Current barriers to initiating insulin therapy in individuals with type 2 diabetes.

Insulin is an essential drug in the treatment of diabetes, often necessary for managing hyperglycemia in type 2 diabetes mellitus (T2DM). It should be considered in cases of severe hyperglycemia requiring hospitalization, after the failure of other treatments, in advanced chronic kidney disease, liver cirrhosis, post-transplant diabetes, or during pregnancy. Moreover, in specific patient subgroups, early initiation of insulin is crucial for hyperglycemia control and prevention of chronic complications. Clinical guidelines recommend initiating insulin when other treatments fail, although there are barriers that may delay its initiation. The timing of initiation depends on individual patient characteristics. Typically, insulinization starts by adding basal insulin to the patient's existing treatment and, if necessary, progresses by gradually introducing prandial insulin. Several barriers have been identified that hinder the initiation of insulin, including fear of hypoglycemia, lack of adherence, the need for glucose monitoring, the injection method of insulin administration, social rejection associated with the stigma of injections, weight gain, a sense of therapeutic failure at initiation, lack of experience among some healthcare professionals, and the delayed and reactive positioning of insulin in recent clinical guidelines. These barriers contribute, among other factors, to therapeutic inertia in initiating and intensifying insulin treatment and to patients' non-adherence. In this context, the development of once-weekly insulin formulations could improve initial acceptance, adherence, treatment satisfaction, and consequently, the quality of life for patients. Currently, two once-weekly basal insulins, insulin icodec and basal insulin BIF, which are in different stages of clinical development, may help. Their longer half-life translates to lower variability and reduced risk of hypoglycemia. This review addresses the need for insulin in T2DM, its positioning in clinical guidelines under specific circumstances, the current barriers to initiating and intensifying insulin treatment, and the potential role of once-weekly insulin formulations as a potential solution to facilitate timely initiation of insulinization, which would reduce therapeutic inertia and achieve better early control in people with T2DM.

Are New Ultra-Rapid-Acting Insulins Associated with Improved Glycemic Control and Reduced Hypoglycemia in Comparison to Conventional Rapid-Acting Insulins for Individuals with Type 1 and Type 2 Diabetes? A Systematic Review and Meta-Analysis.

Introduction: This study aimed to compare efficacy and safety of ultra-rapid-acting insulin analogs (URAIs; faster aspart [FAsp], ultra-rapid lispro [URLi], and technosphere insulin [TI]) with rapid-acting insulin analogs (RAI) in individuals with type 1 (T1D) or type 2 diabetes (T2D). Methods: Searching for randomized control trial comparing the effects of URAI versus RAI that lasted at least 12 weeks, we initially selected 15 studies for analysis. Three studies involving TI were excluded due to a high degree of heterogeneity. The final meta-analysis included only 12 studies with either FAsp or URLi. Results: Mealtime URAI significantly reduced overall early 1 h postprandial glycemia in individuals with T1D (-20.230 mg/dL [95% confidence interval, 95% CI -24.040 to -16.421]; P < 0.001; I2 = 33.42%) and those with T2D (-9.138 mg/dL [95% CI -12.612 to -5.663]; P < 0.001; I2 = 0%). However, the significant reduction in 2 h postprandial glucose remained only in individuals with T1D (-17.620 mg/dL [95% CI -26.047 to -9.193]; P < 0.001; I2 = 65.88%). These benefits were lost when URAI was administered postmeal. At 24-26 weeks, there was no significant difference in HbA1c between groups, but at 52 weeks, a slight reduction in HbA1c with mealtime URAI was observed (-0.080% [95% CI -0.147 to -0.013]; P = 0.019; I2 = 0%). No difference in weight or the rate of severe or confirmed hypoglycemia was observed. Only individuals with T1D showed a small, but significant increase in early 1-h hypoglycemia with URAI (1.468 [95% CI 1.235 to 1.747]; P < 0.001; I2 = 0%). Conclusion: Mealtime URAI improves 1 and 2 h postprandial glycemic control compared to RAI without increasing hypoglycemia or weight gain.

