HbA1c Change and Diabetic Retinopathy During GLP-1 Receptor Agonist Cardiovascular Outcome Trials: A Meta-analysis and Meta-regression

BACKGROUNDLong-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. Glucagon-like peptide 1 receptor agonists (GLP-1RA) lower glucose, but the long-term impact on retinopathy is unknown. GLP-1RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes.PURPOSETo examine the associations between retinopathy, HbA_1c, systolic blood pressure (SBP), and weight in GLP-1RA CVOTs.DATA SOURCESSystematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes.STUDY SELECTIONPublished trial reports were used as the primary data sources.DATA EXTRACTIONHbA_1c, SBP, and weight data throughout follow-up by treatment group were extracted.DATA SYNTHESISRandom-effects model meta-analysis showed no association between GLP-1RA treatment and retinopathy (odds ratio [OR] 1.10; 95% CI 0.93, 1.30), with high heterogeneity between studies (I² = 52.2%; Q statistic P = 0.063). Univariate meta-regression showed an association between retinopathy and average HbA_1c reduction during the overall follow-up (slope = 0.77, P = 0.007), but no relationship for SBP or weight. Sensitivity analyses for HbA_1c showed a relationship at 3 months (P = 0.006) and 1 year (P = 0.002). A 0.1% (1.09 mmol/mol) increase in HbA_1c reduction was associated with 6%, 14%, or 8% increased Ln(OR) for retinopathy at the 3-month, 1-year, and overall follow-up, respectively.LIMITATIONSCVOTs were not powered to assess retinopathy outcomes and differed in retinopathy-related criteria and methodology. The median follow-up of 3.4 years is short compared with the onset of retinopathy.CONCLUSIONSHbA_1c reduction was significantly associated with increased retinopathy risk in meta-regression for GLP-1RA CVOTs. The magnitude of HbA_1c reduction was correlated with retinopathy risk in people with diabetes and additional cardiovascular risk factors, but the long-term impact of improved glycemic control on retinopathy was unmeasured in these studies. Retinopathy status should be assessed when intensifying glucose-lowering therapy.     

Effects of Dulaglutide and Insulin Glargine on Estimated Glomerular Filtration Rate in a Real-world Setting

Purpose

The aims of this study were to use real-world treatment results to compare changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA_1c) among patients with type 2 diabetes who initiated treatment with dulaglutide or insulin glargine and to determine the proportions of patients with renal impairment who initiate each treatment.

Efficacy and Safety of Once-Weekly Efpeglenatide Monotherapy Versus Placebo in Type 2 Diabetes: The AMPLITUDE-M Randomized Controlled Trial

OBJECTIVETo assess the efficacy and safety of the glucagon-like peptide 1 receptor agonist (GLP-1 RA) efpeglenatide versus placebo in patients with type 2 diabetes inadequately controlled with diet and exercise alone.RESEARCH DESIGN AND METHODSAMPLITUDE-M was a phase 3, double-blind, placebo-controlled, multicenter trial that randomized adults with type 2 diabetes suboptimally controlled with diet and exercise alone to once-weekly efpeglenatide (2, 4, or 6 mg) or placebo for up to 56 weeks. The primary objective was to demonstrate the superiority of efpeglenatide versus placebo for HbA_1c reduction at week 30. Secondary objectives included changes in other measures of glycemic control and body weight at weeks 30 and 56.RESULTSAt week 30, HbA_1c was reduced from a baseline of 8.1% (65 mmol/mol) to 6.9% (52 mmol/mol), 6.6% (49 mmol/mol), and 6.4% (47 mmol/mol) with efpeglenatide 2, 4, and 6 mg, respectively. Least squares mean HbA_1c reductions from baseline were statistically superior for each efpeglenatide dose versus placebo (2 mg, −0.5% [95% CI −0.9, −0.2; P = 0.0054]; 4 mg, −0.8% [−1.2, −0.5; P < 0.0001]; 6 mg, −1.0% [−1.4, −0.7; P < 0.0001]). A greater proportion of efpeglenatide-treated patients (all doses) achieved HbA_1c <7% (53 mmol/mol) versus placebo by week 30 (P < 0.0001 for all), and significant reductions in body weight and fasting plasma glucose were also observed for efpeglenatide (4 and 6 mg doses) versus placebo at week 30 (P < 0.05 for all). Consistent with the GLP-1 RA class, gastrointestinal adverse events were most commonly reported; these were generally transient and mild/moderate in severity. Few patients reported hypoglycemia.CONCLUSIONSAs monotherapy in patients with type 2 diabetes, once-weekly efpeglenatide significantly improved glycemic control and body weight with a safety and tolerability profile similar to that of other GLP-1 RAs.     

