Symptomatic Hypoglycemic Events Research Articles

A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects.

The trial (NCT04016974) investigated the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide, the first orally administered glucagon-like peptide-1 analogue for type 2 diabetes, in healthy Chinese subjects. This single-centre, multiple-dose, placebo-controlled trial randomized 32 healthy Chinese adults to once-daily oral semaglutide (3 mg escalating to 14 mg) or placebo for 12 weeks. Blood samples were collected regularly during treatment and follow-up. The primary endpoint was the area under the semaglutide concentration-time curve over a dosing interval (0-24 h) at steady state (AUC0-24h,sema,SS). Secondary pharmacokinetic endpoints included the maximum observed semaglutide plasma concentration at steady state (Cmax,sema,SS). Supportive secondary pharmacodynamics endpoints included changes in body weight and fasting plasma glucose. Treatment with all oral semaglutide doses showed dose-dependent increases in semaglutide exposure in healthy Chinese subjects at steady state, determined by AUC0-24h,sema,SS (233, 552 and 1288 h·nmol/L for 3, 7 and 14 mg of oral semaglutide, respectively) and Cmax,sema,SS. Oral semaglutide treatment was associated with significant reductions in body weight (p = .0001) and fasting plasma glucose (p = .0011) versus placebo at the end of treatment. The safety and tolerability of oral semaglutide were consistent with the known profile of glucagon-like peptide-1 receptor agonists, with no severe or blood-glucose-confirmed symptomatic hypoglycaemic events, serious adverse events or deaths. The most frequent adverse events were gastrointestinal disorders. At steady state, oral semaglutide exposure was dose dependent and close to dose proportionality in healthy Chinese subjects. This is consistent with previous clinical pharmacology results for oral semaglutide.

Clinical characteristics and hospitalisation outcomes of hypoglycaemia in hospitalised patients with type 2 diabetes mellitus

Background/Aim: Strict glycaemic control delays the onset as well the progression of diabetes related microvascular complications. The major roadblock in achieving the target glycated haemoglobin (HbA 1 c) and blood glucose levels is hypoglycaemia. The aim of this study was to assess the clinical characteristics and outcomes of hypoglycaemia in the type 2 diabetes mellitus (T2DM) hospitalised patients. Methods: This was an observational study done for nine months in T2DM patients who had documented hypoglycaemia (blood glucose < 70 mg/ dL) during the hospital stay. T2DM patients with hypoglycaemia on admission , hypoglycaemia due to anti-diabetic drug overdose, intensive care unit (ICU) patients with hypoglycaemia were excluded from the study. Eligible patients were categorised into two groups as symptomatic and as-ymptomatic hypoglycaemia. Clinical features, risk factors, hospitalisation outcome were compared between the symptomatic and asymptomatic hypoglycaemia group. Results: Two hundred patients were enrolled in this study (n = 89, symptomatic group and n = 111, asymptomatic hypoglycaemia). Hypoglycaemic episode in past was significantly associated with symptomatic hypoglycaemic events during hospitalisation [34 (38.2 %) vs 27 (24.3 %)], p = 0.01. Admission blood glucose levels (mg/dL), HbA 1 c (%) were significantly higher in symptomatic hypoglycaemia group [(225.93 vs 178.72, p = 0.008), (8.55 ± 2.49 vs 7.72 ± 1.82, p = 0.007)], respectively. The blood glucose level during the hypoglycaemia episode was significantly higher in patients with asymptomatic hypoglycaemia group (56.38 ± 9.51 vs 44.22 ± 11.21 mg/dL, p < 0.001). Patients with HbA 1 c ≤ 6 % were significantly higher in asymptomatic hypoglycaemia (n = 12, 10.8 % vs n = 2, 2.24 %, p = 0.02). Majority recovered fully without complications and got discharged (n = 155, 77.5 %). Conclusion: In presented study, symptomatic hypoglycaemic patients had significantly higher admission blood glucose levels and HbA 1 c %. Patients with HbA 1 c < 6 % were significantly higher in asymptomatic group. Past history of hypoglycaemia was significantly associated with symptomatic hypoglycaemia during hospitalisation.

Efficacy and Safety of Empagliflozin in Patients with Type 2 Diabetes Mellitus Fasting During Ramadan: A Real-World Study from Bangladesh.

In Bangladesh, there is a large population of Muslims with type 2 diabetes mellitus (T2DM) who fast during Ramadan. Changes in the pattern of meal and fluid intake during this long-fasting hours may increase the risk of hypoglycaemia, hyperglycaemia, and dehydration. Our key point of focus was to evaluate the efficacy and safety of Empagliflozin, a sodium-glucose co transporter 2 inhibitor (SGLT2i), in patients with T2DM while fasting during Ramadan. This was a 24-weeks, multi-centre, open-label, two-arm parallel-group study. In this prospective type of observational study, we enrolled patients taking Empagliflozin and Metformin with or without a DPP-4 inhibitor in one group (n = 274) and a parallel group (n = 219) who were treated with Metformin with or without a DPP-4 inhibitor. The primary endpoint of this study was HbA1c reduction, weight loss and the number of reported or symptomatic hypoglycemic events. In secondary endpoints, we evaluated the changes from baseline in blood pressure, estimated glomerular filtration rate (eGFR), serum creatinine, and serum electrolyte, the proportion of volume depletion (≥1 event) and incidence of other adverse events (AEs) of interest potentially related to SGLT2 inhibitor. During Ramadan, HbA1c reduction was significant in Empagliflozin arm (-0.49% vs -0.12%); [p < 0.001]. From before to the end of the study, significant weight reduction was seen in the Empagliflozin arm (-1.4 kg vs -0.09 kg); [p < 0.001]. We observed no significant increase in the incidence of hypoglycemia (0.7% vs 0.4%, p = 0.267) and volume depletion (2.6% vs 1.8%; p = 0.55) in both arm. All these milder forms events did not require any hospital admission. There was no report of serious adverse events or any discontinuation, or reduction of prescribed doses of empagliflozin during Ramadan. Empagliflozin is efficacious and safe for treating adults with T2DM during Ramadan.

