Initiating GLP-1 Therapy in Combination with FreeStyle Libre Provides Greater Benefit Compared with GLP-1 Therapy Alone.

Background and Aim: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy provides glycemic benefits to individuals with type 2 diabetes (T2D). However, the effects of GLP-1 RA therapy in combination with FreeStyle Libre systems (FSL) are unknown. This study aimed to compare changes in hemoglobin A1c (HbA1c) between people acquiring GLP-1 with FSL (GLP-1+FSL) versus GLP-1 without FSL (GLP-1). Methods: This real-world study used Optum's de-identified Market Clarity Data, a linked electronic health records (EHR)-claims database, and included adults with T2D and HbA1c ≥8% who acquired their first GLP-1 RA medication between 2018 and 2022. GLP-1+FSL subjects acquired their first FSL within ±30 days of their first GLP-1 acquisition. Cohorts were matched 1:5 on baseline insulin therapy, age, sex, baseline HbA1c, and GLP-1 type. Paired changes in HbA1c were compared between unmatched and matched groups at 6 months. Results: The study included 24,724 adults in the unmatched cohort (GLP-1+FSL, n = 478; GLP-1, n = 24,246). The matched cohort included 478 GLP-1+FSL users and 2,390 GLP-1 users: mean age 53.5 ± 11.8 and 53.5 ± 11.3 years, HbA1c 10.25 ± 1.68% and 10.22 ± 1.69%, respectively. HbA1c reduction was greater in the GLP-1+FSL group compared with the GLP-1 group in the unmatched cohort (-2.43% vs. -1.73%, difference 0.70%, P < 0.001, respectively) and in the matched cohort (-2.43% vs. -2.06%, difference 0.37%, P < 0.001). GLP-1+FSL vs. GLP-1 treatment was associated with greater HbA1c reduction in the intensive insulin (-2.32% vs. -1.50%), nonintensive insulin (-2.50% vs. -1.74%), and noninsulin group (-2.46% vs. -1.78%), as well as in patients using semaglutide (-2.73% vs. -1.92%) and dulaglutide (-2.45% vs. -1.71%) GLP-1 RA, all P < 0.001. Conclusions: Adults with suboptimally controlled T2D, initiating GLP-1 RA with FreeStyle Libre, had greater improvement in HbA1c compared with those treated with GLP-1 RA only. These results suggest an additional glycemic benefit of FSL when used with a GLP-1 RA in T2D treatment.

Therapeutic Inertia and Delays in Insulin Intensification in Type 2 Diabetes: A Literature Review.

Background: Therapeutic inertia leading to delays in insulin initiation or intensification is a major contributor to lack of optimal diabetes care. This report reviews the literature summarizing data on therapeutic inertia and delays in insulin intensification in the management of type 2 diabetes. Methods: A literature search was conducted of the Allied & Complementary Medicine, BIOSIS Previews, Embase, EMCare, International Pharmaceutical Abstracts, MEDLINE, and ToxFile databases for clinical studies, observational research, and meta-analyses from 2012 to 2022 using search terms for type 2 diabetes and delay in initiating/intensifying insulin. Twenty-two studies met inclusion criteria. Results: Time until insulin initiation among patients on two to three antihyperglycemic agents was at least 5 years, and mean A1C ranged from 8.7 to 9.8%. Early insulin intensification was linked with reduced A1C by 1.4%, reduction of severe hypoglycemic events from 4 to <1 per 100 person-years, and diminution in risk of heart failure (HF) by 18%, myocardial infarction (MI) by 23%, and stroke by 28%. In contrast, delayed insulin intensification was associated with increased risk of HF (64%), MI (67%), and stroke (51%) and a higher incidence of diabetic retinopathy. In the views of both patients and providers, hypoglycemia was identified as a primary driver of therapeutic inertia; 75.5% of physicians reported that they would treat more aggressively if not for concerns about hypoglycemia. Conclusion: Long delays before insulin initiation and intensification in clinically eligible patients are largely driven by concerns over hypoglycemia. New diabetes technology that provides continuous glucose monitoring may reduce occurrences of hypoglycemia and help overcome therapeutic inertia associated with insulin initiation and intensification.