Dulaglutide Shows Sustained Reduction in Glycosylated Hemoglobin Values: 2-Year US Real-world Study Results

PurposeDue to the chronic and progressive nature of type 2 diabetes mellitus (T2DM), it is important to understand the long-term outcomes associated with antihyperglycemic medications. There are currently few long-term studies evaluating the real-world effectiveness of dulaglutide, a glucagon-like peptide-1 receptor agonist. The primary objective of this retrospective observational study was to evaluate glycemic control over a 24-month follow-up period among dulaglutide initiators with continuous treatment. The study used US claims data from the HealthCore Integrated Research Database between May 2014 and May 2019.MethodsPatients were included if they were ≥18 years old with T2DM and had ≥1 pharmacy claim for dulaglutide during the index period between November 2014 and May 2017 (with index date = set as the earliest dulaglutide fill during index period), continuous enrollment in the 6 months' preindex and 24 months' postindex, ≥1 claim for dulaglutide or ≥60 days’ supply in every quarter during the 24-month follow-up period, and ≥1 glycosylated hemoglobin (HbA_1c) result at both baseline and 24 months.FindingsAt baseline, 872 patients (47.5% female) had a mean (SD) age of 54.5 (8.2) years and an HbA_1c value of 8.68% (1.8%) (71.36 [19.7] mmol/mol). More than two thirds were being treated for dyslipidemia, hypertension, or cardiovascular disease. A significant HbA_1c reduction was observed from baseline to 24 months (−1.3% [–14.2 mmol/mol]; P < 0.0001) for dulaglutide initiators with continuous treatment. A significant reduction in HbA_1c level was also observed for all prespecified subgroups (age, index dulaglutide dose [0.75 mg or 1.5 mg], insulin use, sodium-glucose co-transporter 2 inhibitor use, and dipeptidyl peptidase-4 inhibitor use; all, P < 0.0001). Forty-three percent of patients achieved an HbA_1c value < 7% (53 mmol/mol), and 73% achieved an HbA_1c value < 8% (64 mmol/mol) at 24 months. Most (520 [59.6%]) patients were initiated on dulaglutide 0.75 mg. Of these patients, 70% increased to dulaglutide 1.5 mg during follow-up. The mean time to first dose change was 242 (196) days for 0.75 mg–1.5 mg and 225 (160) days for 1.5 mg–0.75 mg. Antihyperglycemic medication use preindex/postindex included: insulin, 28%/35%; dipeptidyl peptidase-4 inhibitors, 37%/20%; and sodium-glucose co-transporter 2 inhibitors, 29%/44%.ImplicationsIn this real-world study among dulaglutide initiators with continuous treatment, a clinically significant reduction in HbA_1c value was seen at the 3-month assessment and persisted for up to 24 months. These data support the use of dulaglutide as an effective long-term treatment for T2DM in clinical practice.     

Durable Effects of iGlarLixi Up to 52 Weeks in Type 2 Diabetes: The LixiLan-G Extension Study

