10%. Individuals were randomized to treatment with titrated TI (n=26) or titrated insulin aspart (n=34), stratified by baseline HbA1c levels (8% or >8%). All were required to wear a real-time CGM throughout the trial. All patients in the TI group were advised to take supplemental inhalations at 1 and 2h after meals if indicated based on postprandial glucose (PPG) values. The coprimary outcomes were assessed both in the full intent-to-treat population and in those individuals randomized to TI who were compliant with supplemental doses 90% of the time (n=15). The CGM data were analyzed using linear regression models. Results: Overall, those treated with TI versus aspart achieved comparable TIR, but less time spent in hypoglycemia (<60 and <50mg/dL, both P<0.05). In the TI-compliant group (n=15), TIR was significantly greater (62.5%2.6% vs. 53.8%1.7%, P=0.009) and time in hyperglycemia >180mg/dL was lower (34.2%+/- 2.7% vs. 41.0%+/- 1.7%, P=0.045) as compared with the aspart group. PPG was also significantly lower in the TI cohort at 60 and 90min postmeal, and PPGE were lower in the TI-compliant group as compared with the aspart group over 1-4-h postmeal (P<0.05). In addition, there was weight gain in the aspart group compared with weight loss in the TI group (P=0.006) despite higher prandial TI insulin dose. Conclusions: We conclude that using TI appropriately at mealtimes with supplemental dosing improves prandial glucose (TIR and 1-4h) control without any increase in time in hypoglycemia or weight gain in patients with T1DM on MDI. The study results support a larger study using a treat-to-target design to confirm these findings. Clinical trial reg. no. NCT03143816, clinicaltrials.gov.

Purpose of review To identify and evaluate the recent trials of sodium-glucose cotransporter 1 and 2 (SGLT1 and SGLT2, respectively) inhibitor use in patients with type 1 diabetes (T1D). SGLT-2 inhibitors have been approved by the Food and Drug Administration (FDA) and are effectively used in the treatment of type 2 diabetes (T2D). However, many studies (phase I–III) have validated their effects beyond improving glycemic control and have shown potential adjunctive use in adult patients with T1D treated with insulin therapy alone. Recent findings A review of the literature showed that there is a potential adjunctive role for the SGLT inhibitors with insulin in T1D for improving glycemic control. The inTandem3 (A phase III study to evaluate the safety of sotagliflozin in patients with type 1 diabetes who have inadequate glycemic control with insulin therapy alone) and the DEPICT-1 (Dapagliflozin evaluation in patients with inadequately controlled type 1 diabetes) trials demonstrated significant benefits in adult patients with T1D. The SGLT inhibitors may become the first oral medication to be approved for adjunctive use in T1D. Summary The risk of diabetic ketoacidosis still remains a concern, but considering additional benefits beyond glucose control, with proper counseling and education, these medications may allow a larger number of patients to achieve target glucose control without weight gain or increased risk of hypoglycemia.

Diabetes Technology & TherapeuticsVol. 20, No. S2 Original ArticlesOpen AccessPossible Ways to Improve Postprandial Glucose Control in Type 1 DiabetesHalis Kaan Akturk, Amanda Rewers, Hal Joseph, Nicole Schneider, and Satish K. GargHalis Kaan Akturk, Amanda Rewers, Hal Joseph, Nicole Schneider, and Satish K. GargPublished Online:1 Jun 2018https://doi.org/10.1089/dia.2018.0114AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail IntroductionThe Diabetes Control and Complications Trial and subsequent Epidemiology of Diabetes Interventions and Complications trial have unequivocally established that intensive glucose control significantly reduces microvascular and macrovascular long-term diabetes complications in those with type 1 diabetes (T1D).1–3 The improvement in diabetes control was, however, associated with a threefold increase in severe hypoglycemia events, which in many cases result in additional calorie consumption, intentional hyperglycemia, limited insulin titration, and weight gain.4Glucose control, as measured by HbA1c, is widely accepted as the hallmark measure of mean blood glucose (MBG), and is derived from a composite of fasting plasma glucose (FPG) and postprandial glucose (PPG) exposure. The exact role of postprandial hyperglycemia, and how it relates to glycated hemoglobin (HbA1c) are debatable.5–9 Some studies have shown a significant relationship of PPG with HbA1c more than FPG,9,10 whereas other studies suggested the contrary.11,12 Postprandial hyperglycemia contributes significantly to overall glycemic burden and represents one of two key targets along with fasting glucose control for improvement in MBG.One of the greatest challenges and unmet needs in diabetes management is limitations in effectively and consistently controlling postprandial hyperglycemia.3 Increased PPG levels have been significantly associated with increased healthcare resource utilization, including visits, calls, e-mails to healthcare providers, and overnight hospitalizations among adults with diabetes that use multiple daily injections (MDI).13 A measurement of plasma glucose (by self-monitored blood glucose—SMBG) 2 h after the start of a meal has commonly been recommended and has been a key indicator of postprandial hyperglycemia.14 At present, however, there is no international consensus for either the recommended measurement or specific targets for PPG levels for patients with diabetes. Current recommendations are neither well established nor consistently individualized for individuals with T1D; however, the recommended 2-h PPG level <140 mg/dL has been suggested by the American Association of Clinical Endocrinologists (AACE); while values <180 mg/dL have been put forth by the American Diabetes Association (ADA), targets of <160–180 mg/dL were recommended by European Association for the Study of Diabetes (EASD), and <160 mg/dL was the suggested target provided by International Diabetes Federation, all targeting these values with no increase in associated rates of significant hypoglycemia.13Importance of PPG ControlA significant correlation has been observed between postprandial hyperglycemia and elevated intraocular pressure,15 cognitive dysfunction,16 oxidative stress, and many other conditions—with these data generally obtained in retrospective studies.17 The Framingham Offspring Study and the Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe (DECODE) study showed a relationship between postprandial hyperglycemia and cardiovascular disease.18,19 The Study To Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial has shown that decreasing postprandial hyperglycemia may reduce the incidence of new cardiovascular events in people with impaired glucose tolerance.20 However, the Hyperglycemia and Its Effect After Acute Myocardial Infarction on Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (HEART2D) study21 and the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study22 failed to show beneficial effects of lowering PPG.23 A post hoc analysis of the data from the HEART2D study concluded