Juan P. Frias

Insulin Pump Therapy in Patients with Type 2 Diabetes Safely Improved Glycemic Control Using a Simple Insulin Dosing Regimen

BACKGROUND This study assessed insulin dose and dosing patterns required to optimize glycemic control with an insulin pump in patients with type 2 diabetes. METHODS In this 16-week, open-label, multicenter, pilot study, 56 insulin pump-naive patients treated at baseline with two or more oral antidiabetes agents (OADs), basal insulin with or without OADs, or basal-bolus insulin with or without OADs discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin doses were adjusted to optimize glycemic control with the simplest possible insulin regimen. Outcomes included total daily insulin dose, daily basal and bolus insulin doses, number of daily basal rates, hemoglobin A1C, fasting and postprandial glucose, patient-reported outcomes and rate of hypoglycemia. RESULTS After 16 weeks of pump therapy, the mean +/- SD total daily insulin dose was 95 +/- 59 U. The percentage of the total daily insulin dose used as basal and as bolus delivery was 55% and 45%, respectively. Eighty-eight percent of patients were treated with two or fewer daily basal rates. Mean A1C was lowered by 1.2 +/- 1.2% (P < 0.001), and there was no severe hypoglycemia. Mean change in body weight was +1.9 +/- 3.3 kg (P < 0.001). Overall treatment preference improved with pump therapy compared to baseline. CONCLUSIONS Insulin pump therapy using a simple dosing regimen significantly improved glycemic control in patients with type 2 diabetes. Patients experienced limited weight gain, there was no severe hypoglycemia, and overall treatment preference improved significantly.

Infrequently studied congenital anomalies as clues to the diagnosis of maternal diabetes mellitus.

The aim of this study was to identify congenital anomalies (CA) among infants of women with diabetes mellitus (DM) that, even though infrequent or infrequently reported, may suggest diabetic teratogenesis. Using 1976–2005 data from the Spanish Collaborative Study of Congenital Malformations (ECEMC), we compared the frequency of selected CA among 130 infants with CA born to women with pregestational DM (PGDM) and 30,009 infants with CA whose mothers had normal glucose tolerance (NGT). To identify which CA were not only significantly more frequent among infants of mothers with PGDM, but also more specific, we calculated the quotient of their frequencies (frequency ratio: FR). The same analysis was made using data from 927 infants of mothers with gestational DM (GDM). Among the studied defects, several were statistically significantly more frequent among infants of PGDM mothers than among infants of mothers with NGT, although the specificity of their association with DM varied, as indicated by the values of the FR. These included: anorectal atresia/stenosis (FR = 2.81; P = 0.03), hallucal polydactyly (FR = 3.62; P = 0.002), heterotaxy (FR = 5.70; P = 0.049), hypertrophic cardiomyopathy (HCM) (FR = 61.60; P = 0.000000), multicystic dysplastic kidneys (MDK) (FR = 5.13; P = 0.0002), and thymus aplasia/hypoplasia (FR = 29.62; P = 0.000001). The only CA significantly more frequent among infants of women with GDM were HCM (FR = 8.60; P = 0.002) and MDK (FR = 1.80; P = 0.01). Our results suggest that maternal PGDM should be suspected in children with hallucal polydactyly, anorectal atresia/stenosis, heterotaxy, or aplasia/hypoplasia of the thymus. The presence of transient HCM or MDK in a newborn suggests maternal PGDM or GDM. These observations are important in view of the increasing worldwide frequency of DM and the high proportion of individuals with DM in whom the condition remains undiagnosed.

Review of Adverse Events Associated With False Glucose Readings Measured by GDH-PQQ–Based Glucose Test Strips in the Presence of Interfering Sugars

OBJECTIVE To assess the implications of falsely elevated glucose readings measured with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) test strips. RESEARCH DESIGN AND METHODS We conducted a review of the Food and Drug Administrations Manufacturer and User Facility Device Experience database and medical literature for adverse events (AEs) associated with falsely elevated glucose readings with GDH-PQQ test strips in the presence of interfering sugars. RESULTS Eighty-two reports were identified: 16 (20%) were associated with death, 46 (56%) with severe hypoglycemia, and 12 (15%) with nonsevere hypoglycemia. In eight reports (10%), the AE was not described. Forty-two events (51%) occurred in the U.S. Although most events occurred in hospitalized patients, at least 14 (17%) occurred in outpatients. Agents most commonly associated with AEs were icodextrin-containing peritoneal dialysate and maltose-containing intravenous immune globulin. CONCLUSIONS GDH-PQQ test strips pose a safety risk to insulin-using patients treated with agents containing or metabolized to interfering sugars.

