Obesity and diabetes: the final frontier.

INTRODUCTION: Obesity is a key target in the treatment and prevention of diabetes and independently to reduce the burden of cardiovascular disease. We reviewed the options now available and anticipated to deal with obesity. AREAS COVERED: We considered the epidemiology, genetics, and causation of obesity and the relationship to diabetes, and the dietary, pharmaceutical, and surgical management of the condition. The literature search covered both popular media via Google Search and the academic literature as indexed on PubMed with search terms including obesity, childhood obesity, adipocytes, insulin resistance, mechanisms of satiety, bariatric surgery, GLP-1 receptor agonists, and SGLT2 inhibitors. EXPERT OPINION: Although bariatric surgery has been the primary approach to treating obese individuals, the emergence of agents impacting the brain satiety centers now promises effective, non-invasive treatment of obesity for individuals with and without diabetes. The GLP-1 receptor agonists have assumed the primary role in treating obesity with significant weight loss. Long-term results with semaglutide and tirzepatide are now approaching the success seen with bariatric surgery. Future agents combining the benefits of satiety control and thermogenesis to dissipate caloric excess are under investigation.

Current and emerging gluconeogenesis inhibitors for the treatment of Type 2 diabetes.

INTRODUCTION: In the last several decades, fueled by gene knockout and knockdown techniques, there has been substantial progress in detailing the pathways of gluconeogenesis. A host of molecules have been identified as potential targets for therapeutic intervention. A number of hormones, enzymes and transcription factors participate in gluconeogenesis. Many new agents have come into use to treat diabetes and several of these are in development to suppress gluconeogenesis. AREAS COVERED: Herein, the author reviews agents that have been discovered and/or are in development, which control excess gluconeogenesis. The author has used multiple sources including PubMed, the preprint servers MedRxIv, BioRxIv, Research Gate, as well as Google Search and the database of the U.S. Patent and Trademarks Office to find appropriate literature. EXPERT OPINION: It is now clear that lipid metabolism and hepatic lipogenesis play a major role in gluconeogenesis and resistance to insulin. Future efforts will focus on the duality of gluconeogenesis and adipose tissue metabolism. The exploration of therapeutic RNA agents will accelerate. The balance of clinical benefit and adverse effects will determine the future of new gluconeogenesis inhibitors.

The time to develop treatments for diabetic neuropathy.

BACKGROUND: Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN). METHODS: We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide. RESULTS: Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process. EXPERT OPINION: The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.

Commentary: SGLT inhibitors in type 1 diabetes: Place in therapy and a risk mitigation strategy for preventing diabetic ketoacidosis - the STOP DKA protocol.

In the accompanying article, Goldenberg et al. review the promotion of diabetic ketoacidosis by SGLT2 inihibitors. They have carried out a metanalysis showing a 3.5-fold increase in the risk of diabetic ketoacidosis (DKA) in patients with type 1 diabetes under treatment with SGLT2 inhibitors. They make a number of suggestions for attempting to mitigate the risk of DKA in these patients, notably including blood ketone monitoring and the use of supplemental carbohydrates with additional insulin when ketones suggest incipient DKA. Their proposal merits evaluation in a clinical trial involving type 1 diabetes, which should also assess the possible cardiorenal benefits demonstrated with treatment with SGLT2 inhibitors in type 2 diabetes.

The journey from gene knockout to clinical medicine: telotristat and sotagliflozin.

