Clinical perspectives on the frequency of hypoglycemia in treat-to-target randomized controlled trials comparing basal insulin analogs in type 2 diabetes: a narrative review.

The objective of this review was to comprehensively present and summarize trends in reported rates of hypoglycemia with one or two times per day basal insulin analogs in individuals with type 2 diabetes to help address and contextualize the emerging theoretical concern of increased hypoglycemic risk with once-weekly basal insulins.Hypoglycemia data were extracted from treat-to-target randomized clinical trials conducted during 2000-2022. Published articles were identified on PubMed or within the US Food and Drug Administration submission documents. Overall, 57 articles were identified: 44 assessed hypoglycemic outcomes in participants receiving basal-only therapy (33 in insulin-naive participants; 11 in insulin-experienced participants), 4 in a mixed population (insulin-naive and insulin-experienced participants) and 9 in participants receiving basal-bolus therapy. For the analysis, emphasis was placed on level 2 (blood glucose <3.0 mmol/L (<54 mg/dL)) and level 3 (or severe) hypoglycemia.Overall, event rates for level 2 or level 3 hypoglycemia across most studies ranged from 0.06 to 7.10 events/person-year of exposure (PYE) for participants receiving a basal-only insulin regimen; the rate for basal-bolus regimens ranged from 2.4 to 13.6 events/PYE. Rates were generally lower with second-generation basal insulins (insulin degludec or insulin glargine U300) than with neutral protamine Hagedorn insulin or first-generation basal insulins (insulin detemir or insulin glargine U100). Subgroup categorization by sulfonylurea usage, end-of-treatment insulin dose or glycated hemoglobin reduction did not show consistent trends on overall hypoglycemia rates. Hypoglycemia rates reported so far for once-weekly basal insulins are consistent with or lower than those reported for daily-administered basal insulin analogs.

Frequency of diabetic remission, predictors of remission and survival in cats using a low-cost, moderate-intensity, home-monitoring protocol and twice-daily glargine.

OBJECTIVES: The aim of the present study was to retrospectively assess remission rates and survival in diabetic cats managed using a moderate-intensity, low-cost protocol of home blood glucose measurements and insulin adjustment by clients of a cat-only practice, and to determine if predictors of remission, relapse or survival could be identified. METHODS: The records of a cat-only practice were used to identify 174 cats with newly diagnosed diabetes managed using only pre-insulin home blood glucose measurements for insulin dose adjustments based on a protocol provided to clients aimed at maintaining pre-insulin blood glucose in the range of 6.5-11.9 mmol/l (117-214 mg/dl). Cats were excluded for the following reasons: insufficient follow-up in the records; a lack of owner compliance was recorded; they were receiving ongoing corticosteroids for the management of other conditions; they were euthanased at the time of diagnosis; or they were diagnosed with acromegaly or hyperadrenocorticism. RESULTS: Using only pre-insulin blood glucose measurements at home to adjust the insulin dose to maintain glucose in the range of 6.5-11.9 mmol/l, 47% of cats achieved remission, but 40% of those cats relapsed. A minority (16%) of cats were hospitalised for hypoglycaemia. The survival time was significantly longer in cats in remission and Burmese cats. CONCLUSIONS AND RELEVANCE: The cost and time burden of treating diabetic cats may cause some clients to choose euthanasia over treatment. While the highest rates of diabetic remission have been reported in studies of newly diagnosed cats treated with intensive long-acting insulin protocols and low carbohydrate diets, these protocols may not be suitable for all clients. Nearly 50% of cats with newly diagnosed diabetes achieved remission with this low-cost, moderate-intensity, insulin dosing protocol. As remission was significantly associated with survival time, discussing factors in treatment to optimise remission is important, but it is also important to offer clients a spectrum of options. No cats that started treatment in this study were euthanased because the owner did not wish to continue the diabetes treatment.

Efficacy and safety of basal insulins in people with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials.