Incretins and their role in the management of diabetes.

Purpose of reviewTo review data from clinical trials of incretin mimetics in patients with type 2 diabetes. Recent findingsIncretin mimetics are a new class of antidiabetic medication that mimic the actions of the hormone glucagon-like peptide-1. They exhibit several properties, including glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and induction of satiety, which result in improvements in glycemic control with weight loss in patients with type 2 diabetes. Recent 2-year data with exenatide, the only commercially available incretin mimetic, have demonstrated long-term sustained reductions in hemoglobin A1c with progressive weight loss. Glycemic and weight benefits were also recently reported in a 15-week study assessing once-weekly administration of long-acting release exenatide, a formulation currently in phase 3 of clinical development. Once-daily administration of liraglutide, also in phase 3 of development, has recently been shown to improve glycemic and weigh control as monotherapy, and in combination with metformin. The most common side effects of incretin mimetics are gastrointestinal in nature, particularly nausea. SummaryThe ability of incretin mimetics to improve glycemic control and reduce body weight is a unique property that fills an important void in the treatment of patients with type 2 diabetes.

Patient-reported outcomes from a 16-week open-label, multicenter study of insulin pump therapy in patients with type 2 diabetes mellitus.

BACKGROUND This study assessed patient-reported outcomes (PRO) for patients with type 2 diabetes treated by insulin pump therapy. METHODS This 16-week, open-label, multicenter study was conducted with adults (averaging 57 years old, 50% women, 68% white non-Hispanic, with duration of diabetes of 13 years) treated at baseline with oral antidiabetes agents (OAD) only (OAD cohort, n = 17), basal insulin with or without OAD (Basal cohort, n = 17), or multiple daily injections (MDI) with or without OAD (MDI cohort, n = 20). All diabetes medications except metformin were discontinued at baseline, and insulin pump therapy was initiated. PRO were measured at baseline and end of study using two measures of health-related quality of life (QOL)--the Diabetes Symptom Checklist-Revised (DSC-R) and the EuroQol-5 Dimensions (EQ-5D)--and a measure of treatment satisfaction--the Insulin Delivery System Rating Questionnaire (IDSRQ). RESULTS The combined study population (n = 54) experienced significant reductions in DSC-R total symptoms, as well as a significant increase in the EQ-5D Visual Analog Scale score. The OAD cohort experienced no changes in any QOL measure; the Basal and MDI cohorts each experienced significant improvements in several QOL measures. The combined study population experienced significant improvements in all IDSRQ measures except treatment interference, for which change was not significant. The OAD cohort experienced significant improvements in perceived clinical efficacy and overall treatment preference; the Basal and MDI cohorts each experienced significant improvements in five of the seven IDSRQ measures. CONCLUSIONS Insulin pump therapy improved QOL and treatment preference in patients with type 2 diabetes.

A 16-week open-label, multicenter pilot study assessing insulin pump therapy in patients with type 2 diabetes suboptimally controlled with multiple daily injections.

Background: We assessed the efficacy, safety, and patient-reported outcomes (PROs) of insulin pump therapy in patients with type 2 diabetes mellitus (T2DM) who were suboptimally controlled with a multiple daily injection (MDI) regimen. Methods: In this subanalysis of a 16-week multicenter study, 21 insulin-pump-naïve patients [age 57 ± 13 years, hemoglobin A1c (A1C) 8.4 ± 1.0%, body weight 98 ± 20 kg, total daily insulin dose 99 ± 65 U, mean ± standard deviation] treated at baseline with MDI therapy with or without oral antidiabetic agents discontinued all diabetes medications except metformin and initiated insulin pump therapy. Insulin was titrated to achieve the best possible glycemic control with the simplest possible dosing regimen. Outcome measures included A1C, fasting and postprandial glucose, body weight, incidence of hypoglycemia, and PROs. Results: Glycemic control improved significantly after 16 weeks: A1C 7.3 ± 1.0% (−1.1 ± 1.2%, p < .001), fasting glucose 133 ± 33mg/dl (−32 ± 74 mg/dl, p < .005), and postprandial glucose 153 ± 35 mg/dl (−38 ± 46 mg/dl, p < .001). At week 16, the mean daily basal, bolus, and total insulin doses were 66 ± 36, 56 ± 40, and 122 ± 72 U (1.2 U/kg), respectively, and 90% of patients were treated with two or fewer daily basal rates. Body weight increased by 2.8 ± 2.6 kg (p < .001). Mild hypoglycemia was experienced by 81% of patients at least once during the course of the study with no episodes of severe hypoglycemia. There were significant improvements in PRO measures. Conclusions: Insulin pump therapy using a relatively simple dosing regimen safely improved glucose control and PROs in patients with T2DM who were unable to achieve glycemic targets with MDI therapy. Controlled trials are needed to further assess the clinical benefits and cost-effectiveness of insulin pumps in this patient population.

