Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin analog, as part of a basal-bolus regimen in type 2 diabetes: a randomized, active-controlled phase 2/3 study.

BACKGROUND: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin. RESEARCH DESIGN AND METHODS: In this open-label, active-controlled trial, patients with T2D, HbA1c ≥7%-≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, n = 30; 45 mg, n = 31) and IAsp, n = 30. Primary outcome was change from baseline (CFB) in HbA1c at week 24. Secondary outcomes included PPG excursion (PPGE) and PPG assessed from standardized test meal (STM) and 9-point self-monitored blood glucose. RESULTS: The observed mean HbA1c did not improve at week 24 in Tregopil groups (30 mg [0.15%], 45 mg [0.22%] vs. a reduction in IAsp group [-0.77%]). Combined Tregopil group showed better 1-h PPGE control versus IAsp following STM (CFB, estimated treatment difference, 95% CI, -45.33 mg/dL [-71.91, -18.75], p = 0.001) and 1-h PPG trended toward better control. Tregopil showed lower PPGE at 15 min versus IAsp. Clinically significant hypoglycemia was lower with Tregopil versus. IAsp (rate ratio: 0.69). CONCLUSIONS: Tregopil demonstrated an ultrafast, short-duration prandial profile with good safety. While Tregopil's early postprandial effects were comparable to IAsp, its late postprandial effects were inferior. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03430856).

Pharmacokinetics and Pharmacodynamics of Insulin Tregopil in Relation to Premeal Dosing Time, Between Meal Interval, and Meal Composition in Patients With Type 2 Diabetes Mellitus.

We evaluated the pharmacokinetics and pharmacodynamics of oral insulin tregopil in relation to premeal dosing time, between-meal interval, and meal composition type in type 2 diabetes mellitus patients in a randomized, placebo-controlled, crossover study consisting of 3 sequential cohorts. In Cohort 1, insulin tregopil administered 10 to 20 minutes before a meal resulted in optimal postmeal exposure and demonstrated better postprandial glucose-lowering effect (glucose area under concentration-time curve [AUC]) compared to the 30-minute group. In Cohort 2, insulin tregopil pharmacokinetic exposure (plasma AUC) showed a progressive increase through 4, 5, and 6 hours of between-meal interval. The 6-hour between-meal interval resulted in better absorption of insulin tregopil in comparison to 4- and 5-hour intervals. However, no significant differences were observed in pharmacodynamic parameters except for higher glucose AUC0-180min in the insulin tregopil 4-hour group during the afternoon meal as compared to the morning meal. In Cohort 3, a high-fiber meal had the least impact on insulin tregopil absorption and resulted in the highest reduction in plasma glucose levels in the afternoon. A high-fat meal reduced insulin tregopil absorption in the afternoon meal; however, pharmacodynamic response was not diminished significantly. Insulin tregopil has a rapid onset of action of approximately 10 minutes and, when administered 10 to 20 minutes before a meal, demonstrated up to 13% to 18% reduction in blood glucose levels compared to baseline. A 5-hour between-meal interval minimizes the impact of a meal on absorption of subsequent (afternoon) insulin tregopil dose, and the pharmacodynamic response of insulin tregopil is not altered by meal composition. Insulin tregopil was well tolerated in patients with type 2 diabetes mellitus.

Thiazolidinediones: the Forgotten Diabetes Medications.

PURPOSE OF REVIEW: Thiazolidinediones (TZDs) are the only pharmacologic agents that specifically treat insulin resistance. The beneficial effects of TZDs on the cardiovascular risk factors associated with insulin resistance have been well documented. TZD use has been limited because of concern about safety issues and side effects. RECENT FINDINGS: Recent studies indicate that cardiovascular toxicity with rosiglitazone and increase in bladder cancer with pioglitazone are no longer significant issues. There are new data which show that pioglitazone treatment reduces myocardial infarctions and ischemic strokes. New data concerning TZD-mediated edema, congestive heart failure, and bone fractures improves the clinician's ability to select patients that will have minimal significant side effects. Thiazolidinediones are now generic and less costly than pharmaceutical company-promoted therapies. Better understanding of the side effects coupled with clear benefits on the components of the insulin resistance syndrome should promote TZD use in treating patients with type 2 diabetes.

Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open-Label, Placebo-Controlled, Crossover Study.