Aim: The comparative effectiveness of basal insulins has been examined in several studies. However, current treatment algorithms provide a list of options with no clear differentiation between different basal insulins as the optimal choice for initiation. Methods: A comprehensive search of MEDLINE, Embase, Cochrane Library, ISI, and Scopus, and a reference list of retrieved studies and reviews were performed up to November 2023. We identified phase III randomized controlled trials (RCTs) comparing the efficacy and safety of basal insulin regimens. The primary outcomes evaluated were HbA1c reduction, weight change, and hypoglycemic events. The revised Cochrane ROB-2 tool was used to assess the methodological quality of the included studies. A random-effects frequentist network meta-analysis was used to estimate the pooled weighted mean difference (WMD) and odds ratio (OR) with 95% confidence intervals considering the critical assumptions in the networks. The certainty of the evidence and confidence in the rankings was assessed using the GRADE minimally contextualized approach. Results: Of 20,817 retrieved studies, 44 RCTs (23,699 participants) were eligible for inclusion in our network meta-analysis. We found no significant difference among various basal insulins (including Neutral Protamine Hagedorn (NPH), ILPS, insulin glargine, detemir, and degludec) in reducing HbA1c. Insulin glargine, 300 U/mL (IGlar-300) was significantly associated with less weight gain (mean difference ranged from 2.9 kg to 4.1 kg) compared to other basal insulins, namely thrice-weekly insulin degludec (IDeg-3TW), insulin degludec, 100 U/mL (IDeg-100), insulin degludec, 200 U/mL (IDeg-200), NPH, and insulin detemir (IDet), but with low to very low certainty regarding most comparisons. IDeg-100, IDeg-200, IDet, and IGlar-300 were associated with significantly lower odds of overall, nocturnal, and severe hypoglycemic events than NPH and insulin lispro protamine (ILPS) (moderate to high certainty evidence). NPH was associated with the highest odds of overall and nocturnal hypoglycemia compared to others. Network meta-analysis models were robust, and findings were consistent in sensitivity analyses. Conclusion: The efficacy of various basal insulin regimens is comparable. However, they have different safety profiles. IGlar-300 may be the best choice when weight gain is a concern. In contrast, IDeg-100, IDeg-200, IDet, and IGlar-300 may be preferred when hypoglycemia is the primary concern.

Immunogenicity, efficacy, and safety of biosimilar insulin glargine (Gan & Lee glargine) compared with originator insulin glargine (Lantus®) in patients with type 2 diabetes after 26 weeks' treatment: A randomized open label study.

AIM: To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. METHODS: This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. RESULTS: The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. CONCLUSIONS: GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy, and safety, based on the current study.

Consistent glycaemic efficacy and safety of concomitant use of iGlarLixi and sodium-glucose co-transporter-2 inhibitor therapy for type 2 diabetes: A patient-level pooled analysis of three randomised clinical trials.

AIMS: Sodium glucose co-transporter 2 inhibitors (SGLT2is) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with proven cardio- and reno-protective benefits are recommended in people with type 2 diabetes (T2D) at high risk of cardiovascular disease, chronic kidney disease, and/or heart failure. This pooled analysis compared efficacy and safety outcomes of iGlarLixi with or without SGLT2is in people with T2D. METHODS: This post hoc analysis evaluated outcomes in participants who were receiving an SGLT2i when initiating iGlarLixi (SGLT2i users) and those who were not (SGLT2i non-users) in a pooled dataset from three trials: LixiLan-G (advancing from a GLP-1 RA), SoliMix and LixiLan ONE CAN (advancing from basal insulin). RESULTS: Baseline characteristics were generally similar between 219 users and 746 non-users. Least squares mean changes in HbA1c from baseline to Week 26 were similar for users (-1.2 % [95 % confidence intervals: -1.4 %, -1.1 %]) and non-users (-1.2 % [-1.2 %, -1.1 %]). Changes in body weight, fasting glucose and post-prandial glucose were similar between groups, as were hypoglycaemic events. CONCLUSIONS: Pooled results from three studies of adults with T2D demonstrated that iGlarLixi provided similar clinically meaningful improvements in glycaemic control without increased hypoglycaemia risk, regardless of concomitant use of SGLT2is.