Pramlintide Improved Measures of Glycemic Control and Body Weight in Patients With Type I Diabetes Mellitus Undergoing Continuous Subcutaneous Insulin Infusion Therapy

Abstract Objective: To assess the safety and efficacy of the addition of pramlintide to continuous subcutaneous insulin infusion (CSII) therapy in patients with type 1 diabetes mellitus (T1DM). Research Design and Methods: We conducted a post hoc analysis of 2 studies: a 29-week, multicenter, randomized, double-blind, placebo-controlled trial (referred to as RCT) (pramlintide, n = 82; placebo, n = 73) and an open-ended, multicenter, open-label, single-arm, observational study (referred to as clinical practice trial) (n =150), which assessed the addition of pramlintide to CSII therapy in patients with T1DM. Pramlintide was initiated at 15 μg and titrated to 30 or 60 μg with major meals. The mealtime insulin dose was reduced by 30% to 50% at initiation, and then adjusted to optimize glycemic control. Endpoints at 29 weeks (RCT) and 6 months (clinical practice trial) included change in glycated hemoglobin (HbA1c) level, insulin dose, body weight, pre- and postprandial blood glucose level, and tolerability and safety. Results: In both studies, mean baseline age was approximately 42 years, duration of diabetes was 20 to 24 years, and HbA1c level was approximately 8%. Pramlintide reduced blood glucose excursions and improved the percentage of recorded postprandial blood glucose levels < 180 mg/dL. Mean (+ standard deviation) reduction in HbA1c level in the clinical practice trial was −0.3% ± 0.1 % (P < 0.0001), and in the RCT was similar between pramlintide- and placebo-treated patients (−0.4% ± 0.1% and −0.3% ± 0.1%, respectively). Glycemic improvements were accomplished, with reductions in mealtime insulin doses (RCT: pramlintide, −23.8% ± 5.2%; placebo, −3.2% ± 4.1%; P < 0.0005; clinical practice trial: −27.5% ± 2.9%; P < 0.0001) and body weight (RCT: pramlintide, −2.2 kg ± 0.5 kg; placebo, ± 1.4 kg ± 0.3 kg; P < 0.0001; clinical practice trial: −3.2 kg ± 0.4 kg; P < 0.0001). Short-lived nausea, primarily mild to moderate in intensity, was the most common adverse event associated with pramlintide therapy. Severe hypoglycemic events occurred at a rate of 0.56 and 0.34 events per patient-year in pramlintide- and placebo-treated patients, respectively, in the RCT, and at a rate of 0.12 events per patient-year in the clinical practice trial. Conclusion: Addition of pramlintide to CSII therapy was safe and effective in patients with T1DM. Pramlintide should be considered for patients who are not able to optimize glycemic control with CSII therapy alone, particularly those with difficulty controlling postprandial blood glucose levels and/or body weight. Trial registration: www.ClinicalTrials.gov identifiers: NCT00042458, NCT00108004

Continuous Subcutaneous Insulin Infusion in Patients With Type 2 Diabetes A Cohort Study to Establish the Relationship Between Glucose Control and Plasma Oxidized Low Density Lipoprotein

Background: Oxidative stress is a detrimental feature of diabetes implicated in the progression of the disease and its complications. The relationship between insulin therapy and oxidative stress is complex. This study tested the hypothesis that improved glucose control, rather than insulin dose, is central to reduced oxidative stress in patients with type 2 diabetes following continuous subcutaneous insulin infusion (CSII). Methods: In this 16-week, multicenter study, 54 CSII-naïve patients with type 2 diabetes (age 57 ± 10 years, HbA1c 69 ± 15 mmol/mol [8.5 ± 1.4%], diabetes duration 13 ± 6 years) treated with either oral antidiabetic agents (OAD) alone (n = 17), basal insulin ± OAD (n = 17), or multiple daily injections (MDI) ± OAD (n = 20) were the evaluable group. Diabetes medications except metformin were discontinued, and 16 weeks of CSII was initiated. Insulin dose was titrated to achieve optimal glycemic control. A plasma marker of oxidative stress relevant to cardiovascular disease (oxidized low density lipoprotein [ox-LDL]) was assessed at baseline and week 16. Results: CSII improved glycemic control (HbA1c −13 ± 2 mmol/mol [−1.2 ± 0.2%]; fasting glucose −36.6 ± 8.4 mg/dL; mean glucose excursion −23.2 ± 6.5 mg/dL, mean ± SE; all P < .001) and reduced ox-LDL (–10.5%; P < .05). The antioxidant effect was cohort-independent (P > .05), but was significantly more pronounced in patients on statins (P = .019). The effect of CSII was more closely correlated to improvements in glucose excursion (P = .013) than to insulin dose (P > .05) or reduction in HbA1c (P > .05). Conclusions: CSII induces depression of plasma ox-LDL associated with change in glucose control, rather than with change in insulin dose. The effect is augmented in patients receiving statins.

