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Introduction: SoliMix (EudraCT: 2017-003370-13) found better HbA1c, weight benefit, and lower hypoglycemia risk with iGlarLixi vs. premix BIAsp 30 in people with type 2 diabetes (T2D) advancing from basal insulin (BI) + oral antihyperglycemic drugs (OADs) . Methods: Adults with T2D and HbA1c 7.5-10.0 % on BI + 1-2 OADs were randomized to once-daily iGlarLixi or twice-daily BIAsp 30 for 26 weeks. Primary outcomes were non-inferiority in HbA1c change or superiority in body weight change from baseline to Week 26. SoliMix endpoints were assessed here by baseline age ( Results: No differences in treatment effect were observed across subgroups for HbA1c or body weight changes (heterogeneity p>0.05; Table) ; both primary objectives were met in the age, T2D duration, and the eGFR ≥60-0.80) . The advantage of iGlarLixi over BIAsp 30 for Level 2 hypoglycemia was found in all subgroups with no difference in treatment effect (p>0.10) . Conclusions: The primary findings for iGlarLixi vs. BIAsp 30 were unaffected by baseline age, T2D duration, or renal function. Disclosure P.Home: Advisory Panel; Kriya Therapeutics, Consultant; Mundipharma, Sanofi, Other Relationship; AstraZeneca, Sanofi, Research Support; Gan & Lee Pharmaceuticals, Sanofi, Speaker's Bureau; Gan & Lee Pharmaceuticals, Medscape. J.Rosenstock: Consultant; AstraZeneca, Other Relationship; Applied Therapeutics, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Research Support; Genentech, Inc., Merck & Co., Inc., Metacrine, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., vTv Therapeutics. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Djaballah: Employee; Sanofi. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH. L.Melas-melt: None. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. Funding Sanofi

Introduction: SoliMix (EudraCT: 2017-003370-13) found better HbA1c, weight benefit, and lower hypoglycemia risk requiring less insulin with once-daily iGlarLixi vs. twice-daily premix BIAsp 30 in people with type 2 diabetes (T2D) advancing from basal insulin (BI) and oral antihyperglycemic drugs (OADs) . Methods: Adults with T2D and HbA1c 7.5-% on BI + 1-2 OADs were randomized to iGlarLixi or BIAsp 30 for 26 weeks. Primary outcomes were non-inferiority in HbA1c change or superiority in body weight change with iGlarLixi vs. BIAsp 30. This post hoc analysis assessed SoliMix endpoints by baseline HbA1c (7.5-8, >8-9, >9-%) , insulin dose ( Results: No differences in treatment effect were seen across subgroups for change in HbA1c or BMI (heterogeneity p>0.10; Table) ; both primary objectives were met in the HbA1c >8-≤9 %, BMI ≥25-0.10) . Level 2 hypoglycemia incidence and rates were unaffected by baseline HbA1c and BMI (p>0.10) , but p Conclusions: Primary SoliMix findings for iGlarLixi vs. BIAsp 30 were consistent across baseline HbA1c and BMI subgroups but inconsistent for baseline insulin dose. Disclosure P.Home: Advisory Panel; Kriya Therapeutics, Consultant; Mundipharma, Sanofi, Other Relationship; AstraZeneca, Sanofi, Research Support; Gan & Lee Pharmaceuticals, Sanofi, Speaker's Bureau; Gan & Lee Pharmaceuticals, Medscape. R.J.Mccrimmon: Advisory Panel; Novo Nordisk, Sanofi, Research Support; Diabetes UK, European Union, MedImmune. J.Rosenstock: Consultant; AstraZeneca, Other Relationship; Applied Therapeutics, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Sanofi, Zealand Pharma A/S, Research Support; Genentech, Inc., Merck & Co., Inc., Metacrine, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., vTv Therapeutics. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Pegelow: Employee; Sanofi-Aventis Deutschland GmbH. L.Melas-melt: None. K.Djaballah: Employee; Sanofi. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. Funding Sanofi