a lower risk of cardiovascular events with prandial versus basal insulin therapy in a subgroup of older individuals with type 2 diabetes (T2D) and prior acute myocardial infarction, despite similar HbA1c between the two groups.24 No well-controlled, randomized study to date has carefully assessed the impact of PPG excursions on rates of complications or outcomes in T1D.In contrast, at this time, there is no definitive evidence for the precise relationship between PPG excursions and the development and progression of microvascular and macrovascular complications of diabetes.17,25 The ability to draw conclusions from long-term trials with head-to-head comparisons is difficult due to the absence of an ideal therapeutic agent that would only decrease PPG effectively and have a negligible effect on FPG.17 Difficulties in comparing trials to date are also due to limitations in study design, endpoints, and the methods of analysis employed.17Contributors to Postprandial HyperglycemiaThe absorption of carbohydrates in the upper gastrointestinal (GI) tract results in increases in plasma glucose concentrations, which usually starts about 10–20 min after the start of a meal, but this effect can vary significantly based on a number of factors, including, meal composition, duration of diabetes, presence of autonomic dysfunction, and alterations in microbiota of the upper GI tract.26,27 In an individual without diabetes, plasma glucose peaks in ∼60 min after the start of a typical meal and rarely exceeds 140 mg/dL, usually returning to normal levels within 2 to 3 h.14 The corresponding physiologic release of insulin coincides with meal ingestion and is stimulated by glucose (and free fatty acids) with both a rapid increase in insulin concentrations and onset of insulin action within the first 30–120 min after the meal. This response generally controls the significant increase in blood glucose in healthy individuals, regardless of the carbohydrate load consumed since patients with T1D have little or no residual beta cell function after 2 to 3 years following diagnosis (which is in contrast to T2D, where postprandial hyperglycemia is the consequence of both inadequate meal-related insulin release and failure to suppress ongoing hepatic glucose production). However, in both scenarios, rapid prandial insulin effect that can mimic the time action profile of physiological insulin may be desirable in efforts to better control the meal-related excursions in glucose.As noted previously, postprandial hyperglycemia in T1D is multifactorial, and in addition to the factors already discussed, individuals with T1D also have a postprandial paradoxical rise in glucagon (although lesser in magnitude to that seen in T2D), and PPG is impacted by timing, quantity, and composition of the meal, mismatch of meal absorption with exogenous insulin absorption and action (often maximal more than 1 to 2 h after injection), and patient-related causes such as reduced or skipped mealtime insulin dose or challenges with accuracy in estimating total carbohydrate intake.14,28–30Carbohydrate counting has been shown to be an important determining factor of postprandial hypoglycemia and hyperglycemia.31 More recently, continuous glucose monitor (CGM) data revealed the PPG patterns in T1D, including rapid glucose spikes with high glycemic index carbohydrates and late postprandial hyperglycemia with increases in dietary fat and protein.32–36 High-fat meals may alter gastric emptying, often contributing to late blood glucose elevations that can occur as late as 4 to 5 h after the meal,32,33 and can increase free fatty acid levels that impair insulin sensitivity, and further contribute to higher glucose values.35 Higher protein intake has also been shown to increase PPG levels 3–5 h postmeal.32,37 A high-fat and high-protein meal consisting of similar amounts of carbohydrates require more insulin to lower PPG when compared with low-fat, low-protein meals in T1D.38There are also data to suggest that food order has a significant role to play. A study showed that when protein and fat were consumed 15 min before carbohydrates, the mean PPG levels were lower by 28.6%, 36.7%, and 16.8% at 30, 60, and 120 min, respectively.39 The glycemic index of food may also affect PPG levels, as foods with a high glycemic index have been shown to result in even greater and more rapid increase in blood glucose following a meal. On the other hand, those foods with a lower glycemic index result in lesser fluctuations in blood glucose.40,41 One other key variable—namely the specific timing of the subcutaneous insulin dose—in relation to the meal has been shown to be an important factor in PPG control.32,33A recent review concluded that injecting rapid-acting insulin analogs (RAIA; e.g., lispro, aspart, and glulisine) 15–20 min premeal results in ∼30% lower PPG levels and lower reported rates of postmeal hypoglycemia when premeal glucose levels are in range.36 Postprandial administration of RAIAs is a less effective method of controlling PPG levels and may increase a significant risk of hypoglycemia and increased glucose variability.36Therapeutic approaches for T1D management during exercise also need to account for the residual effects of meals, insulin dose, and the impact of activity on glucose turnover, insulin mobilization, glucagon, and sympathetic response.42 Several types of exercises are associated with rapid reductions in glucose (walking and jogging), while other forms of exercises may result in rapid increase in plasma glucose (weight training and high-intensity intervals).42 Duration and type of exercise must also be considered in preventing exercise-induced hypoglycemia and postexercise hyperglycemia.43 The Dose Adjustment For Normal Eating (DAFNE) trial showed that dietary training with flexible insulin dosing improved diabetes outcomes and quality of life, and was cost-effective.44,45 The dietary changes recommended in the DAFNE trial persisted for 6 months and glycemic control was maintained up to 7 years.46,47Gastroparesis is a relatively uncommon long-term complication in poorly controlled patients with diabetes. Patients with gastroparesis may have delayed glucose absorption, thus resulting in a delayed rise in PPG.48 Rarely, patients with gastroparesis may also have rapid absorption of food intake. The use of insulin pumps has been shown to improve PPG better than subjects using MDI.49Therapeutic Options to Address Prandial Glucose ControlMany new basal insulin analogs such as insulin detemir, glargine (U100 and U300), and degludec (U100 and U200), or the use of insulin pumps has allowed effective control of FPG, most without increasing nocturnal hypoglycemia.50–54 In late March, the Food and Drug Administration (FDA) approved specific changes in wording for the use of insulin degludec based on results from the DEVOTE trial that reported reduced rates of severe hypoglycemia.55Mealtime human soluble (regular) insulin (in contrast to porcine/bovine regular insulin) has been used since 1992 in an effort to control PPG. More recently, RAIAs (insulin lispro, glulisine, and aspart) have generally replaced human regular insulin in individuals with T1D as they are