Gene knockout has been a powerful technique to evaluate the physiologic role of selected gene products. Lexicon pioneered high-throughput gene knockout technology and went further in designing agents to inhibit products of gene expression. Two agents have entered late-stage development. Telotristat is an inhibitor of tryptophan hydroxylase (TPH), preventing the production of serotonin. Although this agent blocks the two isoforms of TPH, it does not cross the blood-brain barrier, thus avoiding central neurologic manifestations. It inhibits the peripheral production of serotonin, and in particular prevents serotonin action in the intestines, resulting in decreased peristaltic action. Lexicon successfully developed telotristat to treat carcinoid syndrome not responding adequately to somatostatin inhibitors. Sotagliflozin development proceeded from the observation that dual inhibition of SGLT2 in the kidneys and SGLT1 in the intestines resulted in increased renal glucose excretion, reduced early-phase glucose absorption, as well as increased blood levels of GLP-1 and PYY. Initial development efforts focused on type 1 diabetes and have shown reduced postprandial glucose levels, less tendency to hypoglycemia, and lower HbA1c. Several other SGLT2 inhibitors have been associated with increased frequency of diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin-treated individuals experienced DKA at a higher rate than placebo-treated patients. The sotagliflozin development program has now been extended to trials on type 2 diabetes. Long-term clinical trials will determine the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.

Sotagliflozin: a combined SGLT1/SGLT2 inhibitor to treat diabetes.

INTRODUCTION: Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes. The agent blocks SGLT2 in the kidneys and SGLT1 in the intestines resulting in reduced early phase glucose absorption and increased blood levels of GLP-1. Initial studies were directed at type 1 diabetes. Areas covered: The published information on sotagliflozin is reviewed, along with the results of several pivotal Type 1 diabetes trials. Expert opinion: Sotagliflozin treatment lowers HbA1c and reduces glucose variability in Type 1 diabetes patients. Several other SGLT2 inhibitors have been associated with a tendency to diabetic ketoacidosis (DKA). In the type 1 trials, sotagliflozin treated individuals experienced DKA at a higher rate than placebo treated patients. An additional safety concern arises from the as yet unknown potential risks in women of child bearing potential. The sotagliflozin development program has now been extended to trials in type 2 diabetes. In type 2 diabetes, long-term studies will be needed to assess the benefits and risks of the agent as a possible alternative to currently marketed SGLT2 inhibitors.

Albiglutide for the management of type 2 diabetes.

INTRODUCTION: Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection and approved for use in type 2 diabetes. It has less gastrointestinal side effects than other GLP-1 RAs in current use but does not improve HbA1c or promote weight loss to the same extent as some competitor agents. Area covered: The current use of albiglutide is discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Unlike competitor agents, the gastrointestinal side effects of albiglutide are not much greater than placebo. It has been studied and appears safe at all stages of renal failure. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long-term study is now underway to determine if albiglutide, with its relatively favorable GI tolerance, has a place in the treatment of patients with increased risk of cardiovascular events. At present, albiglutide is a safe agent to introduce GLP-1 RA treatment into the regimen for type 2 diabetes patients and may be the GLP-1 agent of choice in patients with renal insufficiency.

Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: A randomized, open-label clinical trial.

AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c ≤11.0%) either eligible for or currently taking basal insulin (≥10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. RESULTS: For Mk-Gla and Sa-Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 (-1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [-15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa-Gla were similar both in participants who were insulin-treated or insulin-naïve at baseline. CONCLUSIONS: Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM.

Efficacy and safety of sotagliflozin in treating diabetes type 1.

INTRODUCTION: Sotagliflozin is the first dual SGLT1/SGLT2 inhibitor developed for use in diabetes. Sotagliflozin blocks SGLT2 in the kidneys and SGLT1 in the intestines resulting in reduced early phase glucose absorption and increased blood levels of GLP-1 and PYY. Urinary glucose excretion is lower than with other agents as a result of decreased glucose absorption. The primary development effort to date has been in Type 1 diabetes. Areas covered: The published information on sotagliflozin is reviewed, along with the recent results of several pivotal Type 1 diabetes trials. Expert opinion: Sotagliflozin treatment lowers HbA1c and reduces glucose variability, with a trend to less hypoglycemic events. In the Type 1 trials, sotagliflozin treated individuals experienced DKA at a higher rate than placebo treated patients. An additional safety issue arises from the as yet unknown potential risks in women of child bearing potential in whom DKA is of utmost concern. The sotagliflozin development program has now been extended to trials in Type 2 diabetes, and long term studies will be needed to assess the benefits and risks of the agent in comparison to other currently marketed SGLT2 inhibitors.