Introduction: Therapeutic approaches to advancing treatment from basal insulin in T2D require assessment of the benefits and risks of any chosen intervention. Methods: SoliMix was a 26-week, open-label, multicenter study in which adults (N=887) with T2D and HbA1c ≥7.5-≤10.0 % (≥58-≤86 mmol/mol) using basal insulin + metformin ± sodium-glucose co-transporter-2 inhibitors were randomized to once-daily iGlarLixi (fixed-ratio combination of basal insulin glargine 100 U/mL + lixisenatide) or twice-daily premix insulin 30/70 analog (BiAsp 30). HbA1c improved and bodyweight changes were favorable with iGlarLixi vs. BiAsp 30 (primary outcomes), while hypoglycemia event rates were also lower with iGlarLixi vs. BiAsp 30. This subanalysis assessed estimated hypoglycemia event rates over the whole treatment period as a function of HbA1c at Week 26. Results: Modelled event profiles for clinically significant hypoglycemia (ADA Level 2 [ Conclusion: Lower rates of hypoglycemia with iGlarLixi across a broad range of HbA1c suggests that iGlarLixi facilitates greater HbA1c improvement vs. premix insulin 30/70. Disclosure R. J. Mccrimmon: Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, Board Member; Self; Novo Nordisk Foundation, Research Support; Self; AstraZeneca. J. Rosenstock: Board Member; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Consultant; Self; Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Novo Nordisk, Oramed Pharmaceuticals, Inc., Sanofi, Research Support; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Genentech, Inc., Intarcia Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics, Sanofi. P. Home: Consultant; Self; American Diabetes Association, Kriya Technologies, Sanofi, Other Relationship; Self; Association of British Clinical Diabetologists, AstraZeneca, Novartis Malaysia, Sanofi, Research Support; Self; Sanofi. A. Y. Cheng: Advisory Panel; Self; Abbott, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, Research Support; Self; Applied Therapeutics, The Medicine Company, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch Health, Canada, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. V. Fonseca: Consultant; Self; Abbott Diabetes, Asahi Kasei Corporation, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Stock/Shareholder; Self; Amgen Inc., Bravo4health, Mellitus Health. E. Souhami: Employee; Self; Sanofi, Stock/Shareholder; Self; Sanofi. A. Alvarez: Employee; Self; Sanofi. A. H. Boss: Employee; Self; Sanofi, Stock/Shareholder; Self; Novo Nordisk A/S. L. Melas-melt: None. Funding Sanofi

Introduction: No head-to-head trials compare iGlarLixi, a fixed-ratio combination of basal insulin (BI) and glucagon-like peptide-1 receptor agonist, with IDegAsp, a co-formulation of BI analog and meal-time insulin. Methods: A systematic literature search of randomized controlled trials (RCTs) of iGlarLixi and IDegAsp vs. comparators was carried out. Studies were compared by an ITC using a Bayesian framework. Results are given for all trials, Japanese trials, and international trials. Results: Eight RCTs (duration 24-30 weeks) were included. Change in HbA1c with iGlarLixi was greater, and bodyweight trajectory was more favorable than with IDegAsp for all analyses (Figure). A greater percentage of people achieved HbA1c target ( Conclusion: iGlarLixi offers clinical benefit in glycemic control and weight change vs. IDegAsp in those requiring both basal plus meal-time insulin interventions. Disclosure P. Home: Consultant; Self; American Diabetes Association, Kriya Technologies, Sanofi, Other Relationship; Self; Association of British Clinical Diabetologists, AstraZeneca, Novartis Malaysia, Sanofi, Research Support; Self; Sanofi. R. Mehta: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Abbott, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc. K. Hafidh: None. O. Gurova: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi, STADA, Takeda Pharmaceutical Co. A. Alvarez: Employee; Self; Sanofi. P. Serafini: Other Relationship; Self; Sanofi. M. Pourrahmat: Other Relationship; Self; Sanofi. Funding Sanofi

In people with type 2 diabetes uncontrolled by GLP-1 RAs, fixed-ratio combination (FRC; basal insulin + GLP-1 RA) is a recommended option. A PICO-framework systematic review of RCTs followed by an ITC was performed to compare the efficacy and safety of the FRCs iGlarLixi (insulin glargine 100 U/mL + lixisenatide) and IDegLira (insulin degludec + liraglutide) in this population. A fixed effects model was used on the two eligible RCTs. Outcomes: change from baseline to week 26 in HbA1c, clinic fasting plasma glucose (FPG), self-monitored plasma glucose (SMPG), and body weight; proportion achieving HbA1c Disclosure P. Home: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Mundipharma International, Novartis AG, Sanofi. Research Support; Self; GlaxoSmithKline plc., Merck & Co., Inc., Sanofi. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim International GmbH. V.R. Aroda: Consultant; Self; Duke, Novo Nordisk Inc., Sanofi. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Applied Therapeutics, Fractyl Laboratories, Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; IMNE, Medscape. M. Fazeli: None. C. Whittington: Employee; Self; Sanofi US. H. Goswami: None. A. Shaunik: None. M. Pourrahmat: Other Relationship; Self; Sanofi US. L. Blonde: Advisory Panel; Self; AstraZeneca, Gilead Sciences, Inc. Consultant; Self; Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Janssen Scientific Affairs, LLC., Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc., Sanofi. S. Kalra: Advisory Panel; Self; Eli Lilly and Company. Speaker’s Bureau; Self; Novo Nordisk A/S, Sanofi-Aventis. Funding Sanofi