Association of carotid atheroma plaque with IL-18 levels and with polymorphisms in the IL-18 receptor gene in a Mediterranean population. / Asociación de la placa de ateroma carotídea con los niveles plasmáticos de IL-18 y con polimorfismos en el gen del receptor de la IL-18 en la población mediterránea.

BACKGROUND: Atherosclerosis is an inflammatory disease. Interleukin 18 (IL-18) is an inflammatory molecule that has been linked to the development of atherosclerosis and cardiovascular disease. OBJECTIVE: To evaluate the possible relationship between plasma levels of IL-18 and the presence of atherosclerosis evaluated at the carotid level, as well as to analyze the possible modulation by different polymorphisms in a Mediterranean population. MATERIAL AND METHODS: Seven hundred and forty-six individuals from the metropolitan area of Valencia were included, recruited over a period of 2 years. Hydrocarbon and lipid metabolism parameters were determined using standard methodology and IL-18 using ELISA. In addition, carotid ultrasound was performed and the genotype of four SNPs related to the IL-18 signaling pathway was analyzed. RESULTS: Patients with higher plasma levels of IL-18 had other associated cardiovascular risk factors. Elevated IL-18 levels were significantly associated with higher carotid IMT and the presence of atheromatous plaques. The genotype with the A allele of the SNP rs2287037 was associated with a higher prevalence of carotid atheromatous plaque. On the contrary, the genotype with the C allele of the SNP rs2293224 was associated with a lower prevalence of atheromatous plaque. CONCLUSIONS: High levels of IL-18 were significantly associated with a higher carotid IMT and the presence of atheromatous plaques, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the IL-18 receptor gene and the presence of atheroma plaque.

Spanish Consensus on the Use of Intermittently Scanned Continuous Glucose Monitoring in the Management of Patients With Insulin Therapy: The MONITOR Project.

BACKGROUND: Continuous glucose monitoring (CGM) systems are increasingly being adopted as an alternative or adjunct to self-monitoring of blood glucose (SMBG) by patients receiving insulin therapy. However, the available evidence on the role of intermittently scanned CGM or flash CGM (isCGM) remains limited. This consensus aims to evaluate the degree of agreement among Spanish experts on the role of isCGM in the evaluation of glycemic variability, reduction of glycosylated hemoglobin (HbA1c) levels, and selection and adjustment of insulin therapy. METHODS: Delphi methodology was used to achieve consensus in two survey rounds. A total of 431 Spanish endocrinologists participated in the first round of a 34-item questionnaire survey on isCGM and 427 participated in the second round. Any disagreement was resolved in round 2. RESULTS: Consensus was reached for 32 statements, and four items were ultimately agreed upon SMBG after round 2. There was a high degree of consensus that isCGM helps to evaluate glycemic variability, improves HbA1c levels, and can guide therapeutic changes in type 1 diabetes patients. However, there was no consensus on the routine use of the interquartile range to evaluate glycemic variability or the selection of HbA1c as the main parameter for monitoring glycemic control. CONCLUSIONS: Most Spanish experts believe that the isCGM system is appropriate for: (1) identifying glycemic variability and facilitating its management, (2) evaluating hyperglycemia as a complement of HbA1c levels, and (3) guiding therapeutic decisions on insulin selection and dosing. The isCGM system is a useful tool for patients and health care professionals to improve glycemic control in insulin-dependent diabetes.

Expert Recommendations for Using Time-in-Range and Other Continuous Glucose Monitoring Metrics to Achieve Patient-Centered Glycemic Control in People With Diabetes.

New metrics for assessing glycemic control beyond HbA1c have recently emerged due to the increasing use of continuous glucose monitoring (CGM) in diabetes clinical practice. Among them, time in range (TIR) has appeared as a simple and intuitive metric that correlates inversely with HbA1c and has also been newly linked to the risk of long-term diabetes complications. The International Consensus on Time in Range established a series of target glucose ranges (TIR, time below range and time above range) and recommendations for time spent within these ranges for different diabetes populations. These parameters should be evaluated together with the ambulatory glucose profile (AGP). Using standardized visual reporting may help people with diabetes and healthcare professionals in the evaluation of glucose control in frequent clinical situations. The objective of the present review is to provide practical insights to quick interpretation of patient-centered metrics based on flash glucose monitoring data, as well as showing some visual examples of common clinical situations and giving practical recommendations for their management.

