Smart Algorithms for Efficient Insulin Therapy Initiation in Individuals With Type 2 Diabetes: An in Silico Study.

BACKGROUND: Insulin-naive subjects with type 2 diabetes (T2D) start basal insulin titration from a low initial insulin dose (IID), which is adjusted weekly or twice per week based on fasting plasma glucose (FPG) measurement as recommended by the American Diabetes Association (ADA). The procedure to reach the optimal insulin dose (OID) is time-consuming, especially in subjects with high insulin needs (HIN). The aim of this study is to provide a fast and effective, but still safe, insulin titration algorithm in insulin-naive T2D subjects with HIN. METHOD: To do that, we in silico cloned 300 subjects, matching a real population of insulin-naive T2D and used a logistic regression model to classify them as subjects with HIN or subjects with low insulin needs (LIN). Then, we applied to the subjects with HIN both a more aggressive insulin dose initiation (SMART-IID) and two newly developed titration algorithms (continuous glucose monitoring [CGM]-BASED and SMART-CGM-BASED) in which CGM was used to guide the decision-making process. RESULTS: The new titration algorithm applied to HIN-classified individuals guaranteed a faster reaching of OID, with significant improvements in time in range (TIR) and reduction in time above range (TAR) in the first months of the trial, without any clinically significant increase in the risk of hypoglycemia. CONCLUSIONS: Smart basal insulin titration algorithms enable insulin-naive T2D individuals to achieve OID and improve their glycemic control faster than standard guidelines, without jeopardizing patient safety.

Short- and Long-Term Effects on Glucose Control of Nonadherence to Insulin Therapy in People With Type 2 Diabetes An In Silico Study.

BACKGROUND: Strict adherence to multiple daily insulin (MDI) therapy is a cornerstone for the achievement of good glucose control in people with advanced type 2 diabetes (T2D). Here, we aim to in silico assess glucose control in T2D subjects with poor adherence to MDI therapy. METHODS: We tuned the Padova T2D Simulator, originally describing early-stage T2D physiology, around advanced T2D people. One hundred in silico advanced T2D subjects were generated and equipped with optimal MDI therapy: specifically, basal and bolus insulin amounts and injection times were individualized for each subject by applying titration algorithms that iteratively update insulin dose based on glucose deviation from its target. Then, the effect of nonadhering to MDI therapy was assessed using standard glucose control metrics calculated in two 6-month 3-meal/day in silico scenarios: in Scenario 1, subjects received the optimal basal and prandial insulin bolus at each meal; in Scenario 2, subjects received optimal basal insulin and randomly delayed or skipped the prandial insulin bolus in 3 lunches during working days and 1 dinner during weekends. RESULTS: A statistically significant degradation was found in all glucose control outcome metrics in Scenario 2 versus Scenario 1: e.g., percent time above 180 mg/dL increased by 22.2% and glucose management index by 0.2%. CONCLUSIONS: Impaired adherence to MDI therapy in T2D leads to glucose control deteriorations in both short and long terms. Interestingly, short-term hyperglycemia seems being contrasted by residual endogenous insulin secretion, which statistically increased by 3-fold after delayed/skipped insulin boluses compared with optimal ones.

Tailoring the Padova Type 2 Diabetes Simulator for Treatment Guidance in Target Populations.

OBJECTIVE: The Padova type 2 diabetes (T2D) simulator (T2DS) has been recently proposed to optimize T2D treatments including novel long-acting insulins. It consists of a physiological model and an in silico population describing glucose dynamics, derived from early-stage T2D subjects studied with sophisticated tracer-based experimental techniques. This limits T2DS domain of validity to this specific sub-population. Conversely, running simulations in insulin-naïve or advanced T2D subjects, would be more valuable. However, it is rarely possible or cost-effective to run complex experiments in such populations. Therefore, we propose a method for tuning the T2DS to any desired T2D sub-population using published clinical data. As case study, we extended the T2DS to insulin-naïve T2D subjects, who need to start insulin therapy to compensate the reduced insulin function. METHODS: T2DS model was identified based on literature data of the target population. The estimated parameters were used to generate a virtual cohort of insulin-naïve T2D subjects (inC1). A model of basal insulin degludec (IDeg) was also incorporated into the T2DS to enable basal insulin therapy. The resulting tailored T2DS was assessed by simulating IDeg therapy initiation and comparing simulated vs. clinical trial outcomes. For further validation, this procedure was reiterated to generate a new cohort of insulin-naïve T2D (inC2) assuming inC1 as target population. RESULTS: No statistically significant differences were found when comparing fasting plasma glucose and IDeg dose, neither in clinical data vs. inC1, nor inC1 vs. inC2. CONCLUSIONS: The tuned T2DS allowed reproducing the main findings of clinical studies in insulin-naïve T2D subjects. SIGNIFICANCE: The proposed methodology makes the Padova T2DS usable for supporting treatment guidance in target T2D populations.