Treatment Patterns and Outcomes Before and After HumulinR U-500 Initiation Among US Patients with Type2 Diabetes Previously Prescribed ≤ 200Units/day of U-100 Insulin.

IntroductionHumulin R U-500 (U-500R) utilization has increased in the past few years, raising concerns as U-500R is indicated only for patients requiring > 200 units of insulin. Thus, evidence of dispensed total daily dose (dTDD) > 200 units of prior U-100 insulin based on pharmacy claims is increasingly used as a criterion to determine appropriate switching to U-500R by payers. The study compared the treatment patterns and outcomes before and after U-500R initiation among patients who were identified with ≤ 200 units/day U-100 insulin fill in order to understand the appropriateness of switching.MethodsPatients with type 2 diabetes who initiated U-500R (index date = first fill) with ≤ 200 units/day pre-index dTDD and > 200 units/day post-index dTDD were identified in a Veterans Health Administration dataset between 1 January 2014 and 30 June 2017. Descriptive analysis was conducted on treatment patterns (dTDD, insulin dosage [units/kg], adherence, number of prescription fills) and clinical outcomes (HbA1c, symptomatic hypoglycemic events). Associations between U-500R exposure and outcomes were evaluated using mixed-effects models. Subgroups of U-500R syringe and KwikPen users were analyzed separately.ResultsAmong 1191 U-500R initiators identified in the study the mean dTDD increased from the pre- to post-index periods (147.2 vs 346.3; p < 0.0001). The mean HbA1c decreased from pre- to post-initiation (9.6% vs 8.6%; p < 0.0001), and symptomatic hypoglycemia events per patient per year increased (2.0 vs 3.3, p < 0.0001). Mixed-effects models confirmed the significance of the changes (p < 0.0001). Device subgroups followed similar trends.ConclusionsU-500R initiation was associated with large dTDD increases, improved glycemic control, and modest increases in hypoglycemia events, suggesting U-500R initiation may have corrected previous treatment compliance issues. Imposing dTDDs > 200 units before switching to U-500R criterion could hurt the opportunities for patients who need a simplified regimen for better outcomes.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01209-z.

Soliqua (Lixi Lan): Sustained Long Term Cost Efficacy and Safety When Used in Combination with Metformin and Glimepiride

Background: Previous studies using basal insulin documented the lowest daily dose and least hypoglycemic events when combined with Glimepiride and Metformin while attaining desirable glycemic control. However, Pivotal trials with Soliqua excluded Glimepiride as a part of therapy as well as subjects with moderate obesity (BMI &gt; 35kg/m2). Moreover, these trials were relatively short term.&#x0D; Objective: Assess long term efficacy and safety of Soliqua in combination with Glimepiride and Metformin in subjects with type 2 diabetes irrespective of BMI in ‘real world’ experience.&#x0D; Subjects: 30 adults with type 2 diabetes, age range 32-72 years with HbA1C &gt;7.5% while receiving therapy with 1) Glimepiride, Metformin and Basal insulin and 2) Metformin and/or DPP 4 inhibitors and/or other SUs and /or GLP1 RA and/or Basal insulin and/or prandial insulin. Type 2 diabetes was confirmed by presence of C-peptide. Subjects with history of gastroparesis, Triglycerides over 300 mg/dl and pancreatitis were excluded. Subjects with elevated liver enzymes, over 2.5 times normal and EGFR &lt; 30 ml/min were excluded as well.&#x0D; Methods: All prior therapies were discontinued. All subjects were started on Glimepiride 8 mg, Metformin 1000-2000 mg and SC Soliqua was initiated prior to breakfast with daily dose 15 or 30 units as recommended. Daily dose was increased by 2 units every 3 days until AM fasting plasma glucose of 80-130 mg/dl was attained or the dose of 60 units was reached. The stable daily dose of Soliqua was continued until the time of analysis. Comparisons were conducted between body weights (kg), fasting plasma glucose (FPG) and HbA1C prior to initiation of combination therapy (pre Rx) and every 3-6 months until the time of analysis (post Rx).&#x0D; Results: BMI ranged between 22-67 kg/m2. Duration of diabetes was 5-25 years. Duration of therapy with the combination therapy range, 7-56 months. Subjects were divided into 2 groups according to desirable HbA1C levels as per recommendations by ADA: 1) desirable HbA1C is &lt; 7.0%, 2) desirable HbA1C 7-8 %. Both Fasting plasma glucose (mg/dl) and HbA1C (%) declined from 167 ± 10 and 9.7 ± 0.8 to 114 ± 4 and 7.6± 0.3 at the time of analyses (post Rx) respectively in the whole cohort. In 4 (0.13 %) morbidly obese subjects, FPG and HbA1C levels declined though not achieving desirable glycemic goals despite receiving maximal daily dose, 60 units of Soliqua. All four belonged to group 1. In the remaining 17 subjects desirable glycemic levels were attained and maintained. In group 2, desirable glycemia was reached in all 9 subjects. Symptomatic hypoglycemic events confirmed by blood sugar &lt;70 mg/dl were reported by 4 subjects, none requiring secondary assistance. No severe hypoglycemia was reported. Mean daily dose of Soliqua was lower when compared to the pivotal trials.&#x0D; Conclusion: Soliqua is effective and safe in the long term in all subjects irrespective of BMI when administered in combination with Glimepiride and Metformin. Moreover, lesser daily dose required to attain desirable glycemia with this oral combination may render it to be effective without attaining maximum daily dose in subjects with higher BMIs documented in pivotal trials using Metformin alone.