Effect of personality on blood glucose control in patients with type 1 diabetes.

OBJECTIVE: The diagnosis of type 1 diabetes mellitus (DM1) has a major impact on young people and their families. Psychosocial factors, patient motivation, participation and acceptance of the disease are essential to achieve good blood glucose control. Our aims were to analyse personality traits and how they are related to blood glucose control in patients with DM1. METHODS: Sixty-two patients with DM1 over 18 years of age, with at least one-year disease duration and absence of advanced chronic complications were studied. Clinical, biological and personality parameters were measured. The Millon Index of Personality Styles was administered for personality assessment. RESULTS: Significant correlations between different personality variables and glycated haemoglobin (HbA1c) values were found. Individuals with poor blood glucose control had significantly higher scores on the Feeling-guided (53.6±25.7 vs 36.2±26.8, p=0.021), Innovation-seeking (36.7±24.1 vs 21.9±21.4, p=0.025), Dissenting (41.1±24.4 vs 15.6±16.6, p=0.001), Submissive (41.5±25.1 vs 28.3±14.7, p=0.038) and Dissatisfied (37.5±27.5 vs 19.5±20.2, p=0.015) scales. This psychological profile is characterised by greater focus on emotions and personal values (feeling-guided), the tendency to reject conventional ideas (innovation-seeking), an aversion to complying with norms and a preference for autonomy (unconventional/dissenting), labile self-confidence (submissive/yielding) and expressed disagreement with others (dissatisfied/complaining). Factor analysis based on the main components of the variance yielded four factors. Factor characterised as related to rebelliousness or independent judgement and action was correlated with poor blood glucose control (r=0.402, p<0.05). CONCLUSION: The rebellious or non-conformist personality type is closely associated with poor blood glucose control in patients with DM1.

The Controversial Role of Vitamin D in Thyroid Cancer Prevention.

Thyroid cancer is the most common endocrine malignancy and exhibits rising incidence. Annual incidence varies by sex, age, and geographical location. It has been reported that impairment of vitamin D signalling promotes thyroid cancer progression. Recent studies have shown that vitamin D, a fat-soluble vitamin that acts as both a nutrient and a hormone, may have utility in the prevention of autoimmune thyroid-related diseases. However, the precise role of vitamin D in the pathobiology of thyroid cancer is controversial. Previous studies have suggested that elevated serum vitamin D levels have a protective role in thyroid cancer. However, there is also evidence demonstrating no inverse relationship between vitamin D levels and the occurrence of thyroid cancer. Furthermore, recent data provide evidence that circulating vitamin D concentration is inversely correlated with disease aggressiveness and poor prognosis, while evidence of an association with tumour initiation remains weak. Nevertheless, a variety of data support an anti-tumorigenic role of vitamin D and its potential utility as a secondary chemopreventive agent. In this review, we highlighted recent findings regarding the association of vitamin D status with the risk of thyroid cancer, prognosis, potential mechanisms, and possible utility as a chemopreventive agent.

Time-in-range for monitoring glucose control: Is it time for a change?

The HbA1c value has been the gold standard for evaluating glucose control for decades. However, it has limitations such as the lack of information on glycemic variability or the risk of hypoglycemia. The increasing use of continuous glucose monitoring has provided patients and healthcare professionals with a range of useful metrics for the management of diabetes. Among them, Time in Range (TIR) is a simple and intuitive metric that gives information regarding the quality of glucose control. It is defined as the time spent in an individual's target glucose range. TIR is strongly correlated with HbA1c, and it has been linked to the risk of developing microvascular and macrovascular complications. The International Consensus on Time in Range has recently set targets for different diabetes populations. For the majority of people with type 1 or type 2 diabetes, a TIR (70-180 mg/dL or 3.9-10.0 mmol/L) of >70%, a time below range (TBR) <70 mg/dL (<3.9 mmol/L) of <4% and a TBR <54 (<3.0 mmol/L) of <1% are recommended. In this review, we address the latest evidence for the use of TIR as an essential parameter in the management of diabetes.