Oral insulin tregopil (IN-105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN-105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study the effect of IN-105 on pharmacokinetics (PKs) of metformin. In this randomized, open-label, cross-over study, metformin was administered to healthy volunteers receiving IN-105/placebo under fed/fasting conditions. The 90% confidence interval (CI) of the geometric mean ratio of the area under the curve from time zero to infinity (AUC0-inf ; fasting and fed) and peak plasma concentration (Cmax ; fed) of metformin were within 0.80-1.25 acceptance range. Under fasting conditions, the upper bound margin of Cmax was just beyond this range (i.e., 1.27) and was concluded as functionally not relevant. There was no clinically significant effect of sodium caprate/IN-105 on PKs of metformin under fasting/fed conditions, and it was safe.

Ketosis-Prone Diabetes (Flatbush Diabetes): an Emerging Worldwide Clinically Important Entity.

PURPOSE OF REVIEW: Ketosis-prone diabetes or Flatbush diabetes has been widely recognized as a clinical entity since 1984. Most of the early clinical studies focused on African American or Afro-Caribbean individuals. It is now being recognized as an important clinical entity in sub-Saharan Africans, Asian and Indian populations, and Hispanic populations. Major questions remain as to its pathogenesis and whether it is a unique type of diabetes or a subset of more severe type 2 diabetes with greater loss of insulin action in target tissues. This review summarizes the main clinical and mechanistic studies to improve the understanding of ketosis-prone (Flatbush) diabetes. RECENT FINDINGS: Little data are available on the magnitude of KPD in the different susceptible populations. It is relatively common in black populations. KPD is defined as a syndrome in which diabetes commences with ketoacidosis in individuals who are GAD and anti-islet cell antibody negative and have no known precipitating causes. The patients present during middle age, are overweight or mildly obese, and in many reports are more likely to be male. After intensive initial insulin therapy, many patients become insulin independent and can be well controlled on diet alone or diet plus oral medications. The clinical course of KPD is like that of patients with type 2 diabetes rather than that of type 1 diabetes. Little differences are found in the clinical characteristics and clinical outcomes between patients presenting with KPD and those presenting with severe hyperglycemia with no ketoacidosis. The mechanisms responsible for the development of ketosis-prone diabetes as well its remission remain unknown.

Gastric Contractility Modulation - a novel method for the treatment of type 2 diabetes mellitus and obesity.

Because the majority of antidiabetic medications are of limited efficacy and patient compliance with treatment is usually poor, new therapies are still being searched for. In the review a newly developed system for treatment of subjects with type 2 diabetes and concomitant overweight/obesity is described. The system consists of an implantable pulse generator that delivers electrical stimuli through leads implanted in the sero-muscular layer of the stomach. The device recognises and automatically modulates natural electrical activity of the stomach during meals, strengthening gastric contractility. This increase in the force of contractions enhances vagal afferent activity. Modulated signals are transmitted to the regulatory centres in the brain in order to provoke an early response of the gut typical of a full meal. Clinical trials performed to date show that the system improves glycaemic control with minimal patient compliance needed and with added benefits of body weight loss, a decrease in blood pressure, and favourable changes in the lipid profile. The system is safe, well-tolerated, with a low risk of hypoglycaemia, and will probably become an alternative to the use of incretins or to bariatric surgery in obese patients who are unwilling to undergo a major and anatomically irreversible operation.

Heart Failure: a Major Cardiovascular Complication of Diabetes Mellitus.

Heart failure (HF) is a major cardiovascular complication of diabetes mellitus (DM). The greatest risk factor for HF is age, and data indicate that 6 to 10 % of individuals over the age of 65 years suffer from HF. Patients with DM have a 2.5-fold increased risk for developing HF than individuals without DM. The 25 to 40 % of patients with HF who have DM have worse outcome (death from cardiovascular disease or hospitalization for worsening HF) than patients without DM. Hyperglycemia is a risk factor for the development of HF with an increase in incidence of HF rising from 10 % at hemoglobin A1c (HbA1c) 8.0 to 9.0 % to 71 % at a HbA1c > 10 %. Patients with DM and HF are equally distributed between those with low ejection fractions and those with normal ejection fractions. The HF treatment regimens for patients with HF and DM (blockade of angiotensin II synthesis or action, cardioselective ß-adrenergic blockade, mineralocorticoid receptor blockade, and diuretics) are the same as for HF patients without DM, though the benefit on clinical outcomes is not as great. The new angiotensin-neprilysin inhibitors appear to provide increase outcome benefits in both HF patients with or without DM. Glycemic control impacts the clinical outcomes in patients with HF and DM in a U-shaped relationship with poorer survival at low and high mean HbA1c levels. The optimal chronic glycemic control occurs at an HbA1c of 7.5 to 8.0 % for patients with DM who have symptoms of HF.

Interventional treatment of obesity and diabetes: An interim report on gastric electrical stimulation.