Continuous Glucose Monitoring (CGM) Readings During Patient-Reported Symptomatic Hypoglycemia: Assessment of the Advanced Technologies and Treatments for Diabetes Consensus Definition of CGM-Recorded Hypoglycemia.

Aim: Continuous glucose monitoring (CGM) is widely used in clinical practice and research to detect hypoglycemia. A consensus definition of CGM-recorded hypoglycemia is made by a group of international experts under the auspice of the Advanced Technologies and Treatments for Diabetes (ATTD). The purpose of this study is to compare the definition with patient-reported hypoglycemia. Methods: In a prospective, observational study of 186 patients with type 1 diabetes using blinded Medtronic iPro 2 CGM for 6 days, every patient-reported symptomatic hypoglycemic event and interstitial glucose (IG) values at the registration time were classified according to the ATTD definition of CGM-recorded hypoglycemia. For comparison between CGM and self-monitored blood glucose (SMBG) values, the International Hypoglycemia Study Group (IHSG) classification of hypoglycemia and chi-square test were used. Results: A total of 321 events of symptomatic hypoglycemia were reported by 68% of the patients, corresponding to 2.0 ± 2.3 events (mean ± standard deviation) per patient-week. A total of 206 (64%) events met the CGM consensus definition. In the remaining 115 (36%) not-confirmed events, 5 events had an IG <3.9 mmol/L, which lasted <15 min. The overall mean IG value was 3.6 ± 1.1 mmol/L (median 3.1, range 2.2-10.4). In symptomatic hypoglycemic events with both CGM and SMBG data, SMBG confirmed significantly more symptomatic hypoglycemic events than CGM (P < 0.001). Conclusion: CGM-recorded hypoglycemia according to the consensus definition is present at two thirds of all patient-reported events when recorded by the Medtronic iPro 2 system. The recommended minimum duration of a hypoglycemic event of 15 min is supported by the study. SMBG measurements detect significantly more symptomatic hypoglycemic events than Medtronic iPro 2 CGM.

The Durability of an Intensive, Structured Education-Based Rehabilitation Protocol for Best Insulin Injection Practice: The ISTERP-2 Study.

IntroductionStudies on the durability of an intensive, structured education protocol on best insulin injection practice are missing for people with type 2 diabetes mellitus (T2DM). The aim of this study was to assess the durability of an intensive, structured education-based rehabilitation protocol on best insulin injection practice in well-trained subjects from our previous intensive, multimedia intervention study registered as the ISTERP-1 study. A total of 158 subjects with T2DM from the well-trained group of the 6-month-long ISTERP-1 study, all of whom had successfully attained lower glucose levels compared to baseline levels with lower daily insulin doses and with less frequent and severe hypoglycemic episodes, participated in the present investigation involving an additional 6-month follow-up period, called the ISTERP-2 study. MethodsParticipants were randomized into an intervention group and a control group, depending on whether they were provided or not provided with further education refresher courses for 6 months. At the end of the 6 months, the two groups were compared in terms of injection habits, daily insulin dose requirement, number of severe or symptomatic hypoglycemic events, and glycated hemoglobin (HbA1c) levels.ResultsDespite being virtually superimposable at baseline, the two groups behaved quite differently during the follow-up. The within-group analysis of observed parameters showed that the subjects in the intervention group maintained and even improved the good behavioral results learned during the ISTERP-1 study by further reducing both the rate of injection technique errors (p < 0.001) and size of lipohypertrophic lesions at injection sites (p < 0.02). Conversely, those in the control group progressively abandoned best practice, except for the use of ice-cold insulin and, consequently, had significantly higher HbA1c levels and daily insulin dose requirements at the end of the follow-up than at baseline (p < 0.05). In addition, as expected from all the above, the rate of hypoglycemic episodes also decreased in the intervention group (p < 0.05), resulting in a significant difference between groups after 6 months (p < 0.02). ConclusionOur data provide evidence that intensive, structured education refresher courses have no outstanding durability, so that repeated refresher courses, at least at 6-month intervals, are needed to have positive effects on people with T2DM, contributing not only to prevention but also to long-term rehabilitation.Trial RegistrationTrial Registration no. 118 bis/15.04.2018.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01108-9.