Real-World Outcomes of Individualized Targeted Therapy with Insulin Glargine 300 Units/mL in Insulin-Naïve Korean People with Type 2 Diabetes: TOBE Study.

INTRODUCTION: The TOujeo BEyond glucose control (TOBE) study evaluated clinical outcomes with insulin glargine 300 units/mL (Gla-300) in insulin-naïve Korean people with type 2 diabetes mellitus (T2DM) in a real-world setting. METHODS: This 24-week, prospective, non-interventional, multicenter, open-label, single-arm, observational study included adults aged ≥ 20 years with T2DM suboptimally controlled with oral hypoglycemic agents and/or glucagon-like peptide 1 receptor agonists who require basal insulin. Eligible participants were assigned to either general target glycated hemoglobin (HbA1c < 7%) or individualized target groups as per physician's discretion considering guidelines and participants' characteristics. The primary endpoint was the proportion of participants achieving the HbA1c target (individualized or general) at 24 weeks. RESULTS: Among 369 participants, 19.5% (72/369) of participants achieved the HbA1c target at week 24; 37.5% (33/88) in the individualized and 13.9% (39/281) in the general target group. In both target groups, similar reductions in fasting plasma glucose and body weight were observed, with low incidence of hypoglycemia, and T2DM duration was significantly shorter in participants who did versus those who did not achieve the target HbA1c (individualized target group: 9.6 ± 8.0 versus 13.1 ± 8.4 years, P = 0.0454; general target group: 10.2 ± 8.6 versus 12.8 ± 7.4 years, P = 0.0378). CONCLUSIONS: This study showed that initiation of insulin therapy with Gla-300 in people with T2DM using an individualized approach is more effective in achieving an HbA1c target. Moreover, earlier initiation of insulin therapy in people with suboptimally controlled T2DM may increase the success rate of glycemic control. A graphical abstract is available with this article.

Despite various efforts in managing diabetes, individuals with type 2 diabetes mellitus (T2DM) encounter numerous challenges to achieve good glycemic control. The major cause is failure to initiate insulin therapy in a timely manner, primarily because of the fear of hypoglycemia. Insulin glargine 300 units/mL (Gla-300) has smooth and prolonged activity resulting in stable and sustained glycemic control, thus reducing the risk of hypoglycemia. Studies on efficacy and safety of Gla-300 in various populations have been published globally. However, there are limited real-world studies in Asian populations. This study evaluated effectiveness and safety of Gla-300 in Korean people with T2DM who were not on insulin prior to this study but were taking oral glucose-lowering medications. The participants were assigned to two groups: general glycated hemoglobin (HbA1c) target (HbA1c < 7%) and individualized HbA1c target according to the participant's characteristics. Results showed that Gla-300 helped to achieve the glycemic target more effectively using an individualized approach. In both groups, similar reductions in fasting plasma glucose and body weight were observed, with low incidence of hypoglycemia. People who achieve glycemic target had a shorter duration of T2DM than those who did not achieve their glycemic target. This suggests that earlier insulin initiation may be a better approach and may increase the success rate of insulin therapy.

Effects of Tirzepatide Versus Basal Insulins in People With Type 2 Diabetes and Different Baseline Glycemic Patterns: Post Hoc Analyses of the SURPASS-3 and SURPASS-4 Trials.

OBJECTIVE: This post hoc analysis assessed change from baseline to week 52 in glycemic parameters for tirzepatide (5, 10, 15 mg) versus insulin degludec (SURPASS-3 trial) and glargine (SURPASS-4 trial) in people with type 2 diabetes and different baseline glycemic patterns, based on fasting serum glucose (FSG) and postprandial glucose (PPG) values. RESEARCH DESIGN AND METHODS: Participant subgroups with low FSG/low PPG, low FSG/high PPG, high FSG/low PPG, and high FSG/high PPG were defined according to the median values of these measures. RESULTS: All tirzepatide doses and basal insulins were associated with decreased HbA1c, FSG, and PPG values from baseline to week 52 in all subgroups (P < 0.05). Within each subgroup, HbA1c and PPG decreases were greater with tirzepatide than insulin (P < 0.05). FSG decreases were generally similar. There were no differential treatment effects by FSG/PPG subgroup. CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with superior glycemic control compared with insulin, irrespective of baseline glycemic pattern.