dosed closer to mealtime and have been shown to have a more rapid pharmacokinetic (PK) and pharmacodynamic (PD) response.56 The RAIAs have a more rapid onset of action, earlier and higher peak activity with a shorter duration of action than human regular insulin.56 However, RAIAs are still recommended for dosing 15–30 before meals and are known to have significant insulin effect more than 2 h after injection—which many consider inadequate to achieve optimal PPG control.56–58Faster acting insulin aspart (FIasp) is a new formulation of insulin aspart that includes two additional formulation excipients, L-arginine and niacinamide. L-arginine serves as a stabilizing agent and the addition of niacinamide promotes a more rapid formation of insulin monomers after subcutaneous injection, facilitating more rapid absorption across the endothelium into the circulation.59 The pooled analysis of PK and PD studies that compared FIasp versus insulin aspart showed an ∼5 min earlier onset of first appearance of insulin (4 vs. 9 min), an approximately two times higher early insulin exposure, and a 74% greater early glucose-lowering effect for FIasp versus insulin aspart.56 A Japanese study confirmed similar findings.60 Offset of exposure and glucose-lowering effect occurred 12–14 min earlier with FIasp than insulin aspart.56The Onset 1 registration trial at 26 weeks showed not only noninferiority of FIasp in terms of HbA1c compared to insulin aspart, but also superiority for PPG excursions (21.21 mg/dL and 12.01 mg/dL decrease at 1 and 2 h, respectively) without increased risk of hypoglycemia in patients with T1D.58 At 52 weeks in the same trial, overall glycemic control had significantly improved with FIasp versus insulin aspart, consistent with the 26-week study findings.57 A projection analysis that used the Onset 1 trial data showed that FIasp can reduce healthcare-related costs up to £1,715 in England.61 FIasp also improved glucose control in the registration Onsets 2 and 3 trials in patients with T2D.59,62 Currently, FIasp is not currently approved for use in insulin pumps used in the United States. In a recent 6-week small study for pump compatibility, no microscopically confirmed infusion-set occlusions were observed for FIasp.63Glucagon-like peptide (GLP-1) is an incretin hormone secreted by intestinal L cells in response to food intake and works on suppressing postprandial glucagon release, increasing (on demand) insulin secretion (a mechanism not possible in patients with T1D due to general absence of beta-cell insulin release), increasing satiety, and delaying gastric emptying.30,64 Currently, none of the GLP-1 analogs is approved by the FDA to be used in T1D. Shorter-acting GLP-1 analogs have been shown to improve glucose control with associated reductions in insulin dose compared to placebo; however, long-acting GLP-1 analogs have shown to be less consistent as adjunctive therapy for glucose control in patients with T1D.65 In small studies, exenatide improved PPG in patients with T1D.66,67 Liraglutide did not demonstrate significantly greater effects on PPG control in patients with T1D.65,68 While improvement in HbA1c was observed, the changes were small in magnitude—although also associated with modest weight loss. Overall, the studies showed a significant increase in the risk of DKA and severe hypoglycemia in ADJUNCT 1 and 2 trials in T1D.69,70 As a result of these data, the developer of liraglutide officially announced that it would not pursue a new drug application (NDA) to the FDA or European Medicine Agency (EMA) for use of liraglutide for T1D as adjunctive therapy.Pramlintide is an analog hormone to human amylin—a peptide synthesized in the pancreatic beta-cells and co-secreted with insulin. Pramlintide has been approved for adjunctive use in insulin-treated individuals with both T1D and T2D—and exerts its clinical effects by means of increases in satiety, a delay in gastric emptying, and reducing postprandial plasma glucagon concentrations.71 Premeal injections of pramlintide decreased glucose excursions for the first 2 h following a mixed meal by suppressing postprandial glucagon concentrations in a randomized crossover study.71 The time to peak blood glucose was also significantly slower with pramlintide.71 It has been shown that regardless of the duration of diabetes, patients achieved a significantly lower HbA1c and weight loss; however, patients with increased duration of diabetes had significantly more adverse effects, including increased rates of nausea/vomiting and a higher risk of hypoglycemia.72 Another recent study compared pramlintide with liraglutide in patients with T1D in a closed-loop system without premeal bolus insulin administration. Pramlintide suppressed postmeal glucagon levels and lowered hyperglycemia.73 There is an ongoing study (NCT01269047) that compares exenatide and pramlintide in patients with T1D for PPG control.65The only FDA-approved adjunctive therapy for T1D is pramlintide; however, its clinical use is limited due to a number of factors, including the need for significant adjustment in insulin dose in many individuals, treatment-limiting significant side effects such as nausea, vomiting, and decreased food intake in some individuals, and increased rates of hypoglycemia, as well as the higher cost of therapy.29 Pramlintide and GLP-1 analogs delay gastric emptying, and thus may help in delaying the absorption of glucose matching with the action of RAIA.The SGLT2 inhibitors lower blood glucose through inhibition of renal glucose reabsorption in the proximal tubule of the kidney, whereas SGLT1 inhibition delays the absorption of glucose from the upper GI tract, thus blunting PPG.74,75 Sotagliflozin (dual SGLT1 and SGLT2 inhibitor) and dapagliflozin (selective SGLT2 inhibitor) have shown improved glucose control in patients with T1D in recently published randomized, controlled, double-blind studies.76–78 However, none of the SGLT (sodium–glucose cotransporter) inhibitors is FDA or EMA approved for clinical use in patients with T1D.Inhaled insulin has been studied in several forms in an effort to utilize an alternate delivery method (pulmonary absorption) to alter PK/PD of mealtime insulin, while the earlier attempts at pulmonary insulin were generally unsuccessful due to low bioavailability (Exubera®) and limited improvement in time action profile, technology using fumaryl diketopiperazine (the excipient representing an essential part of Technosphere insulin [TI]) for pulmonary delivery of insulin (TI, Afrezza®; Mannkind, Westlake Village, CA). TI had demonstrated even more rapid onset of action compared to the RAIA insulin lispro.79 TI appears in the blood in <1 min, thought to be due, in great part, to the extent of pulmonary alveolar space available for insulin absorption and due to the rapid dissolution of the insulin delivery particles.80 TI also results in more rapid and higher peak action.81 In addition, a study of subjects with T2D has shown more rapid suppression of endogenous glucose production with TI at doses of 24 and 16 U compared to lispro 10 U.82Recently, data were provided to the U.S. FDA that resulted in changes in labeling language for TI that support