Descriptive Regional Subanalysis of a Real-World Study in Patients with Type 2 Diabetes Treated with Gliclazide MR During Fasting: DIA-RAMADAN.

IntroductionTo analyse the safety and effectiveness of gliclazide modified release (MR) in adults with type 2 diabetes mellitus participating in Ramadan from three geographically and culturally different regions of the world included in the DIA-RAMADAN study.MethodsDIA-RAMADAN was a real-world, observational, international, non-comparative study. The global study population was divided into three regional subgroups, with data gathered at inclusion 6–8 weeks prior to Ramadan (V0), during Ramadan (4.5 weeks) and 4–6 weeks after Ramadan (V1). Primary endpoint was the proportion of patients reporting ≥ 1 symptomatic hypoglycaemic events (HE), which were collected using a patient diary along with other adverse events.ResultsPatient numbers from the three regions were n = 564 (46.5%; Indian sub-continent), n = 354 (29.1%; Middle East) and n = 296 (24.4%; South-East Asia). Patient baseline characteristics, demographics, fasting habits and antidiabetic treatments varied between regions. There were similar proportions of symptomatic HE between regions, with no severe HE. Significant weight reductions were observed in all regions following Ramadan, along with reductions in HbA1c and fasting plasma glucose.ConclusionThese real-world study data indicate that gliclazide MR is safe and effective for management of type 2 diabetes during Ramadan in all three regions studied as part of DIA-RAMADAN.Trial RegistrationClinicaltrials.gov identifier NCT04132934.InfographicSupplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01067-1.

Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial

Aims/hypothesisA head-to-head randomised trial was conducted to evaluate hypoglycaemia safety with insulin degludec 200 U/ml (degludec U200) and insulin glargine 300 U/ml (glargine U300) in individuals with type 2 diabetes treated with basal insulin.MethodsThis randomised (1:1), open-label, treat-to-target, multinational trial included individuals with type 2 diabetes, aged ≥18 years with HbA1c ≤80 mmol/mol (9.5%) and BMI ≤45 kg/m2. Participants were previously treated with basal insulin with or without oral glucose-lowering drugs (excluding insulin secretagogues) and had to fulfil at least one predefined criterion for hypoglycaemia risk. Both degludec U200 and glargine U300 were similarly titrated to a fasting blood glucose target of 4.0–5.0 mmol/l. Endpoints were assessed during a 36 week maintenance period and a total treatment period up to 88 weeks. There were three hypoglycaemia endpoints: (1) overall symptomatic hypoglycaemia (either severe, an event requiring third-party assistance, or confirmed by blood glucose [<3.1 mmol/l] with symptoms); (2) nocturnal symptomatic hypoglycaemia (severe or confirmed by blood glucose with symptoms, between 00:01 and 05:59 h); and (3) severe hypoglycaemia. The primary endpoint was the number of overall symptomatic hypoglycaemic events in the maintenance period. Secondary hypoglycaemia endpoints included the number of nocturnal symptomatic events and number of severe hypoglycaemic events during the maintenance period.ResultsOf the 1609 randomised participants, 733 of 805 (91.1%) in the degludec U200 arm and 734 of 804 (91.3%) in the glargine U300 arm completed the trial (87.3% and 87.8% completed on treatment, respectively). Baseline characteristics were comparable between the two treatment arms. For the primary endpoint, the rate of overall symptomatic hypoglycaemia was not significantly lower with degludec U200 vs glargine U300 (rate ratio [RR] 0.88 [95% CI 0.73, 1.06]). As there was no significant difference between treatments for the primary endpoint, the confirmatory testing procedure for superiority was stopped. The pre-specified confirmatory secondary hypoglycaemia endpoints were analysed using pre-specified statistical models but were now considered exploratory. These endpoints showed a lower rate of nocturnal symptomatic hypoglycaemia (RR 0.63 [95% CI 0.48, 0.84]) and severe hypoglycaemia (RR 0.20 [95% CI 0.07, 0.57]) with degludec U200 vs glargine U300.Conclusions/interpretationThere was no significant difference in the rate of overall symptomatic hypoglycaemia with degludec U200 vs glargine U300 in the maintenance period. The rates of nocturnal symptomatic and severe hypoglycaemia were nominally significantly lower with degludec U200 during the maintenance period compared with glargine U300.Trial registrationClinicalTrials.gov NCT03078478FundingThis trial was funded by Novo Nordisk (Bagsvaerd, Denmark)