Trends in Time in Range-Related Publications and Clinical Trials: A Bibliometric Review.

Objective: The goal of this article was to describe trends in publications (including conference abstracts) and clinical trials that report on glycemic time in range (TIR). Data sources: Reviewed databases included but were not limited to MEDLINE and Embase. Clinical trial registries were also sourced. Study selection: All studies reporting TIR published between 2010 and 2021 were included. Clinical trials reporting TIR that started in or after 2010 were also included. Non-English publications, abstracts, and clinical trials were excluded. Book chapters, nonhuman studies, and studies not reporting TIR were excluded. Data extraction: Manuscript/abstract category, publication year, study region, interventional versus observational role of continuous glucose monitoring (CGM), and clinical trial start and completion dates were captured. Glycemic outcomes reported in publications or trials, including TIR as a primary outcome, A1C, time below range (TBR), and time above range (TAR), were also captured. Results: A total of 373 clinical trials, 531 publications, and 620 abstracts were included in the review. The number of trials, publications, and abstracts reporting TIR significantly increased, particularly between 2018 and 2021, during which time the number of clinical trials, publications, and conference abstracts reporting TIR increased by 6-fold, 12-fold, and 4.5-fold, respectively. About 35-44% of studies reported TIR as a primary outcome. Approximately 54% of clinical trials, 47% of publications, and 47% of conference abstracts reported the role of CGM to be observational. TBR was reported more often than TAR. Conclusion: The marked increase in the number of trials, publications, and abstracts reporting TIR highlights the increasing significance and acceptance of TIR as an outcome measure in diabetes management.

Prevalence, Cost, and Burden of Diabetic Ketoacidosis.

Diabetic ketoacidosis (DKA) is a life-threatening complication, which is most common in individuals with type 1 diabetes (T1D) and is a significant risk for morbidity and mortality, and it is an economic burden on individuals, health care systems, and payers. Younger children, minority ethnic groups, and those with limited insurance are at the greatest risk for presentation of DKA at T1D diagnosis. Although monitoring ketone levels is an essential part of acute illness management and for both early detection and prevention of a DKA episode, studies have reported poor adherence to ketone monitoring. Ketone monitoring is particularly important for patients treated with sodium glucose cotransporter 2 inhibitor (SGLT2i) medications, in which DKA can present with only moderately elevated glucose levels, referred to as euglycemic DKA (euDKA). A majority of people with T1D and many with type 2 diabetes (T2D), particularly those using insulin therapy, are using continuous glucose monitoring (CGM) as their preferred method for measurement and management of glycemia. These devices provide a continuous stream of glucose data that enables users to take immediate action to mitigate and/or prevent severe hyperglycemic or hypoglycemic events. An international consensus of leading diabetes experts has recommended the development of continuous ketone monitoring systems, ideally a system that combines CGM technology with measurement of 3-ß-OHB into a single sensor. In this narrative review of current literature, we report on the prevalence and burden of DKA, examine challenges to detecting and diagnosing this condition, and discuss a new monitoring option for DKA prevention.

Budget Impact of the Flash Continuous Glucose Monitoring System in Medicaid Diabetes Beneficiaries Treated with Intensive Insulin Therapy.

Objective: We assessed the economic impact of using the newest flash continuous glucose monitoring (CGM) among Medicaid beneficiaries with diabetes treated with intensive insulin therapy (IIT). Research Design and Methods: A budget impact analysis was created to assess the impact of increasing the proportion of Medicaid beneficiaries with diabetes on IIT, who use flash CGM by 10%. The analysis included glucose monitoring device costs, cost savings due to reductions in glycated hemoglobin, severe hypoglycemia events, and hyperglycemic emergencies such as diabetic ketoacidosis. The net change in costs per person to adopt flash CGM for three populations treated with IIT (adults with type 1 diabetes [T1D] or type 2 diabetes [T2D], and children and adolescents with T1D or T2D) was calculated; these costs were used to estimate the impact of increasing flash CGM use by 10% to the U.S. Medicaid budget over 1-3 years. Results: The analysis found that flash CGM demonstrated cost savings in all populations on a per patient basis. Increasing use of flash CGM by 10% was associated with a $19.4 million overall decrease in costs over the year and continued to reduce costs by $25.3 million in years 2 and 3. Conclusions: Our results suggest that the new flash CGM system can offer cost savings compared to blood glucose monitoring in Medicaid beneficiaries treated with IIT, especially T1D adults, and children and adolescents. These findings support expanding access to CGM by Medicaid plans.