the observation of the first measurable insulin effect that occurs in ∼12 min, and peak effect is noted ∼35–45 min after dosing with a return to baseline insulin effect levels after ∼1.5–3 h.83 Based on the PD, in these studies, the dose of TI required to achieve a similar glucose effect based on glucose infusion rate has been modified to at least 1.5 times the usual dose of subcutaneously injected RAIA. Whether this is the result of formulation properties, pulmonary delivery, or other changes in insulin action or clearance is not known. However, dosing (as an example) for a patient currently utilizing 8 U of RAIA may require 12 U of TI as an initial dose to achieve the similar glucose-lowering effect.84 This dosing recommendation is further supported by analysis of the doses of TI ultimately utilized to achieve similar glucose control in the randomized clinical trials comparing TI to RAIAs where equivalent dose ratios approximating 1.5–2 times dose of TI to RAIA were reported after 12 or more weeks of titration.85–87TI was shown (by design) to achieve a noninferior reduction in HbA1c when compared to RAIA in registration trials in those with T1D. This noninferiority was achieved with significantly less reported hypoglycemia and lesser weight gain compared to the use of RAIA.85 Additional studies confirmed reduced hypoglycemia—an outcome that is, in part, attributed to its rapid "on and off" insulin action with TI.85,88–90 The PD profile reported confers a faster onset and shorter duration of action that may permit more rapid postprandial insulin action that coincides with the rates of glucose absorption after meals.80 A simulation study using modeled data from TI clinical trials suggested that higher doses of TI premeal or split dosing premeal and postmeal of TI may provide improved PPG profile with lesser fluctuations in postmeal glucose than conventional treatment with subcutaneously administered rapid-acting insulin products, and would be likely to do so without increasing the risk of hypoglycemia.91In current clinical use, there are higher rates of reported "underdosing" of TI as documented by lesser clinical effect when 1:1 mealtime insulin dose conversion is used. However, with additional clinical experience, patients and healthcare providers have been advised to consider the higher dose conversion when switching between RAIA and TI, and appropriate titration may allow for more aggressive and higher dosing of TI when clinically indicated.84 TI has a significantly shorter duration of action and different time action profile compared to RAIAs, and for many individuals may require a modified approach to both initiation and titration as well as supplemental dosing 1–3 h postmeal (by inhalation) to achieve the optimal clinical effect. Similarly, with shorter mealtime insulin action following TI inhalation, individual patients may also need to alter (generally increase) their basal insulin dose.A small number of individual reports have identified those who have used TI for PPG control with the hybrid closed-loop (HCL) pump therapy. Given the short duration of action of inhaled TI with meals, and the flexibility of basal adjustments with HCL, some individuals report clinical improvement, although this is not currently an indicated use of TI. However, using TI with HCL system will not account for the total daily insulin dose and thus many patients may experience higher fasting glucose values, and usually not recommended.A small (n = 15) pilot feasibility single-arm study using TI showed a decrease in HbA1c in 6 weeks.92 An investigator-led collaborative open-label, multicenter randomized pilot study (Study Comparing Prandial Insulin Aspart vs. Technosphere Insulin in Patients with Type 1 Diabetes on MDI- or STAT Study) compared TI with insulin aspart effects on PPG control and postprandial time in range (TIR) for 0–4 h postmeal using CGM data. The STAT study showed that PPG was significantly lower at 1 and 2 h postprandial with TI compared to insulin aspart.89,90 In the per-protocol analysis (with additional postprandial TI dose), mean glucose values and postprandial TIR significantly improved compared to insulin aspart.89,90 Details of the STAT study results will be presented at the 2018 ADA and EASD annual meetings in Orlando, FL, and Berlin, Germany, respectively89,90 (data on file with BDC).Due to the rising cost of insulin, biosimilar insulins are also now being developed as an alternative to the established branded RAIA.93–95 Similar PK/PD results have been demonstrated with biosimilar lispro versus insulin lispro in use.96 A crossover study that compared biosimilar lispro and insulin lispro in use for pump compatibility and safety found similar results for infusion set occlusions, hypersensitivity reactions, and hypoglycemia events.97 In T1D and T2D, similar efficacy and safety were found in the SORELLA 1 and SORELLA 2 studies, respectively.98,99 Similar immunogenicity profiles were found between biosimilar lispro and insulin lispro in use in the SORELLA 1 and SORELLA 2 studies.100 Earlier PK/PD studies with biosimilar (follow-on) insulin aspart also showed similar profiles to insulin aspart. Phase 3 clinical trials in T1D and T2D (GEMELLI studies) are ongoing in the United States and Europe for biosimilar insulin aspart approvals (NCT03211858) with the FDA and EMA.101BioChaperone insulin lispro has also been developed to enable the acceleration of insulin absorption. It had previously demonstrated an accelerated insulin action profile across multiple phase 1 and 2 studies in people with T1D and T2D compared to insulin lispro.102–104 A trial (NCT03179332) that compared PK/PD properties of BioChaperone insulin lispro in insulin pumps with insulin aspart and FIasp recently showed superior results according to a press release by Adocia, Inc. (Lyon, France).105 Eli Lilly & Co, Inc. (Indianapolis, IN) recently completed the recruitment for the phases 2 to 3 trials for ultra-rapid-acting insulin lispro for MDI and continuous subcutaneous insulin infusion (CSII) (NCT03056456 and NCT02703350).104 Results from early phase studies of this compound supported faster time action profile than insulin lispro, although full results of phase 3 studies are not currently available.106,107Some other alternative methods have been tried to increase insulin absorption. Insulin co-injected with hyaluronidase to increase insulin absorption may be a promising alternative for PPG management.108–110 Despite favorable results, the company (Halozyme, Inc., San Diego, CA) discontinued development of their product, given both the clinical and regulatory requirements necessary to complete the NDA for the FDA. Investigational devices that apply local heat have been found to increase insulin absorption and thus reduce PPG.111–114 Whether such approaches will achieve improved PPG remains to be determined.ConclusionThe recent availability of HCL systems (artificial pancreas or AP systems) to deliver insulin in response to CGM recorded glucose data and specific insulin administration algorithms have been reported, and demonstrate significant reductions in fasting glucose in many trials.52,54 However, control of PPG continues to remain