The safety of albiglutide for the treatment of type 2 diabetes.

INTRODUCTION: Albiglutide is a marketed long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection. It has significantly less gastrointestinal side effects than other GLP-1 RAs in current use but does not improve HbA1c or promote weight loss to the same extent as competitor agents such as liraglutide. Area Covered: The safety of albiglutide is discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert Opinion: Unlike competitor agents, the gastrointestinal side effects of albiglutide are not much greater than placebo. It has been studied and appears safe at all stages of renal failure. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its relatively favorable GI tolerance, has a place in the treatment of patients with increased risk of cardiovascular events.

Albiglutide: a unique GLP-1 receptor agonist.

INTRODUCTION: Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection. Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents. Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.

Glucagon-like polypeptide agonists in type 2 diabetes mellitus: efficacy and tolerability, a balance.

Glucagon-like polypeptide (GLP-1) receptor agonist treatment has multiple effects on glucose metabolism, supports the ß cell, and promotes weight loss. There are now five GLP-1 agonists in clinical use with more in development. GLP-1 treatment typically can induce a lowering of hemoglobin A1c (HbA1c) of 0.5-1.5% over time with weight loss of 2-5%. In some individuals, a progressive loss of weight occurs. There is evidence that GLP-1 therapy opposes the loss of ß cells which is a feature of type 2 diabetes. The chief downside of GLP-1 treatment is the gastrointestinal motility disturbance which is one of the modes of action of the hormone; significant nausea, vomiting, and diarrhea may lead to discontinuation of treatment. Although daily injection of GLP-1 agents is successful, the development of extended release preparations allows for injection once weekly, and perhaps much longer in the future. The indication for GLP-1 use is diabetes, but now, liraglutide has been approved for primary treatment of obesity. When oral agents fail to control glucose levels in type 2 diabetes, there is a choice between long-acting insulin and GLP-1 agonists as additional treatments. The lowering of HbA1c by either modality is equivalent in most studies. Patients lose weight with GLP-1 treatment and gain weight on insulin. There is a lower incidence of hypoglycemia with GLP-1 therapy but a much higher incidence of gastrointestinal complaints. Insulin dosing is flexible while GLP-1 agents have historically been administered at fixed dosages. Now, the use of combined long-acting insulin and GLP-1 agonists is promising a major therapeutic change. Combined therapy takes advantage of the benefits of both insulin and GLP-1 agents. Furthermore, direct admixture of both in the same syringe will permit flexible dosing, improvement of glucose levels, and reduction of both hypoglycemia and gastrointestinal side effects.

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients.

BACKGROUND: Type 1 diabetes (T1D) results from destruction of pancreatic ß cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining ß cells in patients with newly diagnosed T1D. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS: A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS: In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT00965458. FUNDING: NIH and Astellas.

Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial.

AIMS/HYPOTHESIS: There are limited data comparing dipeptidyl peptidase-4 (DPP-4) inhibitors directly. We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment (RI). METHODS: This study was a parallel-arm, randomised, multicentre, double-blind, 24 week study conducted in 87 centres across Brazil and the USA. Patients with type 2 diabetes, either drug naive or treated with any glucose-lowering agents, who had inadequate glycaemic control (HbA1c 6.5-10.0% [48-86 mmol/mol]) and an estimated GFR <30 ml min(-1) [1.73 m](-2) were randomised (via interactive voice response technology) to vildagliptin 50 mg once daily or sitagliptin 25 mg once daily. These doses are recommended in this patient population and considered maximally effective. Participants, investigators and the sponsor were blinded to group assignment. Efficacy endpoints included change in HbA1c and fasting plasma glucose (FPG) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events. RESULTS: In total, 148 patients were randomised, 83 to vildagliptin and 65 to sitagliptin. All patients were analysed. After 24 weeks, the adjusted mean change in HbA1c was -0.54% (5.9 mmol/mol) from a baseline of 7.52% (59 mmol/mol) with vildagliptin and -0.56% (6.1 mmol/mol) from a baseline of 7.80% (62 mmol/mol) with sitagliptin (p = 0.874). FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin (p = 0.185). Both treatments were well tolerated with overall similar safety profiles. CONCLUSIONS/INTERPRETATION: At their recommended doses for severe RI, vildagliptin (50 mg once daily) compared with sitagliptin (25 mg once daily) demonstrated similar efficacy and both drugs were well tolerated. This study provides further support for the use of DPP-4 inhibitors in patients with severe RI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00616811 (completed) FUNDING: This study was planned and conducted by Novartis.