An exploratory analysis of the cost-effectiveness of insulin glargine 300 units/mL versus insulin glargine 100 units/mL over a lifetime horizon using the BRAVO diabetes model.

BACKGROUND: This analysis assessed the cost-effectiveness of insulin glargine 300 units/mL (Gla-300) versus insulin glargine 100 units/mL (Gla-100) in insulin-naïve adults with type 2 diabetes (T2D) inadequately controlled with oral antidiabetic drugs (OADs). METHODS: Costs and outcomes for Gla-300 versus Gla-100 from a US healthcare payer perspective were assessed using the BRAVO diabetes model. Baseline clinical data were derived from EDITION-3, a 12-month randomized controlled trial comparing Gla-300 with Gla-100 in insulin-naïve adults with inadequately controlled T2D on OADs. Treatment costs were calculated based on doses observed in EDITION-3 and 2020 US net prices, while costs for complications were based on published literature. Lifetime costs ($US) and quality-adjusted life-years (QALYs) were predicted and used to calculate incremental cost-effectiveness ratio (ICER) estimates; extensive scenario and sensitivity analyses were conducted. RESULTS: Lifetime medical costs were estimated to be $353,441 and $352,858 for individuals receiving Gla-300 and Gla-100 respectively; insulin costs were $52,613 and $50,818. Gla-300 was associated with a gain of 8.97 QALYs and 21.12 life-years, while Gla-100 was associated with a gain of 8.89 QALYs and 21.07 life-years. This resulted in an ICER of $7522/QALY gained for Gla-300 versus Gla-100. Thus, Gla-300 was cost-effective versus Gla-100 based on a willingness-to-pay threshold of $50,000/QALY. Compared with Gla-100, Gla-300 provided a net monetary benefit of $3290. Scenario and sensitivity analyses confirmed the robustness of the base case. CONCLUSION: Gla-300 may be a cost-effective treatment option versus Gla-100 over a lifetime horizon for insulin-naïve people in the United States with T2D inadequately controlled on OADs.

Differential Effects of Type 2 Diabetes Treatment Regimens on Diabetes Distress and Depressive Symptoms in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. RESEARCH DESIGN AND METHODS: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years' duration, HbA1c 6.8-8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined differences at 1 year and over the 3-year follow-up. RESULTS: Across treatments, diabetes distress (-0.24, P < 0.0001) and depressive symptoms (-0.67, P < 0.0001) decreased over 1 year. Diabetes distress was lower at 1 year for the glargine group than for the other groups combined (-0.10, P = 0.002). Diabetes distress was also lower for liraglutide than for glimepiride or sitagliptin (-0.10, P = 0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms. CONCLUSIONS: Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress. Glargine lowered diabetes distress modestly at 1 year rather than increasing it. Liraglutide also reduced diabetes distress at 1 year. Results can inform treatment decisions for adults with early T2DM.

Exercise and insulin glargine administration in mothers with diabetes during pregnancy ameliorate function of testis in offspring: Consequences on apelin-13 and its receptor.