Efficacy and safety of adding sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1 and SGLT2 inhibitor, to optimized insulin therapy in adults with type 1 diabetes and baseline body mass index ≥ 27 kg/m2.

Sotagliflozin, a dual sodium-glucose co-transporter (SGLT)1/SGLT2 inhibitor, is currently approved in Europe as an adjunct to optimal insulin therapy in adults with type 1 diabetes (T1D) and a body mass index (BMI) ≥ 27 kg/m2 . In this post hoc analysis, efficacy at 24 weeks and safety at 52 weeks from pooled phase 3 clinical trials were evaluated in patients with baseline BMI ≥ 27 kg/m2 . Sotagliflozin 200 mg and 400 mg added to insulin reduced glycated haemoglobin level and increased time in range assessed by continuous glucose monitoring versus placebo and also reduced body weight and systolic blood pressure. Differences in efficacy endpoints between sotagliflozin and placebo tended to be greater among patients with BMI ≥ 27 kg/m2 compared to those with baseline BMI < 27 kg/m2 . Consistent with published results for the entire population, fewer severe hypoglycaemia and documented hypoglycaemia ≤3.1 mmol/L events and a higher incidence of diabetic ketoacidosis occurred with sotagliflozin versus placebo in patients with BMI ≥ 27 kg/m2 . Sotagliflozin as an adjunct to optimized insulin therapy in overweight/obese patients with T1D addressed some unmet needs and may help achieve optimal glycaemic control, mitigating weight gain without increasing hypoglycaemia risk in this high-risk population.

Real-world evidence of the effectiveness on glycaemic control of early simultaneous versus later sequential initiation of basal insulin and glucagon-like peptide-1 receptor agonists.

AIM: To assess the impact of the timing of initiating both basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on reaching glycaemic control targets over 6 and 12 months in people with type 2 diabetes (T2D) uncontrolled on oral antihyperglycaemic drugs with an HbA1c of 9% or higher. METHODS: This retrospective cohort study assessed the impact of the timing of initiating both basal insulin and GLP-1 RA therapies on reaching glycaemic targets (HbA1c < 7% and <8%, and ≥1% and ≥2% HbA1c reduction) over 12 months in people with markedly uncontrolled T2D (HbA1c ≥ 9%) on oral antihyperglycaemic drugs identified on the Optum Humedica database (electronic medical records; 1 January 2011 to 30 June 2017). Study cohorts were defined by the days between initiating each injectable: cohort A, 30 days or less (simultaneous initiation) and cohorts B, 31-90, C, 91-180, D, 181-270 and E, 271-360 days (sequential initiation). RESULTS: Cohort A had the best glycaemic outcomes at 6 and 12 months for all four endpoints, followed by cohort B. The likelihood of achieving an HbA1c of less than 7% did not significantly differ between cohorts A and B (hazard ratio [95% confidence interval]: 0.87 [0.76-1.01]); cohorts C, D and E were significantly less likely to achieve an HbA1c of less than 7% than cohort A (0.62 [0.53-0.72]; 0.62 [0.53-0.72]; 0.63 [0.54-0.73]). CONCLUSIONS: In people with uncontrolled T2D requiring treatment with a GLP-1 RA and basal insulin, greater improvements in glycaemic control were observed when both therapies were initiated within close proximity of one another (≤90 days) compared with initiation 91-360 days apart.

Two clinical cases of adjunctive use of a SGLT-2 inhibitor in type 1 diabetes.

Type 1 diabetes mellitus (T1DM) prevalence is increasing and despite all available modern treatment options, an overall small but noticeable increase of mean HbA1c was recently observed in various registries. Authorized adjunctive pharmacological treatment options to insulin therapy are still scarce for T1DM. In February 2019, the European Medicines Agency (EMA) approved dapagliflozin as first in class sodium/glucose co-transporter 2 inhibitor (SGLT-2i) adjunctive therapy to insulin in patients with T1DM, which is currently still not approved by the FDA in the United States. SGLT-2is have shown significant improvement in HbA1c, reducing body weight and increasing time-in-range by reducing glycaemic variability, as well as reductions in total daily insulin dose in the trials in persons with T1DM. The cases presented here translate some of the observations gained from clinical trials into a real-world environment. They demonstrate that even highly practised and educated patients can benefit from the addition of a SGLT-2i as adjunctive treatment to insulin in T1DM. In summary, these cases demonstrate that a variety of patients with T1DM in a real-world setting may benefit from SGLT-2i treatment, as they have the potential to improve HbA1c, excess of body weight and increasing TiR among other things.