More Similarities Than Differences Testing Insulin Glargine 300 Units/mL Versus Insulin Degludec 100 Units/mL in Insulin-Naive Type 2 Diabetes: The Randomized Head-to-Head BRIGHT Trial

OBJECTIVE To compare insulin glargine 300 units/mL (Gla-300) versus insulin degludec 100 units/mL (IDeg-100) in this first head-to-head randomized controlled trial. RESEARCH DESIGN AND METHODS BRIGHT (NCT02738151) was a multicenter, open-label, active-controlled, two-arm, parallel-group, 24-week, noninferiority study in insulin-naive patients with uncontrolled type 2 diabetes. Participants were randomized 1:1 to evening dosing with Gla-300 (N = 466) or IDeg-100 (N = 463), titrated to fasting self-monitored plasma glucose of 80–100 mg/dL. The primary end point was HbA1c change from baseline to week 24. Safety end points included incidence and event rates of hypoglycemia. RESULTS At week 24, HbA1c improved similarly from baseline values of 8.7% (72 mmol/mol) in the Gla-300 group and 8.6% (70 mmol/mol) in the IDeg-100 group to 7.0% (53 mmol/mol)—least squares mean difference −0.05% (95% CI −0.15 to 0.05) (−0.6 mmol/mol [−1.7 to 0.6])—demonstrating noninferiority of Gla-300 versus IDeg-100 (P < 0.0001). Hypoglycemia incidence and event rates over 24 weeks were comparable with both insulins, whereas during the active titration period (0–12 weeks) the incidence and rate of anytime (24-h) confirmed hypoglycemia (≤70 and <54 mg/dL) were lower with Gla-300. Both insulins were properly titrated and exhibited no specific safety concerns. CONCLUSIONS Gla-300 and IDeg-100 provided similar glycemic control improvements with relatively low hypoglycemia risk. Hypoglycemia incidence and rates were comparable with both insulins during the full study period but lower in favor of Gla-300 during the titration period. The choice between these longer-acting basal insulins may be determined by factors such as access and cost, alongside clinical considerations.

Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial

BACKGROUND LY3298176 is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is being developed for the treatment of type 2 diabetes. We aimed to examine the efficacy and safety of co-stimulation of the GLP-1 and GIP receptors with LY3298176 compared with placebo or selective stimulation of GLP-1 receptors with dulaglutide in patients with poorly controlled type 2 diabetes. METHODS In this double-blind, randomised, phase 2 study, patients with type 2 diabetes were randomly assigned (1:1:1:1:1:1) to receive either once-weekly subcutaneous LY3298176 (1 mg, 5 mg, 10 mg, or 15 mg), dulaglutide (1·5 mg), or placebo for 26 weeks. Assignment was stratified by baseline glycated haemoglobin A1c (HbA1c), metformin use, and body-mass index (BMI). Eligible participants (aged 18-75) had type 2 diabetes for at least 6 months (HbA1c 7·0-10·5%, inclusive), that was inadequately controlled with diet and exercise alone or with stable metformin therapy, and a BMI of 23-50 kg/m2. The primary efficacy outcome was change in HbA1c from baseline to 26 weeks in the modified intention-to-treat (mITT) population (all patients who received at least one dose of study drug and had at least one postbaseline measurement of any outcome). Secondary endpoints, measured in the mITT on treatment dataset, were change in HbA1c from baseline to 12 weeks; change in mean bodyweight, fasting plasma glucose, waist circumference, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, and proportion of patients reaching the HbA1c target (≤6·5% and <7·0%) from baseline to weeks 12 and 26; and proportion of patients with at least 5% and 10% bodyweight loss from baseline to 26 weeks. This study is registered with ClinicalTrials.gov, number NCT03131687. FINDINGS Between May 24, 2017, and March 28, 2018, 555 participants were assessed for eligibility, of whom 318 were randomly assigned to one of the six treatment groups. Because two participants did not receive treatment, the modified intention-to-treat and safety populations included 316 participants. 258 (81·7%) participants completed 26 weeks of treatment, and 283 (89·6%) completed the study. At baseline, mean age was 57 years (SD 9), BMI was 32·6 kg/m2 (5·9), duration from diagnosis of diabetes was 9 years (6), HbA1c was 8·1% (1·0), 53% of patients were men, and 47% were women. At 26 weeks, the effect of LY3298176 on change in HbA1c was dose-dependent and did not plateau. Mean changes from baseline in HbA1c with LY3298176 were -1·06% for 1 mg, -1·73% for 5 mg, -1·89% for 10 mg, and -1·94% for 15 mg, compared with -0·06% for placebo (posterior mean differences [80% credible set] vs placebo: -1·00% [-1·22 to -0·79] for 1 mg, -1·67% [-1·88 to -1·46] for 5 mg, -1·83% [-2·04 to -1·61] for 10 mg, and -1·89% [-2·11 to -1·67] for 15 mg). Compared with dulaglutide (-1·21%) the posterior mean differences (80% credible set) for change in HbA1c from baseline to 26 weeks with the LY3298176 doses were 0·15% (-0·08 to 0·38) for 1 mg, -0·52% (-0·72 to -0·31) for 5 mg, -0·67% (-0·89 to -0·46) for 10 mg, and -0·73% (-0·95 to -0·52) for 15 mg. At 26 weeks, 33-90% of patients treated with LY3298176 achieved the HbA1c target of less than 7·0% (vs 52% with dulaglutide, 12% with placebo) and 15-82% achieved the HbA1c target of at least 6·5% (vs 39% with dulaglutide, 2% with placebo). Changes in fasting plasma glucose ranged from -0·4 mmol/L to -3·4 mmol/L for LY3298176 (vs 0·9 mmol/L for placebo, -1·2 mmol/L for dulaglutide). Changes in mean bodyweight ranged from -0·9 kg to -11·3 kg for LY3298176 (vs -0·4 kg for placebo, -2·7 kg for dulaglutide). At 26 weeks, 14-71% of those treated with LY3298176 achieved the weight loss target of at least 5% (vs 22% with dulaglutide, 0% with placebo) and 6-39% achieved the weight loss target of at least 10% (vs 9% with dulaglutide, 0% with placebo). Changes in waist circumference ranged from -2·1 cm to -10·2 cm for LY3298176 (vs -1·3 cm for placebo, -2·5 cm for dulaglutide). Changes in total cholesterol ranged from 0·2 mmol/L to -0·3 mmol/L for LY3298176 (vs 0·3 mmol/L for placebo, -0·2 mmol/L for dulaglutide). Changes in HDL or LDL cholesterol did not differ between the LY3298176 and placebo groups. Changes in triglyceride concentration ranged from 0 mmol/L to -0·8 mmol/L for LY3298176 (vs 0·3 mmol/L for placebo, -0·3 mmol/L for dulaglutide). The 12-week outcomes were similar to those at 26 weeks for all secondary outcomes. 13 (4%) of 316 participants across the six treatment groups had 23 serious adverse events in total. Gastrointestinal events (nausea, diarrhoea, and vomiting) were the most common treatment-emergent adverse events. The incidence of gastrointestinal events was dose-related (23·1% for 1 mg LY3298176, 32·7% for 5 mg LY3298176, 51·0% for 10 mg LY3298176, and 66·0% for 15 mg LY3298176, 42·6% for dulaglutide, 9·8% for placebo); most events were mild to moderate in intensity and transient. Decreased appetite was the second most common adverse event (3·8% for 1 mg LY3298176, 20·0% for 5 mg LY3298176, 25·5% for 10 mg LY3298176, 18·9% for 15 mg LY3298176, 5·6% for dulaglutide, 2·0% for placebo). There were no reports of severe hypoglycaemia. One patient in the placebo group died from lung adenocarcinoma stage IV, which was unrelated to study treatment. INTERPRETATION The dual GIP and GLP-1 receptor agonist, LY3298176, showed significantly better efficacy with regard to glucose control and weight loss than did dulaglutide, with an acceptable safety and tolerability profile. Combined GIP and GLP-1 receptor stimulation might offer a new therapeutic option in the treatment of type 2 diabetes. FUNDING Eli Lilly and Company.