MON-135 A Case of Hirata’s Disease

Introduction- Insulin Autoimmune Syndrome (IAS), also known as Hirata's disease, is a rare cause of endogenous hyperinsulinemic hypoglycemia, characterized by episodes of spontaneous hypoglycemia with high serum insulin and elevated insulin autoantibodies in the individuals who have not received exogenous insulin. Only few cases have been reported in Caucasians while there have been more than 300 cases from Japan. Given the rarity of this condition outside of Japan, here we report a case of Hirata’s disease. Case Presentation- A 59-year-old male was brought in to the emergency room with altered mental status and slurred speech. Patient's initial blood glucose was 30 and was given dextrose 10 (D10) en route with remarkable improvement in his mental status and speech and resolution of neuroglycopenic symptoms. Patient’s vital signs and physical exam was unremarkable. Basic initial laboratory workup was unremarkable. He reported no similar episodes in the past. He is not any medications known to cause hypoglycemia. ACTH, cortisol, TSH and T4 levels were normal. Sulfonylurea screen was negative. Hospital Course was complicated by recurrent, symptomatic hypoglycemic events with blood glucose as low as 37mg/dL. Initial suspected diagnosis was insulinoma and he was started on octreotide and D10 drip with continued hypoglycemia episodes postprandial. For further work up, insulin, c-peptide, proinsulin, insulin antibody were ordered during hypoglycemia episode. C-peptide was 3.7 (ULN 3.5) and insulin 156 (ULN 19) and insulin antibody > 50 (ULN 0.4). MRI abdomen revealed normal appearing pancreas and adrenal glands. Based on the presence of high titers of insulin antibodies and high insulin and relatively normal c-peptide levels accompanied by recurrent postprandial hypoglycemia’s, diagnosis of IAS was suspected and was then started on prednisone with a marked decrease in frequency of hypoglycemic episodes. Patient was discharged on oral prednisone with follow up with endocrinologist and is doing well on last outpatient follow up. Discussion- Mechanism of IAS is not well understood and is assumed to be due to antibodies against insulin that initially bind and later releases insulin asynchronously. Eighty percent of IAS patients spontaneously remit. In some individuals, IAS is associated with medications that contain ‘sulfhydryl’ group rendering insulin more immunogenic. Corticosteroids, plasmapheresis and immunosuppressants have been used to treat IAS. A diet consisting of several light meals per day, avoiding simple sugars, is recommended. Conclusion- IAS is a rare cause of hypoglycemia, and it should be suspected in non-diabetic patients with spontaneous hypoglycemia in whom there is failure to localize an abdominal tumor and who demonstrate extremely high insulin levels. Insulin autoantibodies should be tested in such patients to avoid unnecessary invasive testing and surgery.

Unmet Needs in the Management of Type 2 Diabetes Mellitus Patients Starting Insulin Therapy with Basal or Premix Insulin in Routine Clinical Practice in Serbia.

IntroductionType 2 diabetes mellitus (T2DM) is a progressive disease with declining beta cell function, ultimately necessitating insulin therapy. Timely introduction of adequate insulin improves management of diabetes. The aim of this study was to evaluate the unmet needs in the management of T2DM patients recently initiated on insulin therapy in routine clinical practice in Serbia.MethodsThe NEED study was a cross-sectional, observational, multicenter, real-world study conducted in Serbia, involving 26 physicians, endocrinologists, treating individuals with T2DM from 17 secondary health care institutions. Study participants were newly initiated with insulin therapy, being treated with basal or premix insulin ± oral antidiabetics (OAD) for 6–12 months.ResultsFour hundred one individuals were included in the study between October 2016 and March 2017. The mean age of study patients was 61.8 ± 9.2 years with mean BMI 30.0 ± 5.0 kg/m2, and duration of diabetes, prior to initiation of insulin therapy, was 8.4 ± 5.9 years. A basal insulin regimen was used by 287 (71.6%) and premix insulin by 114 (28.4%) subjects. The average daily dose (39.8 ± 13.9 units premix vs. 26.3 ± 13.5 units basal), dose/kg (0.47 ± 0.15 units/kg premix vs. 0.31 ± 0.17 units/kg basal), and number of injections per day were higher in the premix compared with basal insulin regimen (p < 0.01). The percentage of T2DM participants with at least one unmet need was high (95.8%). The majority of participants had two or three unmet needs. The most common unmet needs were: HbA1c > 7.0% (79.3%), at least one documented symptomatic hypoglycemia (≤ 3.9 mmol/l) event in the previous 3 months (63.8%), and two or more doses of insulin per day (53.1%). The mean individual HbA1c target was 6.8% in the NEED study cohort, with only 16% of participants reaching it. Most participants [281 (70.1%)] experienced symptomatic hypoglycemia.ConclusionsThe NEED study showed that new insulin users of either basal or premix HM insulin have many unmet needs in the first 6–12 months of treatment. This confirms that in real-life settings novel insulins should be considered in the management of T2DM to reduce the number of symptomatic hypoglycemic events and reach a better HbA1c level.FundingSanofi, Serbia.

The road less traveled: how to grow a pancreas transplant program.

The volume of pancreas transplants performed annually in the United States (US) has steadily declined for more than a decade. In the face of this negative trend, efforts at several centers are underway to expand their pancreas transplant volumes through alterations in the structure and function of their pancreas transplant programs. We highlight these programmatic changes and emphasize the culture and characteristics of these high volume centers to serve as models for other centers to emulate. As the results of modern-day pancreas transplantation are excellent and continue to improve, pancreas transplant remains an outstanding option for selected patients suffering from diabetes mellitus and end stage renal disease (ESRD) or symptomatic hypoglycemic events (SHEs). Through strong leadership commitment and programmatic restructuring, the transformation of low-volume pancreas transplant centers into high-volume programs is achievable without the need for cost-prohibitive investment. Multiple examples may be cited of transplant centers reinvigorating their pancreas transplant programs, increasing their pancreas transplant evaluations and transplant rates, through personnel reorganization and operational restructuring. As a means of providing a roadmap to encourage other transplant centers to re-energize their pancreas transplant programs, we will outline strategies that can be readily instituted to transform a pancreas transplant program, and delineate the basic steps that any transplant center can take to achieve high-volume success. The negative trends in access to pancreas transplantation in the US may ultimately be addressed by low-volume pancreas transplant programs re-committing themselves through easily achievable institutional changes without substantial added capital investment, thereby maximizing access to pancreas transplantation for their diabetic patients and maintaining excellent outcomes.