Clinical Approach to Flash Glucose Monitoring: An Expert Recommendation.

The flash glucose monitoring (FGM) system FreeStyle Libre® is a device that measures interstitial glucose in a very simple way and indicates direction and speed of glucose change. This allows persons with diabetes to prevent hypoglycemic and hyperglycemic events. Scientific evidence indicates that the system can improve glycemic control and quality of life. To obtain the maximum benefit, it is necessary to properly handle glucose values and trends. Due to the generalization of the system use, the purpose of the document is to provide recommendations for the optimal use of the device, not only in the management of glucose values and trends but also in the prevention of hypoglycemia, actuation in exercise, special situations, and retrospective analysis of the glucose data, among others.

Biosimilars and Novel Insulins.

BACKGROUND: Insulin therapy is the mainstay of treatment for type 1 diabetes and may be necessary in type 2 diabetes. Current insulin analogues present a more physiological profile, are effective, and with less risk of hypoglycemia, but they are expensive. Biosimilar insulins should offer the advantages of insulin analogues at reduced costs. In addition, current rapid-acting insulin analogues are not fast enough to control excessive postprandial glucose excursions in many patients. AREAS OF UNCERTAINTY: Biosimilar insulins demonstrated that are safe and effective, but interchangeability and automatic substitution remain an issue. Ultrafast-acting insulins should reduce postprandial hyperglycemia and improve flexibility in insulin dosing. DATA SOURCES: This systematic review was conducted following widely recommended methods. We searched for each topic in Medline, Embase, the Cochrane Library, and SCISEARCH for relevant citations for the appropriate period. THERAPEUTIC ADVANCES: LY2963016 and MK-1293 are biosimilar insulins of insulin glargine, and SAR342434 is a biosimilar of insulin lispro. The abbreviated developed program demonstrated comparable efficacy and safety and supports their use for treatment of people with diabetes but no interchangeability. Faster-acting insulin aspart is a new formulation of insulin aspart with accelerated subcutaneous absorption. Faster aspart demonstrated noninferiority in reducing HbA1c as compared to insulin aspart with superiority in controlling postprandial hyperglycemia without increasing hypoglycemia, and flexible insulin dosing. CONCLUSIONS: Biosimilar insulins have comparable PK-PD profiles and equivalent efficacy and safety to original insulins at a lower price, making them available for more people with diabetes. Faster aspart is the first ultrafast-acting insulin. New upcoming clinical trials and more clinical experience with faster aspart will show the real potential of this new insulin.

Cost-effectiveness analysis of sensor-augmented pump therapy with low glucose-suspend in patients with type 1 diabetes mellitus and high risk of hypoglycemia in Spain.

OBJECTIVE: To compare the cost-effectiveness of sensor-augmented pump therapy (SAP) [continuous subcutaneous insulin infusion (CSII) plus real-time continuous glucose monitoring (RT-CGM)] with low glucose suspend (MiniMed™ Veo™) and CSII alone in patients with type 1 diabetes mellitus (T1DM) at high risk of hypoglycemia in Spain. METHODS: The IQVIA CORE Diabetes Model was used to estimate healthcare outcomes as life-years gained (LYGs) and quality-adjusted life years (QALYs), and to project lifetime costs. Information about efficacy, resource utilization, and unit costs (€2016) was taken from published sources and validated by an expert panel. Analyses were performed from both the Spanish National Health System (NHS) perspective and the societal perspective. RESULTS: From the NHS perspective, SAP with low glucose suspend was associated to a €47,665 increase in direct healthcare costs and to increases of 0.19 LYGs and 1.88 QALYs, both discounted, which resulted in an incremental cost-effectiveness ratio (ICER) of €25,394/QALY. From the societal perspective, SAP with low glucose suspend increased total costs (including direct and indirect healthcare costs) by €41,036, with a resultant ICER of €21,862/QALY. Considering the willingness-to-pay threshold of €30,000/QALY in Spain, SAP with low glucose suspend represents a cost-effective option from both the NHS and societal perspectives. Sensitivity analyses confirmed the robustness of the model. CONCLUSIONS: From both the Spanish NHS perspective and the societal perspective, SAP with low glucose suspend is a cost-effective option for the treatment of T1DM patients at high risk of hypoglycemia.