a clinical challenge as it requires patient input of proper carbohydrate intake and current insulin action profiles may be limited to respond to rapid increases and decreases in PPG even with the HCL system. CSII or pumps are currently only used in <1% of insulin-requiring patients, so the generalizability of such therapy remains to be determined.Identification of optimal basal and prandial insulin therapies that better mimic normal physiology and utilize rapid and frequent glucose measurement that can facilitate/help patients manage their diabetes at the moment is needed for more effective management. There also remain ongoing efforts to identify a "SMART" (glucose sensing) insulin that alleviates the need for multiple insulin types and may eliminate the need for advanced pump technologies. One such approach uses boronate-based glucose sensing (that is attached to the insulin molecules) for continuous sensing.115,116Effective PPG control still requires multiple daily efforts that include, but are not limited to the following: proper and accurate assessment of carbohydrate intake (DAFNE trial), food composition, insulin dose adjustments based on physical activity, current glucose level (as measured by SMBG), or real-time CGM.30 CGM data allow patients and healthcare providers real-time feedback to control PPG more effectively.117–119 Patients using insulin pumps may bolus with different options (standard, square wave, modified combination, and dual wave) to improve PPG control, especially in patients with gastroparesis.120–122 Development of ultra-RAIA and proper use of very rapid-acting pulmonary insulin such as TI can assist a number of patients in their effort to improve PPG. Until another very rapid-acting prandial insulin is available, appropriate use of currently available insulins (aspart, lispro, glulisine, FIasp, and Technosphere Insulin) along with glucose monitoring (SMBG/CGM) should be considered the standard of care to mitigate/reduce PPG elevations and excursions.Author Disclosure StatementS.K.G. has received Advisory Board Consulting fees from Medtronic, Roche, Merck, Lexicon, Novo-Nordisk, Sanofi, Mannkind, Senseonics, Zealand, and Eli Lilly. S.K.G. has received research grants through the University of Colorado Denver from Eli Lilly, Novo-Nordisk, Merck, Lexicon, Medtronic, Dario, NCI, T1D Exchange, NIDDK, JDRF, Animas, Dexcom, and Sanofi. S.K.G. does not own stocks in any device or pharmaceutical company. H.K.A. has received research grant through the University of Colorado Denver from Mannkind Corporation. Other authors do not have any conflict of interests.References1 Orchard TJ, Nathan DM, Zinman B, et al.: Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015;313:45–53. Crossref, Medline, Google Scholar2 de Boer IH, Rue TC, Cleary PA, et al.: Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med 2011;171:412–420. Crossref, Medline, Google Scholar3 Nathan DM, Cleary PA, Backlund JY, et al.: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653. Crossref, Medline, Google Scholar4 Miller KM, Foster NC, Beck RW, et al.: Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D exchange clinic registry. Diabetes Care 2015;38:971–978. Crossref, Medline, Google Scholar5 Landgraf R: The relationship of postprandial glucose to HbA1c. Diabetes Metab Res Rev 2004;20(Suppl 2):S9–S12. Crossref, Medline, Google Scholar6 Bonora E, Tuomilehto J: The pros and cons of diagnosing diabetes with A1C. Diabetes Care 2011;34(Suppl 2):S184–S190. Crossref, Medline, Google Scholar7 Monnier L, Lapinski H, Colette C: Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of

Sixty patients with T1D on multiple daily injections (MDI) were randomized in a multi-center study, stratified by A1c values (<8.5% or ≥ 8.5%) to the control arm using aspart (n=34) vs. TI group (n=26). Patients in the TI arm were advised to take extra inhalations at 1 and 2 hours after meals based on post-prandial blood glucose (PPBG) values. Baseline characteristics and FEV1 were similar. Using per protocol (PPT) analysis, we examined outcomes over the 4-week period using linear regression with repeated measures. The primary outcomes were TIR (70-180 mg/dL) and PPBG excursions. Compliance with TI was based on its use when indicated at 1- and 2-hour PPBG. Patients with at least 80% compliance were included in PPT (n=15). Seven TI patients were non-compliant; 2 dropped out of the study; and 2 did not have CGM data. CGM glucose patterns and TIR for a patient with 100% or with 56% compliant with TI are shown (Figure 1a and 1b). TIR was significantly higher in the TI-compliant group compared to control or TI-non-compliant groups (Figure 1c). PPBG was also significantly lower in the TI-compliant compared to the control group at 1- and 2-hours post-prandial but not at 3 and 4 hours. PPBG was significantly lower in the compliant vs. non-compliant TI group at all time points (Figure 1d). We conclude that TI improves TIR and PPBG values, if patients use additional inhalations as directed. Disclosure J.K. Snell-Bergeon: Stock/Shareholder; Self; Abbott. Research Support; Self; Roche Diagnostics Corporation. H.K. Akturk: None. A. Rewers: None. B.W. Bode: Research Support; Self; Abbott. Advisory Panel; Self; ADOCIA. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk Inc., Diasome Pharmaceuticals, Inc., Sanofi US, Eli Lilly and Company, MannKind Corporation, Dexcom, Inc., OmniPod, Senseonics. L.J. Klaff: Research Support; Self; Abbott, Intarcia Therapeutics, Inc., MannKind Corporation, Dexcom, Inc., Novartis Pharmaceuticals Corporation, Gelesis, Novo Nordisk Inc., Eli Lilly and Company, Medtronic, Sanofi. A. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical. Research Support; Self; Dexcom, Inc.. Advisory Panel; Self; Eli Lilly and Company, Insulin Algorithms, JDRF, Lexicon Pharmaceuticals, Inc., Livongo Health. Research Support; Self; MannKind Corporation. Other Relationship; Self; Medscape. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Omada Health, Inc., Optum Rx, Inc., Sanofi. Research Support; Self; T1D Exchange. Advisory Panel; Self; The Endocrine Society. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Advisory Panel; Spouse/Partner; Johnson & Johnson Diabetes Institute, LLC. T.S. Bailey: Research Support; Self; Abbott. Consultant; Self; Abbott. Speaker's Bureau; Self; Abbott. Research Support; Self; Ambra BioScience, Ascensia Diabetes Care, Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Calibra Medical. Consultant; Self; Calibra Medical. Research Support; Self; Companion Medical, Dexcom, Inc., Glooko, Inc., GlySens Incorporated, Lexicon Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Medtronic MiniMed, Inc.. Speaker's Bureau; Self; Medtronic MiniMed, Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Senseonics. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Versartis, Inc., Xeris Pharmaceuticals, Inc., MannKind Corporation. S.K. Garg: Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Sanofi US. Advisory Panel; Self; Sanofi US. Research Support; Self; MannKind Corporation, Diasome Pharmaceuticals, Inc., Labstyle Innovations, Lexicon Pharmaceuticals, Inc., Medtronic. Advisory Panel; Self; Novo Nordisk A/S.