Gastric electrical stimulation has been applied to treat human obesity since 1995. Dilatation of the stomach causes a series of neural reflexes which result in satiation and satiety. In non-obese individuals food ingestion is limited in part by this mechanism. In obese individuals, satiation and satiety are defective and unable to limit energy intake and prevent excessive weight gain. Several gastric electrical stimulatory (GES) devices have been developed, tested in clinical trials and even approved for the treatment of obesity. The design and clinical utility of three devices (Transend®, Maestro® and DIAMOND®) that have been extensively studied are presented as well as that of a new device (abiliti®) which is in early development. The Transcend®, a low energy GES device, showed promising results in open label studies but failed to show a difference from placebo in decreasing weight in obese subjects. The results of the clinical trials in treating obese subjects with the Maestro®, a vagal nerve stimulator, were sufficient to gain approval for marketing the device. The DIAMOND®, a multi-electrode GES device, has been used to treat type 2 diabetes and an associated benefit is to reduce body weight and lower systolic blood pressure.

Gastric electrical stimulation treatment of type 2 diabetes: effects of implantation versus meal-mediated stimulation. A randomized blinded cross-over trial.

Gastric electrical stimulation with the implanted DIAMOND device has been shown to improve glycemic control and decrease weight and systolic blood pressure in patients with type 2 diabetes inadequately controlled with oral antidiabetic agents. The objective of this study was to determine if device implantation alone (placebo effect) contributes to the long-term metabolic benefits of DIAMOND(®) meal-mediated gastric electrical stimulation in patients with type 2 diabetes. The study was a 48 week randomized, blinded, cross-over trial in university centers comparing glycemic improvement of DIAMOND(®) implanted patients with type 2 diabetic with no activation of the electrical stimulation (placebo) versus meal-mediated activation of the electrical signal. The endpoint was improvement in glycemic control (HbA1c) from baseline to 24 and 48 weeks. In period 1 (0-24 weeks), equal improvement in HbA1c occurred independent of whether the meal-mediated electrical stimulation was turned on or left off (HbA1c -0.80% and -0.85% [-8.8 and -9.0 mmol/mol]). The device placebo improvement proved to be transient as it was lost in period 2 (25-48 weeks). With electrical stimulation turned off, HbA1c returned toward baseline values (8.06 compared to 8.32%; 64.2 to 67.4 mmol/mol, P = 0.465). In contrast, turning the electrical stimulation on in period 2 sustained the decrease in HbA1c from baseline (-0.93%, -10.1mmol/mol, P = 0.001) observed in period 1. The results indicate that implantation of the DIAMOND device causes a transient improvement in HbA1c which is not sustained beyond 24 weeks. Meal-mediated electrical stimulation accounts for the significant improvement in HbA1c beyond 24 weeks.

A pilot study to compare meal-triggered gastric electrical stimulation and insulin treatment in Chinese obese type 2 diabetes.

BACKGROUND: Gastrointestinal electromodulation therapy is a novel alternative for achieving diabetes control without traditional bariatric surgery. We compared the efficacy of a meal-initiated implantable gastric contractility modulation (GCM) device with that of insulin therapy in obese Chinese type 2 diabetes (T2D) patients, for whom oral antidiabetes drugs (OADs) had failed. PATIENTS AND METHODS: Sixteen obese (body mass index, 27.5-40.0 kg/m(2)) T2D patients with a glycated hemoglobin (HbA1c) level of >7.5% on maximal doses of two or more OADs were offered either insulin therapy (n=8) or laparoscopic implantation of a GCM (n=8). We compared changes in body weight, waist circumference (WC), and HbA1c level 1 year after surgery. RESULTS: The GCM and insulin groups had similar baseline body weight and HbA1c. At 12 months, body weight (-3.2±5.2 kg, P=0.043) and WC (-3.8±4.5 cm, P=0.021) fell in the GCM group but not in the insulin group (P<0.05 for between-group difference). At 6 and 12 months, the HbA1c level fell by 1.6±1.1% and 0.9±1.6% (P=0.011), compared with 0.6±0.3% and 0.6±0.3% (P=0.08) for the insulin group (P=0.15 for between-group difference). The mean 24-h systolic blood pressure (BP) fell by 4.5±1.0 mm Hg in the GCM group (P=0.017) but not in the insulin group. The GCM group required fewer antidiabetes medications (P<0.05) and BP-lowering drugs (P<0.05) than the insulin group. A subgroup analysis showed that patients with a triglyceride level of <1.7 mmol/L had a tendency toward a lower HbA1c level (P=0.090) compared with the controls. CONCLUSIONS: In obese T2D patients for whom OADs had failed, GCM implantation was a well-tolerated alternative to insulin therapy, with a low triglyceride level as a possible predictor for glycemic response.