AIMS: Despite the evidence exhibited that diabetes during gestation (DDG) is linked with reproductive dysfunction in offspring, the underlying cellular mechanisms involved are not precisely defined. This study was designed to assess the impact of voluntary exercise and insulin glargine on DDG-induced metabolic and reproductive disorders in male offspring. MAIN METHODS: Fifty female Wistar rats (three weeks old) received a control diet (n = 10) or high-fat-high-sucrose diet (to induce DDG; n = 40) for six weeks before breeding. From the 7th day of pregnancy onwards, blood glucose over 140 mg/dL was characterized as DDG. Then, the DDG animals were randomly divided into four subgroups with/without voluntary exercise and/or insulin glargine. To evaluate insulin resistance, a glucose tolerance test was performed on the 15th day of pregnancy. After three weeks, male offspring were weaned, and fed a control diet until 12 weeks old. At the end of the experiment, the lipid profile, sex hormones, and apelin-13 in the serum, mRNA expression of apelin receptors (APJ) in the testis and sperm analysis were assessed. KEY FINDINGS: Our results indicated that voluntary exercise and/or insulin glargine administration in mothers with DDG ameliorated lipid profile, and sex hormones alterations, reduced the serum level of apelin-13, as well as increased APJ expression in testis, and quality of sperm in offspring. SIGNIFICANCE: Combined administration of voluntary exercise and insulin glargine during pregnancy by regulating of apelinergic system and inhibiting the metabolic and reproductive complications induced by DDG, can be considered as a suitable therapeutic strategy for improving sub-or in-fertility in the male offspring.

Continuous Glucose Monitoring-Based Metrics and Hypoglycemia Duration in Insulin-Experienced Individuals With Long-standing Type 2 Diabetes Switched From a Daily Basal Insulin to Once-Weekly Insulin Icodec: Post Hoc Analysis of ONWARDS 2 and ONWARDS 4.

OBJECTIVE: This post hoc analysis assessed continuous glucose monitoring (CGM)-based metrics and hypoglycemia duration with once-weekly insulin icodec versus once-daily basal insulin analogs in insulin-experienced individuals with long-standing type 2 diabetes from two 26-week phase 3a trials (ONWARDS 2 and ONWARDS 4). RESEARCH DESIGN AND METHODS: Time in range (TIR) (3.9-10.0 mmol/L), time above range (TAR) (>10.0 mmol/L), and time below range (TBR) (<3.9 mmol/L and <3.0 mmol/L) were assessed during three CGM time periods (switch [weeks 0-4], end of treatment [weeks 22-26], and follow-up [weeks 27-31]) for icodec versus comparators (ONWARDS 2, insulin degludec [basal regimen]; ONWARDS 4, insulin glargine U100 [basal-bolus regimen]) using double-blind CGM data. CGM-derived hypoglycemic episode duration (<3.9 mmol/L) was assessed. RESULTS: In both trials, there were no statistically significant differences in TIR, TAR, or TBR (<3.0 mmol/L) for icodec versus comparators across all time periods. In the end-of-treatment period, mean TIR was 63.1% (icodec) vs. 59.5% (degludec) in ONWARDS 2 and 66.9% (icodec) vs. 66.4% (glargine U100) in ONWARDS 4. Mean TBR <3.9 mmol/L and <3.0 mmol/L remained within recommended targets (<4% and <1%, respectively) across time periods and treatment arms. Hypoglycemic episode duration (<3.9 mmol/L) was comparable across time periods and treatment arms (median duration ≤40 min). CONCLUSIONS: In insulin-experienced participants with long-standing type 2 diabetes, CGM-based TIR, TAR, and CGM-derived hypoglycemia duration (<3.9 mmol/L) were comparable for icodec and once-daily basal insulin analogs during all time periods. TBR remained within recommended targets.

Comparison of efficacy and safety of insulin degludec/liraglutide and insulin glargine U-100/lixisenatide in individuals with type 2 diabetes mellitus using professional continuous glucose monitoring.