Insulin Degludec Has Lower Hypoglycemia Risk than Insulin Glargine U100 in Older People with Type 2 Diabetes (T2D)

Vulnerability to hypoglycemia increases with age. To further assess the safety of insulin in older patients, the risk of hypoglycemia was investigated post-hoc in the SWITCH 2 treat-to-target, 64-week, crossover trial. Patients with T2D and high risk of hypoglycemia were randomized, double-blind, to either degludec or insulin glargine U100 ± OADs. The primary endpoint was the number of positively adjudicated severe (external assistance) or symptomatic hypoglycemic events (plasma glucose &amp;lt;56 mg/dL) during the two 16-week maintenance periods. For patients ?65 (n=450) and &amp;gt;65 (n=270) years, baseline median [range] diabetes duration was 12.0 [1-40] vs. 15 [1-54] years, mean A1C was 7.7 vs. 7.4%, and mean eGFR was 87.0 vs. 63.7 mL/min/1.73m2. No significant differences in A1C reduction (degludec vs. glargine U100) were seen for patients ?65 and &amp;gt;65 years. During the maintenance period, degludec had a lower risk of hypoglycemia (overall/nocturnal symptomatic) vs. glargine U100 in patients ?65 (31/43%) and &amp;gt;65 years (30/41%) (Figure). The number of severe hypoglycemia episodes was not significantly lower. The adverse event rate was 3.2 and 3.3 events/patient-year for ?65 years and 3.5 and 4.1 events/patient-year for &amp;gt;65 years, for degludec and glargine U100, respectively. Degludec was safe and effective, and the frequency of hypoglycemia was lower than glargine U100 in patients ?65 and &amp;gt;65 years with T2D. Disclosure S.R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk A/S, Takeda, Sanofi-Aventis, Boehringer Ingelheim GmbH. Consultant; Self; Eli Lilly and Company, Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Takeda, AstraZeneca, Boehringer Ingelheim GmbH. J. DeVries: Research Support; Self; Dexcom, Inc., Medtronic, Novo Nordisk A/S. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. Advisory Panel; Self; Sanofi. Research Support; Self; Senseonics. Speaker's Bureau; Self; Senseonics. Advisory Panel; Self; Zealand Pharma A/S. C.H. Wysham: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. C.T. Hansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. M.V. Hansen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. 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.

Better Postprandial Glucose (PPG) Control with BioChaperone Combo (BC Combo) than with Lispro Mix25 (LMx) or Separate Glargine and Lispro (G+L) Administrations in Subjects with Type 2 Diabetes (T2DM)

BC Combo is a co-formulation of prandial insulin lispro (25%) and basal insulin glargine (75%) with a rapid “prandial“ insulin component and prolonged flat “basal“ component compared to LMx. In this study the effects of BC Combo on PPG vs. LMx and G+L were investigated. Thirty-nine T2DM subjects (mean±SD age 60.8±7.5 years and HbA1c 7.97±0.6%) were randomized to receive the three insulin combinations immediately before a standardized solid meal test (MMT, 20% protein 30% fat 50% carbohydrates) in a double-blind, double-dummy, cross-over design. The individual insulin dose was the same for each visit day (mean 0.62 U/kg). BC Combo demonstrated improved PPG compared to LMx (Figure, reduction ∆AUCBG,0-2h of 18%, p=0.0009) and G+L (reduction ∆AUCBG,0-2h of 10%, p=0.0450). The proportion of subjects experiencing documented symptomatic hypoglycemic events (plasma glucose &amp;lt;70 mg/mL) over 24h was numerically lower with BC Combo (15.8%) vs. LMx (32.4%) and G+L (21.6%). The total insulin PK profile of BC Combo showed a faster time to insulin peak and a lower exposure in the late prandial phase (2-6 h) than LMx and G+L. In conclusion, BC Combo demonstrated superior PPG control in T2DM subjects with numerically fewer subjects experiencing symptomatic hypoglycemia compared to both LMx and separate G+L. Disclosure T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research &amp; Development, MedImmune, Merck Sharp &amp; Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker's Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L. Plum-Moerschel: None. C. Mégret: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. T. Herbrand: None. V. Vacher: Employee; Self; ADOCIA. E. Anastassiadis: None. O. Klein: None. M. Gaudier: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. O. Soula: Board Member; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA. Employee; Spouse/Partner; ADOCIA. S. Glezer: Stock/Shareholder; Self; Sanofi. Stock/Shareholder; Spouse/Partner; Sanofi. Employee; Self; ADOCIA, Novo Nordisk Inc.. Employee; Spouse/Partner; Pfizer Inc., Teva Pharmaceutical Industries Ltd.. Stock/Shareholder; Spouse/Partner; Teva Pharmaceutical Industries Ltd.. B. Alluis: None. G. Meiffren: Employee; Self; ADOCIA. Stock/Shareholder; Self; ADOCIA.