The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy.

OBJECTIVE: This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy. RESEARCH DESIGN AND METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12 weeks in 170 patients with type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m(2)) that was inadequately controlled with sitagliptin alone (A1C ≥7.5%) during a 12-week run-in period. The primary efficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, stratification by baseline A1C, and percentage of A1C responders. RESULTS: Imeglimin reduced A1C levels (least-squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (between-group difference 0.72%, P < 0.001). The corresponding changes in FPG were -0.93 mmol/L with imeglimin vs. -0.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ≥0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8% of subjects receiving imeglimin achieved a decrease in A1C level of ≤7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well tolerated, with a safety profile comparable to placebo and no related treatment-emergent adverse events. CONCLUSIONS: Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies.

The DIAMOND system in the treatment of type 2 diabetes mellitus in an obese patient.

Obesity and type 2 diabetes mellitus have reached epidemic proportions worldwide. As the majority of antidiabetic medications are of limited efficacy and patient adherence to long-term therapy is one of the main limiting factors of effective blood glucose and body weight control, new therapies are still looked for. The DIAMOND system seems to be one of the most promising among them. This system recognizes natural electrical activity of the stomach and automatically applies electrical stimulation treatment during/after eating with subsequent modulation of signals transmitted to the regulatory centers in the brain in order to provoke an early response of the gut typical of a full meal. We present the case of a 47-year-old obese woman with type 2 diabetes. During treatment with this system, serum glucose and hemoglobin A1c levels significantly decreased. Body weight loss and waist circumference reduction were observed. Additionally, beneficial effect on lipid profile was found.

Metabolic surgery for type 2 diabetes: appraisal of clinical evidence and review of randomized controlled clinical trials comparing surgery with medical therapy.

Bariatric surgical procedures were originally developed to treat morbid obesity where their benefits certainly outweigh their potential side effects. Although they are very beneficial in improving metabolic control in type 2 diabetes, there are many medical treatments that are also effective. The role of bariatric surgery as primary therapy for type 2 diabetes depends on whether the benefit exceeds the surgical and nutritional complications, which are significant. The ultimate role for bariatric surgery in treating type 2 diabetes can only be determined by large, long-term randomized clinical trials which compare clinical outcomes of bariatric surgery with those of current intensive medical treatment. The four reported small, mostly 1-year trials have shown superior glycemic control by surgery as compared with medical treatment, but at the expense of significant surgical complications and unknown nutritional liability. They show that future trials will have to be much larger and last for at least 5-10 years.

Autoimmune polyglandular syndromes: interplay between the immune and the endocrine systems leading to a diverse set of clinical diseases and new insights into immune regulation.

During the last 50 years, three major classes of autoimmune polyglandular syndromes (APSs) have been defined, and their characteristics and heritability have been delineated. Simultaneously, studies of the immunologic bases of these syndromes provided fundamental information in understanding immune regulation. Genetic analyses of patients and their families with APS type 1 (autoimmune polyendocrinopathy candidiasis, ectodermal dystrophy) identified the autoimmune regulator (AIRE) gene, which drives the expression of peripheral tissue-specific antigens in thymic cells and is critical in the development of self-tolerance. Mutations in this gene cause APS type 1. In contrast, studies in APS type 2 have been instrumental in understanding the role of human leukocyte antigen type II and related molecules in the pathogenesis of polygenetic autoimmune diseases such as type 1A diabetes. Immune dysfunction polyendocrinopathy, enteropathy, X-linked syndrome, which is caused by mutations in the forkhead box P3 gene, has been a model for studying regulatory T cell biology. The APSs epitomize the synergies that the merger of clinical and basic science can achieve. This is the environment that George Eisenbarth was able to create at the Barbara Davis Center for Diabetes.

Metabolic surgery for type 2 diabetes with BMI <35 kg/m(2) : an endocrinologist's perspective.

Is bariatric surgery as primary therapy for type 2 diabetes mellitus (T2DM) with body mass index (BMI) <35 kg/m(2) justified? Open-label studies have shown that bariatric surgery causes remission of diabetes in some patients with BMI <35 kg/m(2). All such patients treated had substantial weight loss. Diabetes remission was less likely in patients with lower BMI than those with higher BMI, in patients with longer than shorter duration and in patients with lesser than greater insulin reserve. Relapse of diabetes increases with time after surgery and weight regain. Deficiencies of data are lack of randomized long-term studies comparing risk/benefit of bariatric surgery to contemporary intensive medical therapy. Current data do not justify bariatric surgery as primary therapy for T2DM with BMI <35 kg/m(2).