OBJECTIVEIn the LixiLan-G trial, switching to iGlarLixi, a once-daily titratable fixed-ratio combination of insulin glargine 100 units/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, improved glucose control in type 2 diabetes uncontrolled with GLP-1 RAs over 26 weeks versus continuing prior GLP-1 RA. A prespecified, 26-week, single-arm extension of LixiLan-G aimed to determine the durability of iGlarLixi efficacy and safety over 52 weeks.RESEARCH DESIGN AND METHODSParticipants with type 2 diabetes uncontrolled by GLP-1 RAs (glycated hemoglobin [HbA_1c] 7–9% [53–75 mmol/mol]) were initially randomized to switch to iGlarLixi or continue prior GLP-1 RA. Those randomized to iGlarLixi who completed the 26-week primary end point period could continue iGlarLixi open-label treatment over a 26-week extension to assess durability of efficacy and safety.RESULTSGlycemic control achieved with iGlarLixi at week 26 (mean HbA_1c 6.7% [50 mmol/mol]) was maintained at week 52 (mean HbA_1c 6.7% [50 mmol/mol]; mean ± SD change from baseline at week 52: −1.0 ± 0.9% [11 ± 10 mmol/mol]). Proportions of participants reaching HbA_1c <7% (53 mmol/mol) with iGlarLixi were similar at week 26 (62%) and 52 (64%), as were those reaching this target without documented symptomatic (<3.0 mmol/L) hypoglycemia (57% and 58%). Safety of iGlarLixi was similar at weeks 26 and 52, with low rates of documented symptomatic hypoglycemia and gastrointestinal events.CONCLUSIONSThe efficacy and safety of iGlarLixi at the end of the 26-week randomized treatment period was maintained over the 26-week extension period in the LixiLan-G trial.     

Feasibility of Simplification From a Basal-Bolus Insulin Regimen to a Fixed-Ratio Formulation of Basal Insulin Plus a GLP-1RA or to Basal Insulin Plus an SGLT2 Inhibitor: BEYOND,a Randomized,Pragmatic Trial

OBJECTIVEBEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium–glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control.RESEARCH DESIGN AND METHODSParticipants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA_1c at 6 months.RESULTSBaseline characteristics were similar among the three groups (mean HbA_1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA_1c level (−0.6 ± 0.8, −0.6 ± 0.8, and −0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA_1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group.CONCLUSIONSBEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.     

Exenatide Once Weekly: Effectiveness,Tolerability, and Discontinuation Predictors in a Real-world Setting

PurposeThe goal of this study was to evaluate the effectiveness and safety of exenatide once weekly (EOW) and to determine predictors of treatment response and drug discontinuation in patients with type 2 diabetes mellitus (T2DM) followed up for 18 months in a real-world setting.MethodsThis retrospective cohort study included patients with T2DM who initiated EOW 2 mg between 2014 and 2019 in an outpatient diabetes clinic in Italy. Data were collected at baseline and at follow-up visits (6, 12, and 18 months after EOW). We estimated glycosylated hemoglobin (HbA_1c) and body weight mean changes from baseline to follow-up visits and assessed the proportion of patients reaching HbA_1c target ≤7% and a 5% weight loss after 12 months of treatment. We then attempted to establish predictors of glycemic and weight response, and compared patient characteristics between subjects who persisted on treatment versus those who discontinued EOW.FindingsOne-hundred eighty-six patients (46.2% male) were included in the study. The mean (SD) age and diabetes duration were 63.2 (8.9) years and 10.7 years (18.3), respectively. Significant reductions in HbA_1c values (−0.9%; 95% CI, −1.1 to −0.8) and body weight (−2.8 kg; 95% CI, −3.4 to −2.2) were observed after 6 months. Sixty-one percent of patients (87 of 143) achieved target HbA_1c values ≤ 7% after 12 months, and 34% (45 of 134) exhibited a weight loss of at least 5% of baseline body weight. Blood glucose and weight reductions were maintained after an 18-month follow-up. Predictors of adequate glycemic and weight response were shorter diabetes duration and nonuse of a different GLP-1RA, respectively. Patients on sulfonylureas failed to reach metabolic and body weight targets. The most common adverse events were gastrointestinal side effects (7.5%) and injection site reactions (6.4%), followed by headache (1.1%) and allergic reactions (1.1%). Forty-three percent of patients (79 of 186) discontinued EOW. The main reasons for discontinuation were insufficient HbA_1c improvement and/or limited weight reduction (19.9%), side effects (16.1%), or patient decision (6.5%). Predictors of discontinuation were higher HbA_1c levels at baseline and use of basal insulin therapy before EOW treatment.ImplicationsEOW treatment, in a real-world setting, offers sustained and effective glycemic control and weight loss over 18 months in patients with T2DM. Diabetes duration and basal insulin therapy, however, may affect the outcome of EOW treatment, suggesting that early initiation of EOW could improve glycemic control and reduce the risk of treatment discontinuation.     