Improved Glycemic Control in a Patient Group Performing 7-Point Profile Self-Monitoring of Blood Glucose and Intensive Data Documentation: An Open-Label, Multicenter, Observational Study.

IntroductionRegular self-monitoring of blood glucose (SMBG) is recommended as an integral part of therapy for all patients with diabetes treated with insulin. In the current study, the effects on glycemic control of taking 7-point SMBG profiles and using a diabetes management system (DMA) on a smartphone were investigated.MethodsIn a 12-week, open-label, multicenter, observational study, 51 patients [26 with type 1 diabetes mellitus (T1DM) and 25 with type 2 diabetes mellitus (T2DM)] were instructed to perform SMBG at least seven times a day using DMA combined with the iBGStar® SMBG system. HbA1c was measured at regular visits to the study sites. Patients reviewed and managed their data as well as their treatment on their own and there were no further assistance or treatment recommendations. Adverse events (AEs) were recorded throughout.ResultsOverall, mean (SD) change from baseline in HbA1c at week 12 was −0.46 (0.57)% [−5 (6) mmol/mol (p < 0.0001)]. The change in HbA1c was observed in patients with T1DM [−0.27 (0.45)% (−3 [5] mmol/mol; p = 0.0063)] and T2DM [−0.65 (0.62)% (−7 [7] mmol/mol; p < 0.0001)]. The change in HbA1c was not correlated with an increased number of hypoglycemic events (blood glucose less than 55 mg/dL). The majority of AEs were symptomatic hypoglycemic events (42 events; nine patients).ConclusionsGlycemic control can be improved, without receiving any recommendations or advice on insulin dose, by performing daily 7-point SMBG profiles and using electronic documentation with a smartphone app. These results must be confirmed in a larger controlled trial, but they already strengthen the importance of structured SMBG in diabetes therapy.FundingSanofi.

Effects of dipeptidyl peptidase-4 inhibitors in type 2 diabetes patients with moderate to severe chronic kidney disease: Meta-analysis of randomized controlled trials using unadjusted data.

Three meta-analyses recently evaluated the effects of dipeptidyl peptidase (DPP)-4 inhibitors in type 2 diabetes (T2D) patients with chronic kidney disease (CKD). However, the combination of adjusted and unadjusted data in these meta-analyses may be questionable. The present study performed a meta-analysis of the effects of DPP-4 inhibitors in T2D patients with moderate to severe CKD using unadjusted data from randomized controlled trials (RCTs). The PubMed, Embase (via Ovid), and Cochrane Central databases were searched for papers regarding the effects of DPP-4 inhibitors in CKD patients published before 1 August 2016. Data were independently extracted by two authors. A pooled analysis of unadjusted data was performed using random-effects models. Twelve studies representing 10 RCTs were included in the present analysis. Comparing mean HbA1c change between placebo and treatment, DPP-4 inhibitors significantly improved HbA1c levels at 12 weeks (mean difference [MD] -0.42; 95% confidence interval [CI] -0.54, -0.29), but improvements in HbA1c were seen only in dialysis patients at 24 weeks (MD -0.52; 95% CI -0.72, -0.32)*. Improvements in HbA1c were equivalent between DPP-4 inhibitors and sulfonylureas at 52 or 54 weeks. There were no significant differences in the incidence of severe or any hypoglycemic events between DPP-4 inhibitors and control (placebo or sulfonylureas) at 12, 24, and 52 or 54 weeks. However, DPP-4 inhibitors induced fewer symptomatic hypoglycemic events compared with sulfonylureas at 52 or 54 weeks. *[Correction added on 30 October 2017, after first online publication: The value '0.32' has been corrected to '-0.32'.] CONCLUSIONS: The present analysis shows that DPP-4 inhibitors are effective and comparable with sulfonylureas in T2D patients with moderate to severe CKD.

Multivariate Prediction Equations for HbA 1c Lowering, Weight Change, and Hypoglycemic Events Associated with Insulin Rescue Medication in Type 2 Diabetes Mellitus: Informing Economic Modeling

Type 2 diabetes mellitus (T2DM) is chronic and progressive and the cost-effectiveness of new treatment interventions must be established over long time horizons. Given the limited durability of drugs, assumptions regarding downstream rescue medication can drive results. Especially for insulin, for which treatment effects and adverse events are known to depend on patient characteristics, this can be problematic for health economic evaluation involving modeling. To estimate parsimonious multivariate equations of treatment effects and hypoglycemic event risks for use in parameterizing insulin rescue therapy in model-based cost-effectiveness analysis. Clinical evidence for insulin use in T2DM was identified in PubMed and from published reviews and meta-analyses. Study and patient characteristics and treatment effects and adverse event rates were extracted and the data used to estimate parsimonious treatment effect and hypoglycemic event risk equations using multivariate regression analysis. Data from 91 studies featuring 171 usable study arms were identified, mostly for premix and basal insulin types. Multivariate prediction equations for glycated hemoglobin A1c lowering and weight change were estimated separately for insulin-naive and insulin-experienced patients. Goodness of fit (R2) for both outcomes were generally good, ranging from 0.44 to 0.84. Multivariate prediction equations for symptomatic, nocturnal, and severe hypoglycemic events were also estimated, though considerable heterogeneity in definitions limits their usefulness. Parsimonious and robust multivariate prediction equations were estimated for glycated hemoglobin A1c and weight change, separately for insulin-naive and insulin-experienced patients. Using these in economic simulation modeling in T2DM can improve realism and flexibility in modeling insulin rescue medication.