Purpose of reviewTo identify and evaluate the recent trials of sodium-glucose cotransporter 1 and 2 (SGLT1 and SGLT2, respectively) inhibitor use in patients with type 1 diabetes (T1D). SGLT-2 inhibitors have been approved by the Food and Drug Administration (FDA) and are effectively used in the treatment of type 2 diabetes (T2D). However, many studies (phase I-III) have validated their effects beyond improving glycemic control and have shown potential adjunctive use in adult patients with T1D treated with insulin therapy alone.Recent findingsA review of the literature showed that there is a potential adjunctive role for the SGLT inhibitors with insulin in T1D for improving glycemic control. The inTandem3 (A phase III study to evaluate the safety of sotagliflozin in patients with type 1 diabetes who have inadequate glycemic control with insulin therapy alone) and the DEPICT-1 (Dapagliflozin evaluation in patients with inadequately controlled type 1 diabetes) trials demonstrated significant benefits in adult patients with T1D. The SGLT inhibitors may become the first oral medication to be approved for adjunctive use in T1D.SummaryThe risk of diabetic ketoacidosis still remains a concern, but considering additional benefits beyond glucose control, with proper counseling and education, these medications may allow a larger number of patients to achieve target glucose control without weight gain or increased risk of hypoglycemia.

Diabetes Technology & TherapeuticsVol. 20, No. S2 Challenges and Emerging Therapies for Improved Diabetes OutcomesOpen AccessEver-Increasing Insulin-Requiring Patients GloballySatish K. Garg, Amanda H. Rewers, and Halis Kaan AkturkSatish K. GargDepartment of Medicine and Pediatrics, University of Colorado Denver, Aurora, Colorado.Barbara Davis Center for Diabetes, Aurora, Colorado.Search for more papers by this author, Amanda H. RewersBarbara Davis Center for Diabetes, Aurora, Colorado.Search for more papers by this author, and Halis Kaan AkturkDepartment of Medicine and Pediatrics, University of Colorado Denver, Aurora, Colorado.Barbara Davis Center for Diabetes, Aurora, Colorado.Search for more papers by this authorPublished Online:1 Jun 2018https://doi.org/10.1089/dia.2018.0101AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Prevalence of diabetes continues to increase worldwide and now involves about half a billion people globally.1–3 The majority of this increase involves patients diagnosed with type 2 diabetes (T2D).3 Unfortunately, even today about 40%–50% of patients are undiagnosed.4 Recent data from the Centers for Disease Control and Prevention (CDC) show a slight increase in the prevalence of diabetes in the United States to be about 9% with about 84 million people with prediabetes.4 Type 1 diabetes (T1D) is also increasing worldwide at a rate of ∼3%–5% annually.5–8 This increase in patients with T1D involves not only the Western world but also emerging economies.3 Since there is a significant delay in diagnosing and initiating effective treatment for T2D, there is an ever-increasing number of patients requiring insulin. The total number of insulin-requiring patients today is expected to be around 150–200 million (by all means this is an underestimate). Thirty millions of these are patients with T1D6 of which 1.5–3 million are in the United States, a number that is likely to triple in the next three decades.8,9 About 10%–20% of patients with T2D are misdiagnosed (antibody positive), which makes about 40–80 million patients requiring insulin.10,11 Another 20%–30% of patients with T2D will require insulin therapy during the course of T2D due to significant beta cell loss over time and delays in diagnosing and initiating necessary treatments on time.10,12 Thus, cumulatively we have about 150–200 million people requiring insulin therapy worldwide.The majority of patients with diabetes (T1D and T2D) do not achieve target A1cs (<7% or 6.5%) as recommended by the American Association of Clinical Endocrinologists (AACE), American Diabetes Association (ADA), European Association of Study for Diabetes (EASD), and other local/national diabetes organizations.13–15 It is also unfortunate that about two-third of the patients with T1D are overweight or obese,16 and, of course, the majority of patients with T2D are either overweight or obese.1 Patients, especially those with T1D, also face morbidity and mortality risks from severe hypoglycemia and diabetic ketoacidosis.17,18Recent guidelines by American College of Physicians published in Annals of Internal Medicine19 were ill-conceived and make no sense in recommending A1c goals to be 8% from 7% as recommended by global diabetes organizations. It adds confusion to a general practitioner for diabetes care.Because of this tremendous increase in the number of patients, especially those requiring insulin therapy, the cost of healthcare related to diabetes and its complications is ever increasing.4,20 Global economic burden related to diabetes is expected to increase to 2.5 trillions of dollars annually by 2030.21 It is estimated that global costs for all insulins alone have escalated to about 30 billion U.S. dollars,22 which is likely to continually increase.23,24 Part of this increase in the cost of all insulins is a disproportionate increase in costs (sometimes it is 5–10 times higher) in the United States.25–29Total mortality rate in T1D and T2D is significantly higher than that in nondiabetic volunteers.4,29 Fortunately, the rate of almost all long-term complications of diabetes has been decreasing in the past two decades4,30; however, the total number of patients with those complications has been increasing because of the global increase in the prevalence of diabetes.30 The decrease in the rate of complications has been largely attributed to small but significant improvements in glycosylated hemoglobin, availability of several new therapies (new classes of drugs such as new longer acting and rapid-acting insulin analogues, Dipeptidyl peptidase IV (DPP IV) inhibitors, newer once a day or weekly Glucagon-like polypetide-1 (GLP-1) analogues, and Sodium-glucose transport protein 2 (SGLT-2) inhibitors) for managing diabetes effectively.31–34 In addition, the availability of several insulin analogues (insulin lispro, aspart, glulisine, FIasp, glargine, detemir, U300 glargine, and U100 and U200 degludec)35–43 allows effective intensive insulin therapy in insulin-requiring patients with no further increase in hypoglycemia despite improving glucose control, (which has usually been the hurdle to intensify insulin therapy).35,36,39 Last, but not least, the availability of new technologies such as continuous glucose monitors (CGMs), insulin pumps, and hybrid closed-loop systems has further advanced diabetes management