AIM/INTRODUCTION: Insulin glargine U100/lixisenatide and insulin degludec/liraglutide are fixed-ratio combinations containing basal insulin and a glucagon-like peptide-1 receptor agonist capable of reducing both fasting and postprandial blood glucose levels with a single formulation. This study aimed to compare the time in range (TIR) and the time below range (TBR) level 1 using professional continuous glucose monitoring and to establish criteria for the differential use of the fixed-ratio combinations. MATERIALS AND METHODS: Thirty-six outpatients with type 2 diabetes mellitus (24 men and 12 women; average age, 62.1 years) were randomly assigned to the groups. At 0 and 18 weeks, a device was worn to compare the TIR and TBR level 1. The correlation between the C-peptide index at baseline and TIR at 18 weeks was assessed. RESULTS: The TIR and TBR level 1 showed no significant differences between the two groups. Both groups showed significant positive correlations between the C-peptide index and the TIR (P = 0.002, r = 0.679; P = 0.002, r = 0.681, respectively). The changes in glycemic variability, therapeutic indices, and body mass index were not significantly different among the groups (P > 0.05). The receiver operating curve analysis revealed that the cut-off values of the C-peptide index to achieve TIR of >70% at 18 weeks were 1.258 (sensitivity, 77.8%; specificity, 100%) and 1.099 (sensitivity, 57.1%; specificity, 90.9%) in the insulin glargine U100/lixisenatide and insulin degludec/liraglutide groups, respectively. CONCLUSIONS: A TIR of >70% was achieved for both fixed-ratio combinations without significant differences.

Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial.

OBJECTIVE: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin. RESEARCH DESIGN AND METHODS: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4. RESULTS: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%. CONCLUSIONS: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management.

Longitudinal Effects of Glucose-Lowering Medications on ß-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and ß-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting ß-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test ß-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of ß-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of ß-cell function, the nature of the change in ß-cell responses reflected those in ß-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and ß-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of ß-cell function in the progression of type 2 diabetes.

Impact of Glucose-Lowering Medications on Health-Related Quality of Life in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: Diabetes is associated with reduced health-related quality of life (HRQoL). Information on the relationship between HRQoL and glucose-lowering medications in recently diagnosed type 2 diabetes (T2D) is limited. We assessed changes in HRQoL in participants with T2D receiving metformin plus one of four glucose-lowering medications in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: A total of 5,047 participants, baseline mean age 57 years, with <10 years T2D duration and glycated hemoglobin level 6.8-8.5% and taking metformin monotherapy, were randomly assigned to glargine, glimepiride, liraglutide, or sitagliptin. HRQoL was evaluated at baseline for 4,885 participants, and at years 1, 2, and 3, with use of the self-administered version of the Quality of Well-being Scale (QWB-SA) and SF-36 physical (PCS) and mental (MCS) component summary scales. Linear models were used to analyze changes in HRQoL over time in intention-to-treat analyses. RESULTS: None of the medications worsened HRQoL. There were no differences in QWB-SA or MCS by treatment group at any time point. PCS scores improved with liraglutide versus other groups at year 1 only. Greater weight loss during year 1 explained half the improvement in PCS scores with liraglutide versus glargine and glimepiride. Liraglutide participants in the upper tertile of baseline BMI showed the greatest improvement in PCS scores at year 1. CONCLUSIONS: Adding liraglutide to metformin in participants within 10 years of T2D diagnosis showed improvement in the SF-36 PCS in comparisons with the other medications at 1 year, which was no longer significant at years 2 and 3. Improvement was related to weight loss and baseline BMI.

Real-world study of the concomitant use of biphasic insulin aspart 30/70 with GLP-1 receptor agonist versus first-generation basal insulin with GLP-1 receptor agonist in type 2 diabetes.

AIMS: Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1RA) to treat type 2 diabetes (T2D) is common. While many studies have investigated concomitant therapy with basal insulin+GLP-1RA, few have reported on premixed insulin+GLP-1RA. We aimed to address this gap using data from the Clinical Practice Research Datalink Aurum database in England. METHODS: This retrospective cohort study with propensity score matching assessed glycaemic levels and other clinical outcomes in people with T2D, comparing biphasic insulin aspart 30/70 (BIAsp 30) + GLP-1RA with basal insulin (insulin detemir/glargine U100) + GLP-1RA (from 2006 to 2021). RESULTS: In total, 4770 eligible people were identified; 1511 had a BIAsp 30 + GLP-1RA regimen and were propensity score-matched to an equal number receiving basal+GLP-1RA. There was no significant difference in glycated haemoglobin (HbA1c) reduction between cohorts at 6 months (p = 0.15), with a decrease of -1.07 (95% CI: -1.16; -0.98) %-points (-11.7 mmol/mol [95% CI: -12.7; -10.7]) in the BIAsp 30 + GLP-1RA cohort, versus -0.97 (95% CI: -1.07; -0.88) %-points (-10.6 mmol/mol [95% CI: -11.7; -9.6]) in the basal+GLP-1RA cohort. Body mass index (BMI) decreased by -0.35 kg/m2 (95% CI: -0.52;-0.18) at 6 months with BIAsp 30 + GLP-1RA, versus -0.72 kg/m2 (95% CI: -0.90;-0.54) with basal+GLP-1RA (p = 0.003). BMI was influenced by the initiation sequence of GLP-1RA in relation to insulin (p < 0.0001). Hypoglycaemia rates were low and not significantly different between cohorts. CONCLUSIONS: Combining BIAsp 30 + GLP-1RA provides glycaemic control with no significant difference to that of propensity score-matched people receiving basal insulin+GLP-1RA, with no increase in hypoglycaemia risk or weight gain.