Durability of Triple Combination Therapy Versus Stepwise Addition Therapy in Patients With New-Onset T2DM: 3-Year Follow-up of EDICT

OBJECTIVETo compare the long-term efficacy of initiating therapy with metformin/pioglitazone/exenatide in patients with new-onset type 2 diabetes mellitus (T2DM) versus sequential addition of metformin followed by glipizide and insulin.RESEARCH DESIGN AND METHODSDrug-naive patients (N = 318) with new-onset T2DM were randomly assigned to receive for 3 years either 1) combination therapy with metformin, pioglitazone, and exenatide (triple therapy) or 2) sequential addition of metformin followed by glipizide and insulin (conventional therapy) to maintain HbA_1c at <6.5% (48 mmol/mol). Insulin sensitivity and β-cell function were measured at baseline and 3 years. The primary outcome was the difference in HbA_1c between the groups at 3 years.RESULTSBaseline HbA_1c ± SEM values were 9.0% ± 0.2% and 8.9% ± 0.2% in the triple therapy and conventional therapy groups, respectively. The decrease in HbA_1c resulting from triple therapy was greater at 6 months than that produced by conventional therapy (0.30% [95% CI 0.21–0.39]; P = 0.001), and the HbA_1c reduction was maintained at 3 years in patients receiving triple therapy compared with conventional therapy (6.4% ± 0.1% and 6.9% ± 0.1%, respectively), despite intensification of antihyperglycemic therapy in the latter. Thus, the difference in HbA_1c between the two treatment groups at 3 years was 0.50% (95% CI 0.39–0.61; P < 0.0001). Triple therapy produced a threefold increase in insulin sensitivity and 30-fold increase in β-cell function. In conventional therapy, insulin sensitivity did not change and β-cell function increased by only 34% (both P < 0.0001 vs. triple therapy).CONCLUSIONSTriple therapy with agents that improve insulin sensitivity and β-cell function in patients with new-onset T2DM produces greater, more durable HbA_1c reduction than agents that lower glucose levels without correcting the underlying metabolic defects.     

Historical HbA1c Values May Explain the Type 2 Diabetes Legacy Effect: UKPDS 88

OBJECTIVEType 2 diabetes all-cause mortality (ACM) and myocardial infarction (MI) glycemic legacy effects have not been explained. We examined their relationships with prior individual HbA_1c values and explored the potential impact of instituting earlier, compared with delayed, glucose-lowering therapy.RESEARCH DESIGN AND METHODSTwenty-year ACM and MI hazard functions were estimated from diagnosis of type 2 diabetes in 3,802 UK Prospective Diabetes Study participants. Impact of HbA_1c values over time was analyzed by weighting them according to their influence on downstream ACM and MI risks.RESULTSHazard ratios for a one percentage unit higher HbA_1c for ACM were 1.08 (95% CI 1.07–1.09), 1.18 (1.15–1.21), and 1.36 (1.30–1.42) at 5, 10, and 20 years, respectively, and for MI was 1.13 (1.11–1.15) at 5 years, increasing to 1.31 (1.25–1.36) at 20 years. Imposing a one percentage unit lower HbA_1c from diagnosis generated an 18.8% (95% CI 21.1–16.0) ACM risk reduction 10–15 years later, whereas delaying this reduction until 10 years after diagnosis showed a sevenfold lower 2.7% (3.1–2.3) risk reduction. Corresponding MI risk reductions were 19.7% (22.4–16.5) when lowering HbA_1c at diagnosis, and threefold lower 6.5% (7.4–5.3%) when imposed 10 years later.CONCLUSIONSThe glycemic legacy effects seen in type 2 diabetes are explained largely by historical HbA_1c values having a greater impact than recent values on clinical outcomes. Early detection of diabetes and intensive glucose control from the time of diagnosis is essential to maximize reduction of the long-term risk of glycemic complications.     