Validation in daily clinical situations of Diascope®, a software developed to help healthcare professionals individualize antidiabetic treatment in type 2 diabetes. / Validación en situaciones clínicas reales del DiaScope®, un software de ayuda al profesional sanitario en la individualización del tratamiento antidiabético en la diabetes tipo 2.

INTRODUCTION: DiaScope® is a software to help in individualized prescription of antidiabetic treatment in type 2 diabetes. This study assessed its value and acceptability by different professionals. MATERIAL AND METHODS: DiaScope® was developed based on the ADA-EASD 2012 algorithm and on the recommendation of 12 international diabetes experts using the RAND/UCLA appropriateness method. The current study was performed at a single session. In the first phase, 5 clinical scenarios were evaluated, selecting the most appropriated therapeutic option among 4 possibilities (initial test). In a second phase, the same clinical cases were evaluated with DiaScope® (final test).Opinion surveys on DiaScope® were also performed (questionnaire). RESULTS: DiaScope® changed the selected option 1 or more times in 70.5% of cases. Among 275 evaluated questionnaires, 54.0% strongly agree that DiaScope® allowed finding easily a similar therapeutic scenario to the corresponding patient, and 52.5 among the obtained answers were clinically plausible. Up to 58.3% will recommend it to a colleague. In particular, primary care physicians with >20 years of professional dedication found with DiaScope® the most appropriate option for a particular situation against specialists or those with less professional dedication (p<.05). DISCUSSION: DiaScope® is an easy to use tool for antidiabetic drug prescription that provides plausible solutions and is especially useful for primary care physicians with more years of professional practice.

Following the results of the EMPA-REG OUTCOME trial with empagliflozin, is it possible to speak of a class effect?

BACKGROUND: The recently published cardiovascular outcomes data for the first sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, have shown cardiovascular safety and additional benefits in patients with type 2 diabetes and established cardiovascular disease. Empagliflozin showed lower rates of death from cardiovascular causes or from any causes and lower hospitalization rates from heart failure compared with placebo, both in addition to standard care. This commentary discusses the existence of a possible class effect considering the available evidence described for other SGLT2 inhibitors. MAIN TEXT: Empagliflozin, dapagliflozin and canagliflozin share the same mechanism of action, and it is a plausible hypothesis that some of the benefits of empagliflozin treatment could also be expected from other SGLT2 inhibitors. However, the rapid and persistent occurrence of cardiovascular benefits observed with empagliflozin and the different results shown by the three inhibitors in meta-analyses of some of their respective Phase II and III trials might suggest another possible mechanism of action, perhaps related to the different selectivity to inhibit SGLT-2 and other SGLT family members that these compounds present. CONCLUSION: There is still lack of evidence to answer whether the cardiovascular benefits observed with empagliflozin in the EMPA-REG OUTCOME study could be seen as a "class effect", which is also attributable to dapagliflozin and canagliflozin.

Efficacy and safety of empagliflozin in combination with other oral hypoglycemic agents in patients with type 2 diabetes mellitus. / Eficacia y seguridad de empagliflozina en combinación con otros hipoglucemiantes orales en pacientes con diabetes mellitus tipo 2.