The Use of Rescue Insulin in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE participants (type 2 diabetes duration <10 years, baseline A1C 6.8%-8.5% on metformin monotherapy, N = 5,047) were randomly assigned to insulin glargine U-100, glimepiride, liraglutide, or sitagliptin and followed quarterly for a mean of 5 years. Rescue insulin (glargine or aspart) was to be started within 6 weeks of A1C >7.5%, confirmed. Reasons for delaying rescue insulin were reported by staff-completed survey. RESULTS: Nearly one-half of GRADE participants (N = 2,387 [47.3%]) met the threshold for rescue insulin. Among participants assigned to glimepiride, liraglutide, or sitagliptin, rescue glargine was added by 69% (39% within 6 weeks). Rescue aspart was added by 44% of glargine-assigned participants (19% within 6 weeks) and by 30% of non-glargine-assigned participants (14% within 6 weeks). Higher A1C values were associated with adding rescue insulin. Intention to change health behaviors (diet/lifestyle, adherence to current treatment) and not wanting to take insulin were among the most common reasons reported for not adding rescue insulin within 6 weeks. CONCLUSIONS: Proportionately, rescue glargine, when required, was more often used than rescue aspart, and higher A1C values were associated with greater rescue insulin use. Wanting to use noninsulin strategies to improve glycemia was commonly reported, although multiple factors likely contributed to not using rescue insulin. These findings highlight the persistent challenge of intensifying type 2 diabetes treatment with insulin, even in a clinical trial.

Once-weekly Insulin Icodec as Compared to Once-daily Basal Insulins: A Meta-analysis.

BACKGROUND: Once-weekly basal insulin icodec has been tested in clinical trials for efficacy and safety over currently available glargine-100 and degludec in different clinical settings for type 2 diabetes. We performed this meta-analysis to evaluate its overall safety and efficacy as compared to glargine-100 and degludec (nonicodec), from all available randomized controlled trials. METHODS: Seven trials comparing once-daily basal insulin analogs to once-weekly basal insulin icodec were included. Based on available information, outcomes in terms of HbA1c, fasting plasma glucose reduction, and increase in time in range (TIR) were compared. Side-effects were compared for overall hypoglycemia, severe hypoglycemia, and weight gain. The pooled effect size for continuously distributed data was measured as a reduction in "estimated differences in mean (with 95% CI)." For categorical data, the pooled effect size was measured as the Mantel-Haenszel risk ratio (with 95% CI). RESULTS: Analyzing against the nonicodec comparators together, the "estimated mean changes" in HbA1c and fasting plasma glucose favoring icodec were -0.22% (-0.35, -0.10) and -1.59 mg% (-9.26, 6.08) respectively. The "estimated mean increment" in weight for icodec was 0.64 kg (0.61, 0.67). The "estimated mean percentage" increment in TIR for icodec was 4.24% (2.99, 5.49). The Mantel-Haenszel risk ratios for all hypoglycemic events and severe hypoglycemia for icodec were 1.24 (1.02, 1.50) (P = .03) and 0.81 (0.31, 2.08) (P is not significant), respectively, suggesting a 24% increased incidence of all hypoglycemia with icodec. CONCLUSION: Once-weekly basal insulin icodec as compared to once-daily basal insulin analogs had a slight increase in the risk of overall hypoglycemia and weight gain, without any difference in severe hypoglycemia, with similar glycemic control (in terms of fasting plasma glucose, HbA1c, and TIR).