Adherence as a Predictor of Glycemic Control Among Adolescents With Type 1 Diabetes: A Retrospective Study Using Real-world Evidence

PurposeMetabolic control among adolescents with type 1 diabetes mellitus (T1DM) is generally poor. Nonadherence is a contributor to this poor glycemic control, leading to adverse outcomes. The findings of studies reporting the association between adherence and glycemic control are conflicting. This study aimed to assess the level of adherence among adolescents with T1DM and its relationship with glycemic control.MethodsThis was a retrospective, cross-sectional study that was conducted at Sidra Medicine, a state-of-the-art tertiary health care facility for women and children in Qatar. Mean blood or interstitial glucose monitoring frequency (BGMF) was used to assess adherence level among adolescents with T1DM, whereas glycemic control was assessed via documented glycated hemoglobin A_1c (HbA_1c). Adolescents who had a mean BGMF of ≥4 checks per day were considered adherent, and those who had an HbA_1c level of <7% were considered as having controlled diabetes. Correlational and logistic regression analyses were performed to assess the relationship between adherence and glycemic control, incorporating other covariates into the model.FindingsThe rate of adherence among adolescents with T1DM in Qatar was 40.9%. Adherent adolescents had significantly lower median HbA_1c levels compared with nonadherent adolescents (9.0% vs. 9.7%; P = 0.002). A significant negative correlation was found between BGMF and HbA_1c level (correlation coefficient r_s = ?0.325; P < .001). Approximately 97% of nonadherent adolescents compared with 87% of adherent adolescents had suboptimal diabetes control (HbA_1c ≥7%) (P = .016). Furthermore, nonadherent adolescents were 78% less likely to have controlled diabetes compared with adherent adolescents (adjusted odds ratio = 0.221; 95% CI, 0.063?0.778; P = 0.019). The combined effect of the determinants of glycemic control among adolescents with T1DM that were included in the multiple regression model was able to explain approximately 9% of the variances in glycemic control (Cox and Snell R² = 0.092).ImplicationsThe current findings suggest that nonadherence was highly prevalent among adolescents with T1DM and was a significant independent predictor of glycemic control, explaining 9% of the variability. This finding warrants further exploration of other possible predictors of poor glycemic control among the adolescent population. Comprehensive interventions, including educational, technological, and health service delivery aspects, aimed at improving adherence and ultimately optimizing glycemic control are warranted in adolescents with T1DM.     

Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

OBJECTIVESulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA_1c reduction.RESEARCH DESIGN AND METHODSAs an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA_1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.RESULTSAfter establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA_1c reduction at a genome-wide scale (P < 5 × 10⁻⁸). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10⁻⁸), lower reduction in HbA_1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10⁻⁵⁸). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA_1c (P = 4.80 × 10⁻⁸). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10⁻⁷), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA_1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.CONCLUSIONSWe have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.     

The Effect of Exenatide Once Weekly on Carotid Atherosclerosis in Individuals With Type 2 Diabetes: An 18-Month Randomized Placebo-Controlled Study

OBJECTIVEGlucagon-like peptide 1 receptor agonists (GLP-1RAs) improved multiple proatherogenic risk factors and reduced cardiovascular events in recent clinical trials, suggesting that they may slow progression of atherosclerosis. We tested whether exenatide once weekly reduces carotid plaque progression in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODSIn a double-blind, pragmatic trial, 163 participants were randomized (2:1) to exenatide (n = 109) or placebo (n = 54). Changes in carotid plaque volume and composition were measured at 9 and 18 months by multicontrast 3 Tesla MRI. Fasting and post–high-fat meal plasma glucose and lipids, and endothelial function responses, were measured at 3, 9, and 18 months.RESULTSExenatide reduced hemoglobin A_1c (HbA_1c) (estimated difference vs. placebo 0.55%, P = 0.0007) and fasting and postmeal plasma glucose (19 mg/dL, P = 0.0002, and 25 mg/dL, P < 0.0001, respectively). Mean (SD) change in plaque volume in the exenatide group (0.3% [2%]) was not different from that in the placebo group (−2.2% [8%]) (P = 0.4). The change in plaque volume in the exenatide group was associated with changes in HbA_1c (r = 0.38, P = 0.0004), body weight, and overall plasma glucose (r = 0.29, P = 0.007 both). There were no differences in changes in plaque composition, body weight, blood pressure, fasting and postmeal plasma triglycerides, and endothelial function between the groups.CONCLUSIONSExenatide once weekly for up to 18 months improved fasting and postprandial glycemic control but did not modify change in carotid plaque volume or composition. This study raises the possibility that short-term antiatherosclerotic effects may not play a central role in the cardiovascular benefits of GLP-1RAs.     