Effectiveness of Digital Medicines to Improve Clinical Outcomes in Patients with Uncontrolled Hypertension and Type 2 Diabetes: Prospective, Open-Label, Cluster-Randomized Pilot Clinical Trial.

BACKGROUND: Hypertension and type 2 diabetes mellitus are major modifiable risk factors for cardiac, cerebrovascular, and kidney diseases. Reasons for poor disease control include nonadherence, lack of patient engagement, and therapeutic inertia. OBJECTIVE: The aim of this study was to assess the impact on clinic-measured blood pressure (BP) and glycated hemoglobin (HbA1c) using a digital medicine offering (DMO) that measures medication ingestion adherence, physical activity, and rest using digital medicines (medication taken with ingestible sensor), wearable sensor patches, and a mobile device app. METHODS: Participants with elevated systolic BP (SBP ≥140 mm Hg) and HbA1c (≥7%) failing antihypertensive (≥2 medications) and oral diabetes therapy were enrolled in this three-arm, 12-week, cluster-randomized study. Participants used DMO (includes digital medicines, the wearable sensor patch, and the mobile device app) for 4 or 12 weeks or received usual care based on site randomization. Providers in the DMO arms could review the DMO data via a Web portal. In all three arms, providers were instructed to make medical decisions (medication titration, adherence counseling, education, and lifestyle coaching) on all available clinical information at each visit. Primary outcome was change in SBP at week 4. Other outcomes included change in SBP and HbA1c at week 12, and low-density lipoprotein cholesterol (LDL-C) and diastolic blood pressure (DBP) at weeks 4 and 12, as well as proportion of patients at BP goal (<140/90 mm Hg) at weeks 4 and 12, medical decisions, and medication adherence patterns. RESULTS: Final analysis included 109 participants (12 sites; age: mean 58.7, SD years; female: 49.5%, 54/109; Hispanic: 45.9%, 50/109; income ≤ US $20,000: 56.9%, 62/109; and ≤ high school education: 52.3%, 57/109). The DMO groups had 80 participants (7 sites) and usual care had 29 participants (5 sites). At week 4, DMO resulted in a statistically greater SBP reduction than usual care (mean -21.8, SE 1.5 mm Hg vs mean -12.7, SE 2.8 mmHg; mean difference -9.1, 95% CI -14.0 to -3.3 mm Hg) and maintained a greater reduction at week 12. The DMO groups had greater reductions in HbA1c, DBP, and LDL-C, and a greater proportion of participants at BP goal at weeks 4 and 12 compared with usual care. The DMO groups also received more therapeutic interventions than usual care. Medication adherence was ≥80% while using the DMO. The most common adverse event was a self-limited rash at the wearable sensor site (12%, 10/82). CONCLUSIONS: For patients failing hypertension and diabetes oral therapy, this DMO, which provides dose-by-dose feedback on medication ingestion adherence, can help lower BP, HbA1c, and LDL-C, and promote patient engagement and provider decision making. TRIAL REGISTRATION: Clinicaltrials.gov NCT02827630; https://clinicaltrials.gov/show/NCT02827630 (Archived by WebCite at http://www.webcitation.org/6rL8dW2VF).

Efficacy and safety of a medication dose reminder feature in a digital health offering with the use of sensor-enabled medicines.