The glycemic efficacy of weekly Albi 50 mg to replace prandial insulin lispro (Lis) was evaluated in T2DM inadequately controlled on a multiple daily insulin regimen (≥3 injections/day). Basal/bolus insulin was optimized during a 4 week run-in phase before randomization to: 1) Albi + optimized insulin glargine (Gla), with prandial Lis subsequently discontinued by week 4 (n = 402) or 2) optimized Lis + optimized Gla (n = 412). At 26 week, the LS mean ± SE change from baseline in HbA1c was −1.04 ± 0.04 vs. −1.10 ± 0.04% (treatment difference 0.[95% CI, −0.05, 0.17]%; non-inferiority p In conclusion, Albi meaningfully improved glucose control; prandial insulin was stopped in 54% of participants, allowing substantial reductions in insulin dose and number of injections, less hypoglycemia, and body weight loss. Disclosure J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. A.J. Nino: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. J. Soffer: Employee; Self; GlaxoSmithKline plc.. Other Relationship; Self; GlaxoSmithKline plc.. J.M. Mallory: None. L.M. Erskine: Employee; Self; GlaxoSmithKline plc.. Stock/Shareholder; Self; GlaxoSmithKline plc. A. Acusta: Employee; Self; GlaxoSmithKline plc. J.F. Dole: Employee; Self; GlaxoSmithKline plc. M. Carr: Employee; Self; GlaxoSmithKline plc. P. Home: Consultant; Self; AstraZeneca. Other Relationship; Self; Biocon, Boehringer Ingelheim GmbH. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Hanmi Pharmaceutical. Other Relationship; Self; Janssen Research & Development. Consultant; Self; Janssen Research & Development, Merck & Co., Inc.. Other Relationship; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; AntriaBio, Inc., Earlysign, Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Sanofi. Consultant; Self; Sanofi.

Pooled participant-level data from 16 RCTs (≥ 24 weeks) were used to explore the association of demographic and clinical markers with different levels of HbA1c achieved at Week 24 in insulin-naive people with T2DM on oral agents after starting insulin glargine 100 U/mL (Gla-100). A stepwise logistic regression analysis was performed to identify potential predictive and exploratory factors for attaining an HbA1c < 7.0%. In total, 46%, 37%, and 17% of 3,415 participants (53% male) included in the analysis achieved Week 24 HbA1c < 7.0%, 7.0-8.0%, and > 8.0%, respectively. Key clinical findings and multivariate analysis results are shown in the Table. Sex, diabetes duration, baseline BMI, HbA1c, FPG, and overall 2h-PPG were significant predictors of attaining HbA1c < 7.0% at Week 24, whereas change in FPG or 2h-PPG were not. FPG and 2h-PPG levels in the HbA1c > 8.0% group remained highest despite a higher Gla-100 dose (0.52 U/kg) and lower overall hypoglycaemia (PG < 3.9 mmol/L) rate at Week 24. In people with T2DM, high baseline HbA1c, FPG, and PPG levels are important predictors of failure of basal insulin/OAD therapy to achieve desired glycaemic goals. A more active treatment strategy targeting both fasting and postprandial hyperglycaemia appears to be indicated for people with poor glycaemic control after starting basal insulin therapy. Disclosure D.R. Owens: Consultant; Self; Boehringer Ingelheim GmbH, Roche Diagnostics Corporation, Eli Lilly and Company, Sanofi, Takeda Development Centre Europe Ltd.. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Roche Diagnostics Corporation, Eli Lilly and Company, Sanofi, Takeda Development Centre Europe Ltd. W. Landgraf: Employee; Self; Sanofi-Aventis Deutschland GmbH. Stock/Shareholder; Self; Sanofi. M. Zhang: Employee; Self; Sanofi US. Stock/Shareholder; Self; Sanofi US. B.M. Frier: Advisory Panel; Self; Novo Nordisk A/S, Eli Lilly and Company. Consultant; Self; Locemia Solutions, Zucara Therapeutics. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company, Roche Pharma, AstraZeneca. L. Meneghini: Advisory Panel; Self; Novo Nordisk Inc., Sanofi US. Consultant; Self; Sanofi US, Novo Nordisk Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; American Diabetes Association. P. Home: Consultant; Self; AstraZeneca. Other Relationship; Self; Biocon, Boehringer Ingelheim GmbH. Research Support; Self; GlaxoSmithKline plc.. Consultant; Self; Hanmi Pharmaceutical. Other Relationship; Self; Janssen Research & Development. Consultant; Self; Janssen Research & Development, Merck & Co., Inc.. Other Relationship; Self; Merck & Co., Inc.. Research Support; Self; Merck & Co., Inc.. Other Relationship; Self; Novo Nordisk A/S. Consultant; Self; AntriaBio, Inc., Earlysign, Roche Diabetes Care Health and Digital Solutions. Research Support; Self; Sanofi. Consultant; Self; Sanofi. G.B. Bolli: Speaker's Bureau; Self; Menarini Group, Sanofi. Research Support; Self; Sanofi.