without increase in hypoglycemia while achieving target A1cs.44–47It is important to keep in mind that new technologies may not be the answer for the majority of the insulin-requiring patients because of increasing cost and difficulties in implementing these technologies in clinical practice.48 Currently, <1% of insulin-requiring patients are using either insulin pumps alone and/or CGMs or hybrid closed-loop systems.11,49,50 The majority of patients using pumps are in the United States or in Western Europe. However, the need for insulin-requiring patients is far higher in the rest of the world,51 where cost is a major issue in implementing CGM or pump therapy.26 Thus, the majority of the insulin-requiring patients would benefit from an alternative platform that uses insulin-delivery pens that have memory functions (in development) in them, along with data being transmitted to a mobile device on an app. The patient's CGM/self-monitoring of blood glucose (SMBG) data would also transmit to the same app and thus advise them on day-to-day diabetes management.In this supplement, Welsh focuses on the role of CGM in insulin-requiring patients, especially in T2D.52 They emphasize that the use of CGMs effectively improves glucose control without increasing hypoglycemia. In fact, it is important to note that the majority of the recent studies they included show that a large number of patients continue to use CGMs. In part, this may be due to improvement (accuracy) in technologies such that the majority of the currently available CGMs have an Mean Absolute Relative Difference of <10%.52 In his review, Bob Ratner underscores the importance of hypoglycemia in diabetes care and how, in the near future, some of the newer insulin analogues might even get a favorable label change by the Food and Drug Administration (FDA).53Helena Rodbard and Thomas Danne highlight the role of new GLP analogues, especially the those that can be used once a week (dulaglutide and semaglutide), and the new SGLT1 and SGLT2 inhibitors in diabetes care, respectively.54,55 Thomas Danne also highlights the possible adjunctive use of SGLT inhibitors in T1D (not yet approved by the FDA or European Medicines Agency (EMA)), in addition to their role in T2D.55 H. Kaan Akturk highlights the ways to improve postprandial glucose, especially using technosphere insulin (Afrezza, Mannkind, Inc., CA) due to the rapid onset of action (recent FDA label change).56Weaver and Hirsch summarize the results of small studies related to different artificial pancreas systems showing no increase in hypoglycemia or ketoacidosis while emphasizing we are far from a system that replicates islet cell function in a fully automated multihormonal system.57Lal et al. present emerging technologies including novel insulin, insulin delivery devices, glucose monitoring technology, and decision support systems that may be applicable for the majority of the insulin-requiring patients.58 Although SGLT1 and 2 inhibitors sound promising for patients with T1D, the proper mitigation plan for reducing the risk of diabetic ketoacidosis (DKA) is needed.55Messer et al. discuss skin issues with the chronic use of insulin-delivery devices and CGMs.59 In addition to addressing these concerns, they offer prophylactic and alternative ways to reduce skin issues with these devices.59 David Rodbard emphasizes differences in glucose variability (GV) parameters in T1D and T2D, and the difficulties in implementing GV in clinical practice.60 He also gives us a view into the future for new indices for possible GV.60 It is possible that in the near future, we will start quantifying glucose control not only by HbA1c but also by time-in-range, which may become a more important marker for day-to-day diabetes management.61 However, A1c measurements may be more important for population health and determining long-term complications of diabetes. Even though GV has never been proven to be an independent risk factor for long-term complications of diabetes, both patients and providers strongly believe that if GV can be effectively reduced, the quality of patients' life who require insulin therapy significantly improves. Tim Bailey, while stressing emerging technologies in diabetes care, also emphasize realistic expectations regarding artificial pancreas systems and the challenges in implementing the new technologies in daily clinical practice.62I hope that you will enjoy and learn by reading this supplement. I sincerely want to thank all the authors who contributed in a timely manner to the supplement and the sponsors for providing an unrestricted educational grant to make this possible. We collectively need to have a clear message for the providers even though we might disagree. I strongly believe that the future is bright for patients with diabetes as they will continue to live longer with all the advances in the field. Unfortunately, the price of living longer that nobody talks about is the burden to the society that needs to be dealt appropriately.Author Disclosure StatementS.K.G. has received Advisory Board Consulting fees from Medtronic, Roche, Merck, Lexicon, Novo-Nordisk, Sanofi, Mannkind, Senseonics, Zealand, and Eli Lilly. S.K.G. has received research grants through the University of Colorado Denver from Eli Lilly, Novo-Nordisk, Merck, Lexicon, Medtronic, Dario, NCI, T1D Exchange, NIDDK, JDRF, Animas, Dexcom, and Sanofi. S.K.G. does not own stocks in any device or pharmaceutical company. Both A.H.R. and H.K.A. have no disclosures or conflicts of interest to report.References1 International Diabetes Federation: Diabetes Atlas 7th ed. Brussels, Belgium, 2015. Google Scholar2 Whiting DR, Guariguata L, Weil C, Shaw J: IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311–321. Crossref, Medline, Google Scholar3 Cho NH, Shaw JE, Karuranga S, et al.: IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018;138:271–281. Crossref, Medline, Google Scholar4 Centers for Disease Control and Prevention: National Diabetes Statistics Report 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf (accessed May 17, 2018). Google Scholar5 Forlenza GP, Rewers M: The epidemic of type 1 diabetes: what is it telling us? Curr Opin Endocrinol Diabetes Obes 2011;18:248–251. Crossref, Medline, Google Scholar6 Garg SK, Henry RR, Banks P, et al.: Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med 2017;377:2337–2348. Crossref, Medline, Google Scholar7 Mayer-Davis EJ, Dabelea D, Lawrence JM: Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. N Engl J Med 2017;377:301. 