Add-on treatment with intermediate-acting insulin versus sliding-scale insulin for patients with type 2 diabetes or insulin resistance during cyclic glucocorticoid-containing antineoplastic chemotherapy: a randomized crossover study.

The aim of this study was to compare the effectiveness and safety of intermediate-acting insulin (IMI) titrated on body weight and glucocorticoid dose with that of short-acting sliding-scale insulin (SSI) in patients on recurrent high-dose glucocorticoid-containing chemotherapy. We enrolled 26 patients with type 2 diabetes mellitus or random blood glucose level >12 mmol/l in a previous cycle of chemotherapy in a randomized crossover study. In two consecutive cycles of glucocorticoid-containing chemotherapy, participants were treated with either IMI or SSI, as add-on to routine diabetes medication. We compared time spent in target range (3.9-10 mmol/l), measured by continuous glucose monitoring (CGM), and the occurrence of hypoglycaemia. IMI resulted in a higher proportion of glucose values within target range than SSI (34.4 vs 20.9%; p < 0.001). There were no severe or symptomatic hypoglycaemic events. Two participants in each group had a subclinical hypoglycaemia detected only by CGM. Once-daily IMI resulted in better glycaemic control than SSI in patients with glucocorticoid-induced hyperglycaemia during chemotherapy. Safety was not compromised as the incidence of hypoglycaemia was low and not different between both regimens.

Efficacy of lixisenatide in patients with type 2 diabetes: A post hoc analysis of patients with diverse β-cell function in the GetGoal-M and GetGoal-S trials

AimsTo evaluate the impact of β-cell function on the efficacy of lixisenatide, a once-daily prandial glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes (T2D). Materials and methodsIn this post hoc analysis, patients from the Phase 3 GetGoal-M and GetGoal-S clinical trials randomized to lixisenatide 20μg once daily were stratified into quartiles by baseline β-cell function, as measured by the secretory units of islet in transplantation (SUIT) index. ResultsPatients (N=437) were distributed evenly among SUIT index quartiles 1 to 4 (lowest to highest β-cell function). Clinical outcomes improved from baseline across all SUIT quartiles; mean changes at week 24 were: glycated hemoglobin (HbA1c; % [mmol/mol]), −0.99 (−10.8), −0.87 (−9.5), −0.86 (−9.4), −0.83 (−9.1); and postprandial plasma glucose (PPG; mmol/L), −7.9, −5.6, −5.5, −4.3 (overall effect P<0.0001). Furthermore, postprandial glucagon was reduced in all SUIT quartiles, while insulinogenic index improved only in patients with higher baseline SUIT (overall effect P=0.0286). No severe symptomatic hypoglycemic events were reported. ConclusionsLixisenatide treatment resulted in reductions in HbA1c and PPG levels across all SUIT quartiles. This suggests that non-insulin-related actions of lixisenatide contribute to improved glycemic control in T2D.

Risk factors for hypoglycemia in patients with type 2 diabetes, hospitalized in internal medicine wards: Findings from the FADOI-DIAMOND study

AimsHypoglycemia is a potential risk in the management of patients suffering from type 2 diabetes (T2DM) and hospitalized in internal medicine units (IMUs). The aim of this analysis was to evaluate incidence of hypoglycemia and related risk factors in a group of patients admitted to IMUs. MethodsWe used the FADOI-DIAMOND study carried out in 53 Italian IMUs. The DIAMOND design included two cross-sectional surveys interspersed with an educational program. In both phases each center reviewed the charts of the last 30 hospitalized patients with known T2DM (n=3167), including information about hypoglycemia during hospital stay. The association between occurrence of hypoglycemia and potential predictors was evaluated by means of a multivariable logistic regression analysis. ResultsA total of 385 symptomatic hypoglycemic events were observed (rate=12%). Advanced age, cognitive dysfunction, and nephropathy were associated with hypoglycemia. Hypoglycemia occurred in 19.4% of patients treated according to the insulin sliding-scale method versus 11.4% of patients treated with basal bolus (p<0.01). More patients with hypoglycemia received sulfonylureas versus the no-hypoglycemia group (28.3% versus 20.6%, p<0.001). Significantly longer length of hospital stay and increased in-hospital mortality were found in the group with hypoglycemia compared with the no-hypoglycemia group (12.7±10.9 versus 9.6±6.5 days; 8.8% versus 4.8%, p<0.01). ConclusionsHypoglycemia in hospitalized patients with diabetes is associated with increased length of hospitalization and in-hospital mortality. Identification of patients at increased risk of hypoglycemia may be important for optimally adapting treatment and patient management.