INTRODUCTION: To analyze the efficacy and safety of empagliflozin combined with other oral hypoglycemic agents in patients with type 2 diabetes mellitus. METHODS: Pooled analysis of three phase III trials in patients with type 2 diabetes mellitus (n=1,801) who received placebo or empagliflozin 10 or 25mg once daily for 24 weeks, in combination with metformin, metformin+sulphonylurea or pioglitazone ± metformin. RESULTS: Empagliflozin significantly decreased HbA1c (adjusted mean reduction vs placebo with empagliflozin 10mg: -0.58% [95% CI: -0.66; -0.49]; P<.0001, and with empagliflozin 25mg: -0.62% [95% CI: -0.70; -0.53], P<.0001), weight (adjusted mean reduction vs placebo with empagliflozin 10mg: -1.77kg [95% CI: -2.05; -1.48]; P<.0001, and with empagliflozin 25mg: -1.96kg [95% CI: -2.24; -1.67], P<.0001), and systolic and diastolic blood pressure (SBP/DBP). Adverse effect rates were 64% with placebo, 63.9% with empagliflozin 10mg, and 60.9% with empagliflozin 25mg. Documented episodes of hypoglycemia (≤70mg/dL and/or requiring care) occurred in 3.9% of patients with placebo, 6.9% of patients with empagliflozin 10mg, and 5.3% of patients with empagliflozin 25mg. Urinary tract infections developed in 9.4% of patients with placebo, 10.2% of patients with empagliflozin 10mg, and 8.3% of patients with empagliflozin 25mg. Genital infections were reported in 1.0% of patients with placebo, 4.6% of patients with empagliflozin 10mg, and 3.5% of patients with empagliflozin 25mg. CONCLUSIONS: Empagliflozin combined with other oral treatments decreased HbA1c, body weight, and SBP/DBP as compared to placebo, with a good safety and tolerability profile.

Real-time estimation of plasma insulin concentration from continuous glucose monitor measurements.

Continuous glucose monitors can measure interstitial glucose concentration in real time for closed-loop glucose control systems, known as artificial pancreas. These control systems use an insulin feedback to maintain plasma glucose concentration within a narrow and safe range, and thus to avoid health complications. As it is not possible to measure plasma insulin concentration in real time, insulin models have been used in literature to estimate them. Nevertheless, the significant inter- and intra-patient variability of insulin absorption jeopardizes the accuracy of these estimations. In order to reduce these limitations, our objective is to perform a real-time estimation of plasma insulin concentration from continuous glucose monitoring (CGM). Hovorka's glucose-insulin model has been incorporated in an extended Kalman filter in which different selected time-variant model parameters have been considered as extended states. The observability of the original Hovorka's model and of several extended models has been evaluated by their Lie derivatives. We have evaluated this methodology with an in-silico study with 100 patients with Type 1 diabetes during 25 h. Furthermore, it has been also validated using clinical data from 12 insulin pump patients with Type 1 diabetes who underwent four mixed meal studies. Real-time insulin estimations have been compared to plasma insulin measurements to assess performance showing the validity of the methodology here used in comparison with that formerly used for insulin models. Hence, real-time estimations for plasma insulin concentration based on subcutaneous glucose monitoring can be beneficial for increasing the efficiency of control algorithms for the artificial pancreas.

Stability and performance of rapid-acting insulin analogs used for continuous subcutaneous insulin infusion: a systematic review.

AIM: We review and summarize the literature on the safety and stability of rapid-acting insulin analogs used for continuous subcutaneous insulin infusion (CSII) in patients with diabetes. METHODS: Two predefined search strategies were systematically implemented to search Medline and the Cochrane Register of Clinical Trials for publications between 1996 and 2012. RESULTS: Twenty studies were included in the review: 13 in vitro studies and 7 clinical studies. In vitro studies investigated the effects of extreme CSII conditions (high temperature and mechanical agitation) on the risk of catheter occlusions and insulin stability factors, such as potency, purity, high molecular weight protein content, pH stability, and preservative content (m-cresol, phenol). Under these conditions, the overall stability of rapid-acting insulin analogs was similar for insulin lispro, insulin aspart, and insulin glulisine, although insulin glulisine showed greater susceptibility to insulin precipitation and catheter occlusions. A limited number of clinical trials were identified; this evidence-based information suggests that the rate of catheter occlusions in patients with type 1 diabetes using CSII treatment may vary depending on the rapid-acting analog used. CONCLUSIONS: Based on a limited amount of available data, the safety, stability, and performance of the three available rapid-acting insulin analogs available for use with CSII were similar. However, there is limited evidence suggesting that the risk of occlusion may vary with the insulin preparation under certain circumstances.