Treatment responses to basal insulin glargine 300 U/ml and glargine 100 U/ml in newly defined subphenotypes of type 2 diabetes: A post hoc analysis of the EDITION 3 randomized clinical trial.

INTRODUCTION: To compare responses to basal insulin glargine 300 U/ml (IGlar-300) and 100 U/ml (IGlar-100) in newly defined subphenotypes of type 2 diabetes. METHODS: Insulin-naive participants (n = 858) from the EDITION 3 trial were assigned to subphenotypes 'Mild Age-Related Diabetes (MARD)', 'Mild Obesity Diabetes (MOD)', 'Severe Insulin Resistant Diabetes (SIRD)' and 'Severe Insulin Deficient Diabetes (SIDD)'. Key variables were analysed at baseline and 26 weeks. RESULTS: Participants were comprised of MOD 56.1% (n = 481), SIDD 22.1% (n = 190), MARD 18.2% (n = 156) and SIRD 3.0% (n = 26). After 26 weeks a similar decrease in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) of 16-19 mmol/mol and 1.4-1.7 mmol/L, respectively, occurred in MARD and MOD with both insulins. SIDD had the most elevated HbA1c and FPG (80-83 mmol/mol/11.1-11.4 mmol/L) and reduction in both HbA1c and FPG was greater with IGlar-100 than with IGlar-300 (-18 vs. -15 mmol/mol and -1.6 vs. -1.3 mmol/L, respectively; each p = .03). In SIDD, despite receiving the highest basal insulin doses, HbA1c decline (57-60 mmol/mol/7.3-7.6%) was suboptimal at week 26. In MOD and SIDD lower incidences with IGlar-300 were found for level 1 nocturnal hypoglycaemia [odds ratio (OR) 0.59, 95% confidence intervals (CI) 0.36-0.97; OR 0.49, 95% CI 0.24-0.99]. In addition, fewer level 2 hypoglycaemia episodes occurred at any time with IGlar-300 in SIDD (OR 0.31, 95% CI 0.13-0.77). CONCLUSION: Both insulins produce comparable outcomes in type 2 diabetes subphenotypes, but in SIDD, add-on treatment to basal insulin is required to achieve glycaemic targets.

Sex hormone-binding globulin and heart failure hospitalizations in patients with dysglycemia: Experiences from the outcome reduction with an Initial Glargine Intervention trial.

INTRODUCTION: Sex hormone-binding globulin (SHBG), which binds most of circulating testosterone in blood, has been linked to dysglycemia and cardiovascular disease but the relationship with heart failure remains unclear. AIM: To study the relation between SHBG and heart failure hospitalizations. METHODS: SHBG levels were analysed in dysglycemic participants at high cardiovascular risk (n = 8401) followed for a median of 6.2 years in the Outcome Reduction with an Initial Glargine Intervention trial. Cox regression was used to estimate hazard ratios (HRs) per one standard deviation increase for heart failure hospitalizations adjusted for age, comorbidities, biochemical data (including testosterone) and pharmacological treatment. RESULTS: 5553 men and 2848 women were included. Heart failure hospitalizations occurred in 349 (6.3 %) men and 123 (4.3 %) women. One standard deviation increase in SHBG was independently associated with an increased risk of heart failure hospitalizations in men (HR 1.15, 95 % CI 1.03-1.28; p = 0.011) but not in women (HR 1.15; 95 % CI 0.96-1.39; p = 0.14). CONCLUSIONS: In patients with dysglycemia and high cardiovascular risk, increasing SHBG was associated with greater risk of HF hospitalizations independent of testosterone concentrations in men but not in women, suggesting the effects could be mediated through androgen-independent pathways.