The regulation of liver and skeletal muscle glycogen synthase by plasma insulin and glucose has not been investigated in vivo at physiological blood glucose concentrations. We have,therefore, used the glucose clamp technique to investigate the effects of these variables independently in rats. Short-term streptozocin-(0.15 g/kg) diabetic animals were used in addition to normal rats to avoid endogenous insulin secretion during hyperglycemic clamps. In normal and diabetic animals, 3 h of hyperinsulinemia without change in blood glucose concentrations caused only a small increase in liver glycogen synthase activity (+ 34%), whereas hyperglycemic clamps at 6.0 and 10.0 mmol/L resulted in marked increases (+ 268 and +394% of basal, P < 0.001). Liver glycogen concentrations at the end of the clamps reflected these changes. In skeletalmuscle, glycogen synthase was increased by +58% by the euglycemic hyperinsulinemic clamp and was not increased significantly further by hyperglycemia. Similarly, muscle glycogen concentration increased with the 4.0-mmol/L clamp but during the hyperglycemic clamps was only raised more indirect proportion to blood glucose concentrations. The results confirm that blood glucose concentration is the major short-term regulator of glycogen synthase activity in the liver but that insulin is of prime importance in skeletal muscle.

Severely diabetic (0.15 g/kg streptozocin) rats were transplanted with fetal pancreatic islets (1) under the renal capsule to model peripheral insulin delivery, or (2) into the splenic pulp to model portal delivery. In both groups of transplanted rats, weight gain and blood glucose concentrations were normal. Peripheral insulin delivery abolished the physiologic portal-peripheral insulin concentration gradient but was not associated with peripheral hyperinsulinemia. Incorporation of 3H2O into liver glycogen and the increase in hepatic glycogen concentration after a meal were normal in animals receiving insulin peripherally for 10 wk. Activation of liver glycogen synthase in response to the meal was also normal. Hepatic insulin receptor status in animals with peripheral insulin delivery was identical to that of normal control and splenic pulp islet-transplanted rats. The findings indicate that portal insulin delivery is not a prerequisite for normal hepatic glycogen metabolism in the rat, and that receptor upregulation and increased hepatic extraction of insulin are unlikely to explain the normal hepatic metabolism with peripheral insulin delivery.

Severely diabetic (150 mg/kg streptozocin, STZ) rats were transplanted with fetal pancreatic islets: (1) under the renal capsule to model peripheral insulin delivery, and (2) into the splenic pulp to model portal delivery. In both groups of transplanted animals, weight gainand blood glucose levels were normal as were peripheral plasma insulin levels. Plasma nonesterified fatty acids, glycerol, acetoacetate, 3-hydroxybutyrate, triglyceride, and cholesterol levels were normal in the two groups of transplanted animals as were VLDL-triglyceride turnover and totalketone body turnover. Adipose tissue lipoprotein lipase activity was also normal in both the fed and fasting states. The findings indicate that consistent normoglycemia and normalization of manyaspects of lipid metabolism can be achieved in the rat with peripheral insulin delivery without associated hyperinsulinemia.