Achieving Good Metabolic Control Without Weight Gain with the Systematic Use of GLP-1-RAs and SGLT-2 Inhibitors in Type 2 Diabetes: A Machine-learning Projection Using Data from Clinical Practice

PurposeRecently, the 2022 American Diabetes Association and European Association for the Study of Diabetes (ADA-EASD) consensus report stressed the importance of weight control in the management of patients with type 2 diabetes; weight control should be a primary target of therapy. This retrospective analysis evaluated, through an artificial-intelligence (AI) projection of data from the AMD Annals database—a huge collection of most Italian diabetology medical records covering 15 years (2005–2019)—the potential effects of the extended use of sodium–glucose co-transporter 2 inhibitors (SGLT-2is) and of glucose-like peptide 1 receptor antagonists (GLP-1-RAs) on HbA_1c and weight.MethodsData from 4,927,548 visits in 558,097 patients were retrospectively extracted using these exclusion criteria: type 1 diabetes, pregnancy, age >75 years, dialysis, and lack of data on HbA_1c or weight. The analysis revealed late prescribing of SGLT-2is and GLP-1-RAs (innovative drugs), and considering a time frame of 4 years (2014–2017), a paradoxic greater percentage of combined-goal (HbA_1c <7% and weight gain <2%) achievement was found with older drugs than with innovative drugs, demonstrating aspects of therapeutic inertia. Through a machine-learning AI technique, a “what-if” analysis was performed, using query models of two outcomes: (1) achievement of the combined goal at the visit subsequent to a hypothetical initial prescribing of an SGLT-2i or a GLP-1-RA, with and without insulin, selected according to the 2018 ADA-EASD diabetes recommendations; and (2) persistence of the combined goal for 18 months. The precision values of the two models were, respectively, sensitivity, 71.1 % and 69.8%, and specificity, 67% and 76%.FindingsThe first query of the AI analysis showed a great improvement in achievement of the combined goal: 38.8% with prescribing in clinical practice versus 66.5% with prescribing in the “what-if” simulation. Addressing persistence at 18 months after the initial achievement of the combined goal, the simulation showed a potential better performance of SGLT-2is and GLP-1-RAs with respect to each antidiabetic pharmacologic class or combination considered.ImplicationsAI appears potentially useful in the analysis of a great amount of data, such as that derived from the AMD Annals. In the present study, an LLM analysis revealed a great potential improvement in achieving metabolic targets with SGLT-2i and GLP-1-RA utilization. These results underscore the importance of early, timely, and extended use of these new drugs.     

HbA1c Reduction in Dulaglutide-Treated Patients Irrespective of Duration of Diabetes,Microvascular Disease,and BMI: A Post Hoc Analysis From the REWIND Trial

OBJECTIVETo evaluate participant characteristics and long-term changes in glycated hemoglobin (HbA_1c) levels in patients treated with dulaglutide 1.5 mg in a post hoc analysis of the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial.RESEARCH DESIGN AND METHODSChange from baseline in HbA_1c was assessed during and up to 72 months of treatment before and after adjustment for duration of diabetes, prior microvascular disease (nephropathy or retinopathy), and BMI. Slope analyses were used to assess the change in HbA_1c during 0–12 months and 12–72 months of therapy.RESULTSHbA_1c was significantly reduced in patients treated with dulaglutide compared with placebo during 72 months of treatment (least-squares mean difference = −0.61%, P < 0.001), regardless of diabetes duration, prior microvascular disease, and BMI (all interaction P > 0.07). Significant reductions were apparent at all time points and were independent of these baseline characteristics. Slope analyses revealed that the dulaglutide group experienced a higher rate of HbA_1c reduction compared with the placebo group from 0 to 12 months before and after adjustment. The dulaglutide group also experienced a higher rate of HbA_1c increase from 12 to 72 months compared with the placebo group that became nonsignificant after adjustment for diabetes duration, prior microvascular disease, and BMI combined. Despite the greater rate of HbA_1c increase in the dulaglutide group during this period, mean HbA_1c values remained below baseline in the dulaglutide group and below mean HbA_1c values in the placebo group.CONCLUSIONSDulaglutide 1.5-mg treatment was statistically associated with a long-lasting decrease in HbA_1c over 72 months, irrespective of baseline duration of diabetes, microvascular disease, and BMI.     