OBJECTIVES: Over one-half of patients with chronic diseases, such as hypertension and type 2 diabetes (DM), do not take medicines as prescribed. This study assessed the efficacy and safety of "seeing" versus "not seeing" medication dose reminders regarding medication adherence and risk for overdose. DESIGN: Post hoc analysis. SETTING AND PARTICIPANTS: Outpatient setting. Adult subjects (18 years of age or older) with uncontrolled hypertension and DM. MAIN OUTCOME MEASURES: Subjects enrolled in this institutional review board-approved study were assigned to either use digital health (DH) with the use of sensor-enabled medicines (coencapsulated medicines with an ingestible sensor) for 4 or 12 weeks or receive usual care based on a cluster-randomized design. All subjects were followed for 12 weeks. Subjects using DH were included in the post hoc study consisting of an efficacy analysis and a safety analysis. A main efficacy outcome of comparison of subjects taking medicine with or without "seeing" DH medication dose reminders was assessed. Safety analysis assessed risk of overdosing after DH medication dose reminders. RESULTS: In 57 subjects included in the efficacy analysis, DH device reminder messages were associated with a 16 ± 16% increase (75 ± 18% when seeing vs. 59 ± 24% when not seeing mobile dose reminders) in medication taking if not taken before dose reminder. The mean overall adherence for all subjects was 86 ± 12%; the mean on-time adherence was 69.7 ± 19.7%. Subjects with lower adherence benefited more from seeing DH reminder messages. In the safety study (n = 74 subjects and 24,426 medication ingestions), no events of overdoses related to DH medication dose reminders occurred. CONCLUSION: This study demonstrates benefits of DH medication dose reminders to improve medication adherence, especially in patients with lower adherence; DH medication dose reminders also appear to be safe.

Association of self-monitoring of blood glucose use on glycated hemoglobin and weight in newly diagnosed, insulin-naïve adult patients with type 2 diabetes.

BACKGROUND: Clinical trials have shown that self-monitoring of blood glucose (SMBG) combined with patient education and medication titration can lead to improved glycated hemoglobin (HbA1c) and reduced weight in recently diagnosed non-insulin-treated type 2 diabetes mellitus (T2DM) patients. This retrospective matched cohort study assessed the association of SMBG with achieving long-term clinical outcomes in these patients in a real-world clinical setting. METHODS: Using electronic medical records (2008-2011), we selected a population of adult patients recently diagnosed with T2DM not receiving insulin who were SMBG users and a population of non-SMBG controls with similar demographic and clinical characteristics using propensity score matching. The main study outcomes compared between the two groups were time to achieve (1) HbA1c <7% for patients with baseline HbA1c ≥ 7% and (2) a ≥ 5% reduction in weight from baseline. RESULTS: Of the 589 patients identified in each group, 113 in each group had a baseline HbA1c ≥ 7% (mean, 8.2%). The SMBG users were more likely to achieve an HbA1c <7% (12 months: 58.4% versus 38.9%, p = .0037; 36 months: 84.0% versus 70.0%, p = .0013) and to do so faster (median, 6.5 versus 20.5 months; log-rank p = .0016). Self-monitoring of blood glucose was associated with faster weight reduction (median time to achieve a ≥ 5% reduction, 23.5 versus 35.9 months for SMBG and non-SMBG, respectively; log-rank p = .0005). CONCLUSIONS: In newly diagnosed T2DM insulin-naïve patients, SMBG users had an improved rate of achieving long-term glycemic control and weight loss in a real-world clinical setting.

Importance of blood glucose meter and carbohydrate estimation accuracy.