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Post-prandial hyperglycemia is difficult to control due to lack of an ideal prandial insulin. TI (Afrezza®) has the most rapid onset of action, lasts for 2 hours. Sixty patients with T1D on multiple daily injections (MDI) were randomized in a multi-center study, stratified by baseline A1c values (<8.5% or ≥ 8.5%) to the control group using aspart (n=34) vs. TI group (n=26). The TI arm was advised to take extra inhalations at 1 and 2 hours after meals based on PPBG. Baseline characteristics were similar (Figure 1a). Forced Expiratory Volume did not differ at all times. We used intent-to-treat analysis, and examined outcomes over a 4-week period using linear regression with repeated measures. Mean CGM glucose, SD, time in range (70-180 mg/dL), % time in hyper- (>180 mg/dL) or hypoglycemia (<70, <60, or <50 mg/dL) were similar in both groups. PPBG at 1 hour was lower in the TI group (mean ± SE PPBG difference -31.7±6.6 mg/dL, p<0.0001). PPBG was numerically lower at 2 hours (mean ± SE PPBG -13.0±7.1 mg/dL, p=0.07) with no difference at 3 and 4 hours (Figure 1b). The TI group increased bolus insulin dose (mean ± SD of 47.8 ± 23.9 U/day) compared to the control group (23.0 ± 9.8 U/day; p<0.0001) in week 1. Bolus insulin dose in the TI group was higher (28.2 U/day; p<0.0001), and did not differ by study week (p=0.25). We conclude that TI improves PPBG when treat-to-target algorithms are used in patients with T1D on MDI. Disclosure H.K. Akturk: None. J.K. Snell-Bergeon: Stock/Shareholder; Self; Abbott. Research Support; Self; Roche Diagnostics Corporation. A. Rewers: None. L.J. Klaff: Research Support; Self; Abbott, Intarcia Therapeutics, Inc., MannKind Corporation, Dexcom, Inc., Novartis Pharmaceuticals Corporation, Gelesis, Novo Nordisk Inc., Eli Lilly and Company, Medtronic, Sanofi. A. Peters: Advisory Panel; Self; Abbott, Bigfoot Biomedical. Research Support; Self; Dexcom, Inc.. Advisory Panel; Self; Eli Lilly and Company, Insulin Algorithms, JDRF, Lexicon Pharmaceuticals, Inc., Livongo Health. Research Support; Self; MannKind Corporation. Other Relationship; Self; Medscape. Advisory Panel; Self; Merck & Co., Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Omada Health, Inc., Optum Rx, Inc., Sanofi. Research Support; Self; T1D Exchange. Advisory Panel; Self; The Endocrine Society. Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Advisory Panel; Spouse/Partner; Johnson & Johnson Diabetes Institute, LLC. B.W. Bode: Research Support; Self; Abbott. Advisory Panel; Self; ADOCIA. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Medtronic MiniMed, Inc., Novo Nordisk Inc., Diasome Pharmaceuticals, Inc., Sanofi US, Eli Lilly and Company, MannKind Corporation, Dexcom, Inc., OmniPod, Senseonics. T.S. Bailey: Research Support; Self; Abbott. Consultant; Self; Abbott. Speaker's Bureau; Self; Abbott. Research Support; Self; Ambra BioScience, Ascensia Diabetes Care, Becton, Dickinson and Company. Consultant; Self; Becton, Dickinson and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Calibra Medical. Consultant; Self; Calibra Medical. Research Support; Self; Companion Medical, Dexcom, Inc., Glooko, Inc., GlySens Incorporated, Lexicon Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Medtronic MiniMed, Inc.. Consultant; Self; Medtronic MiniMed, Inc.. Speaker's Bureau; Self; Medtronic MiniMed, Inc.. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Senseonics. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Versartis, Inc., Xeris Pharmaceuticals, Inc., MannKind Corporation. S.K. Garg: Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Sanofi US. Advisory Panel; Self; Sanofi US. Research Support; Self; MannKind Corporation, Diasome Pharmaceuticals, Inc., Labstyle Innovations, Lexicon Pharmaceuticals, Inc., Medtronic. Advisory Panel; Self; Novo Nordisk A/S.

The Diabetes Fear of Injecting and Self-Testing Questionnaire (D-FISQ) has been validated in the adult population (1–4), but there is no reliable tool to assess needle fear in the pediatric population with type 1 diabetes. Our objectives were to demonstrate the reliability of the D-FISQ in the pediatric type 1 diabetic population, to evaluate the prevalence of needle fear, and to determine the ability of medical care providers to identify needle fear. Patients aged 2–21 years with type 1 diabetes were eligible to participate if they had a diabetes duration of >1 month, took insulin by injection, and were English speaking. Exclusion criteria included being a ward of the state, using continuous subcutaneous insulin infusion therapy, and not having a parent/legal guardian present. Potential subjects were approached by study personnel at regularly scheduled clinic visits, and consent was obtained. The study was approved by the institutional review board. The D-FISQ was administered to each subject and his/her parent or guardian. The D-FISQ is a 30-item self-report questionnaire consisting of two subscales that measure fear of self-injecting (FSI) and fear of self-testing (FST), the latter measuring fear of blood glucose testing (1). The D-FISQ was administered to each parent and each child as follows. If the child self-administered his/her own injections and/or …

Abstract: The HLA genotype DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 confers a 25‐fold increase in the risk of type 1 diabetes. In persons with this genotype, DRB1*0405, *0402, and *0401 subtypes have been reported to further increase risk, whereas the *0403 and *0406 alleles confer a relative protection. We compared the frequencies of the DRB1*04 alleles in 193 type 1 diabetic patients with the HLA‐DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotype (140 non‐Hispanic white [NHW] and 53 Hispanic) and 205 nondiabetic controls (142 NHW and 63 Hispanic). In addition, 87 NHW first‐degree relatives of type 1 diabetes patients were studied: 33 positive and 54 negative for autoantibodies to insulin, GAD65, or IA‐2. The HLA‐DRB1 was typed using standard PCR SSOP methods. DRB1*0401 (OR, 2.19; 95% CI, 1.36‐3.54) in NHW and *0405 (OR, 3.78; 95% CI, 1.43‐10.0) in Hispanics were significantly associated with T1DM, whereas DRB1*0403 was protective (OR, 0.19; 95% CI, 0.04‐0.89 in NHWs; OR, 0.10; 95% CI, 0.01‐0.83 in Hispanics). Associations between the DRB1*04 alleles and prediabetic islet autoimmunity were generally in the same direction as those with diabetes. Among diabetic patients, the mean age of diagnosis appeared to be higher among those with the *0403 and *0407 allele compared with the others. In summary, on the DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotypes, the *0403 allele confers relative protection from type 1 diabetes and development of islet autoantibodies in both Hispanics and NHWs and is associated with older age at diabetes diagnosis. Although the associations between diabetes and *0401 and *0405 appear to differ somewhat between Hispanics and NHWs, overall there is no significant difference between these two ethnic groups.