Adding Once-Daily Lixisenatide for Type 2 Diabetes Inadequately Controlled by Established Basal Insulin: A 24-week,randomized, placebo-controlled comparison (GetGoal-L)

OBJECTIVE

To examine the efficacy and safety of adding the once-daily glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide to established basal insulin therapy alone or together with metformin, in people with type 2 diabetes and elevated glycated hemoglobin (HbA_1c).

RESEARCH DESIGN AND METHODS

We conducted a double-blind, parallel-group, placebo-controlled trial. Patients (n = 495) with established basal insulin therapy but inadequate glycemic control were randomized to add lixisenatide 20 μg or placebo for 24 weeks. Basal insulin dosage was unchanged except to limit hypoglycemia. HbA_1c reduction from baseline was the primary end point.

RESULTS

Mean duration of diabetes was 12.5 years, duration of insulin use was 3.1 years, insulin dosage was 55 units/day, and baseline HbA_1c was 8.4%. With lixisenatide, the placebo-corrected change of HbA_1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA_1c at end point was 7.8%. HbA_1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, –3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, –1.3 kg; P < 0.0001) and insulin dosage (–3.7 units/day; P = 0.012) were greater with lixisenatide. Main adverse events (AEs) with lixisenatide were gastrointestinal. Symptomatic hypoglycemia was 28% for lixisenatide and 22% for placebo; 4 of 328 subjects (1.2%) had severe hypoglycemia with lixisenatide vs. 0 of 167 with placebo.

CONCLUSIONS

By improving HbA_1c and postprandial hyperglycemia without weight gain in type 2 diabetes with inadequate glycemic control despite stable basal insulin, lixisenatide may provide an alternative to rapid-acting insulin or other treatment options.In type 2 diabetes, additional therapies are needed over time to maintain acceptable glycemic control (1–3). When lifestyle measures and oral antihyperglycemic agents are no longer sufficient, the addition of basal insulin optimized by systematic titration of dosage can restore glycated hemoglobin (HbA_1c) to 7.0% for 50–60% of people with type 2 diabetes (2,4,5). However, some people do not initially achieve this glycemic target with basal insulin plus oral therapy, and others experience later deterioration of control (6–9). Further therapy, especially for postprandial hyperglycemia, is then needed. A traditional option has been to add one or more injections of prandial insulin (10), but adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) is a recently proposed alternative that may improve glycemic control without additional weight gain and, perhaps, with less hypoglycemia. Drugs of this class have effects that complement those of basal insulin; they potentiate endogenous insulin responses to hyperglycemia, suppress inappropriately elevated glucagon secretion, and favor weight loss by promoting satiety (11,12). In addition, GLP-1RAs can slow gastric emptying, further blunting postprandial hyperglycemia. However, slowing of gastric emptying appears to be greater with short-acting than with long-acting GLP-1RAs (13), possibly related to the observation that, with time, continuous exposure of GLP-1 leads to a reduction in its effect on gastric emptying (14).Lixisenatide is a novel GLP-1RA that, like other drugs of its class, has demonstrated significant improvements in glycemic control, low rates of hypoglycemia, and a beneficial effect on weight (15–17). Lixisenatide taken once daily (15) improves HbA_1c levels by reducing fasting plasma glucose (FPG) and has robust postprandial glucose (PPG) effects (18,19). Lixisenatide was granted marketing authorization by the European Medicines Agency in February 2013 (20). The objective of this study was to examine the efficacy and safety of adding once-daily lixisenatide to established basal insulin therapy (dosage maintained except for the avoidance of hypoglycemia), alone or together with metformin, in people with long-duration type 2 diabetes and inadequate glycemic control.