BACKGROUND: The clinical significance of blood glucose meter (BGM) error in the presence of increasing carbohydrate errors in diabetes patients who use both the BGM result and the carbohydrate estimation to dose insulin is unknown. METHODS: This Monte Carlo simulation modeled diabetes patients who calculate insulin dosages based on BGM results and carbohydrate estimations. It evaluated the likelihood of on-target insulin dosing and clinically significant insulin dose errors based on data from five BGMs with different levels of performance (expressed as bias and imprecision [coefficient of variation (%CV)]) and increasing levels of carbohydrate estimation errors. The study was performed across three separate preprandial glucose (PPG) ranges (90-150, 150-270, and 270-450 mg/dl). RESULTS: When carbohydrate estimation is accurate (%CV = 0%), the likelihood for on-target insulin doses ranged 50.1-98.5%. The likelihood depended on BGM performance and PPG range. In the presence of carbohydrate estimation errors (%CV = 5-20%), the likelihood of on-target insulin dosages markedly decreased (range, 27.2-80.1%) for all BGMs, the likelihood of insulin underdosing (range, 0-12.8%) and overdosing (range, 0-32.3%) increased, and the influence of BGM error on insulin dosing accuracy was blunted. Even in the presence of carbohydrate error, the BGM with the best performance (bias 1.35% and %CV = 4.84) had the highest probability for on-target insulin dosages. CONCLUSIONS: Both BGM and carbohydrate estimation error contribute to insulin dosing inaccuracies. The BGM with the best performance was associated with the most on-target insulin dosages.

The association of self-monitoring of blood glucose use with medication adherence and glycemic control in patients with type 2 diabetes initiating non-insulin treatment.

BACKGROUND: The value of self-monitoring of blood glucose (SMBG) for persons with type 2 diabetes who do not use insulin remains controversial. This observational study compares the likelihood of medication adherence and change in glycated hemoglobin (A1C) for non-insulin-using patients using SMBG versus those not using SMBG. The study also assessed the association between diabetes medication adherence and SMBG use. PATIENTS AND METHODS: Data were extracted on 5,172 patients who began non-insulin diabetes medication between October 1, 2006, and March 31, 2009. The study assessed change in A1C associated with SMBG use and testing frequency at different categorical levels of baseline A1C. The likelihood of medication adherence for SMBG users was compared with that for non-SMBG users at different categorical levels of baseline A1C. The study further explored the interactions between SMBG use and medication adherence on change in A1C. RESULTS: SMBG users had greater reductions in A1C compared with nonusers when the baseline A1C was ≥ 7%. Increasing SMBG frequency was associated with greater reductions in A1C. The study also examined the associations among SMBG use, medication adherence, and change in A1C. SMBG users had greater decreases in A1C for both medication-adherent and -nonadherent patients. As expected, medication adherence was associated with greater reductions in A1C for both SMBG nonusers and users. It is interesting that medication-nonadherent SMBG users had similar reductions in A1C compared with medication-adherent non-SMBG users. CONCLUSIONS: Both SMBG use and medication adherence were associated with similar degrees of A1C reduction after controlling for baseline A1C, suggesting that both factors may be important for attaining glycemic control.

Association between sitagliptin adherence and self-monitoring of blood glucose.

BACKGROUND: We evaluated the association between self-monitoring of blood glucose (SMBG) use and sitagliptin or sitagliptin/metformin (SSMT) adherence. SSMT was chosen as these medications have little risk of hypoglycemia and are believed to not require SMBG data for titration. METHODS: This was an observational study using data extracted from a large United States insurance claims database (i3 InVision™ Data Mart, Ingenix, Inc.). Data were extracted on noninsulin-using patients initiating SSMT for each 12-month period pre- and post-SSMT initiation. Logistic regression was used to assess the relationship between SMBG use and the likelihood of being medication adherent (defined as a medication possession ratio of ≥75%) while controlling for covariates. RESULTS: This analysis included 7,306 patients (57.6% male; mean age 54.2 years). Mean pre-SSMT hemoglobin A1c (HbA1c) was 8.0%. In the post-SSMT initiation period, 58% of patients were adherent with SSMT. Older age, male gender, prior use of oral diabetes medication, and lower HbA1c were associated with improved SSMT adherence. SMBG use was associated with improved adherence [odds ratio (OR) ranged from 1.198 to 1.338; p < .05] compared with patients with no SMBG use pre- or post-SSMT initiation. For patients who began SMBG after starting SSMT, greater SMBG use was associated with better adherence (OR 1.449 for higher vs 1.246 for lower strip use; p < .05). CONCLUSIONS: This study demonstrated that SMBG is associated with improved SSMT adherence. This relationship is strengthened with greater SMBG use.