DPP-4 inhibitors: focus on safety.

INTRODUCTION: Dipeptidyl peptidase inhibitors (DPP-4-i) are highly selective inhibitors of the enzyme DPP-4. They act by increasing levels of incretin hormones, which have potent effects on insulin and glucagon release, gastric emptying, and satiety. Our goal is to review the safety issues related to DPP-4-i. AREAS COVERED: This review is based upon a PubMed search of the literature using keywords alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin, DPP-4-i, glucagon-like polypeptide-1 agonists, as well as extensive personal clinical trial experience with each of these agents. The current DPP-4-i have very different chemical structures. Saxagliptin has significant cytochrome P450 metabolism and carries a risk of drug interactions. Linagliptin has primarily entero-hepatic excretion, a benefit in renally impaired patients. A concern arose related to congestive heart failure in the SAVOR TIMI trial of saxagliptin. Several major cardiac studies are underway, with two concluded. Despite lingering uncertainty related to pancreatitis and pancreatic cancer, large randomized trials have not shown an increased risk with DPP-4-i treatment. Cutaneous adverse effects occur with a low frequency with some of these agents. EXPERT OPINION: DPP-4-i are an additional choice in the group of anti-hyperglycemics. Their principal advantage is a low incidence of hypoglycemia, making these agents desirable in patients such as the elderly and those with cardiac disease. Several large trials have hinted at less cardiac risk with DPP-4-i than with sulfonylureas. The CAROLINA Trial comparing linagliptin and glimepiride may provide a conclusive answer to this question.

Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Type 1 diabetes results from autoimmune targeting of the pancreatic ß cells, likely mediated by effector memory T (Tem) cells. CD2, a T cell surface protein highly expressed on Tem cells, is targeted by the fusion protein alefacept, depleting Tem cells and central memory T (Tcm) cells. We postulated that alefacept would arrest autoimmunity and preserve residual ß cells in patients newly diagnosed with type 1 diabetes. METHODS: The T1DAL study is a phase 2, double-blind, placebo-controlled trial in patients with type 1 diabetes, aged 12-35 years who, within 100 days of diagnosis, were enrolled at 14 US sites. Patients were randomly assigned (2:1) to receive alefacept (two 12-week courses of 15 mg intramuscularly per week, separated by a 12-week pause) or a placebo. Randomisation was stratified by site, and was computer-generated with permuted blocks of three patients per block. All participants and site personnel were masked to treatment assignment. The primary endpoint was the change from baseline in mean 2 h C-peptide area under the curve (AUC) at 12 months. Secondary endpoints at 12 months were the change from baseline in the 4 h C-peptide AUC, insulin use, major hypoglycaemic events, and HbA1c concentrations. This trial is registered with ClinicalTrials.gov, number NCT00965458. FINDINGS: Of 73 patients assessed for eligibility, 33 were randomly assigned to receive alefacept and 16 to receive placebo. The mean 2 h C-peptide AUC at 12 months increased by 0.015 nmol/L (95% CI -0.080 to 0.110) in the alefacept group and decreased by 0.115 nmol/L (-0.278 to 0.047) in the placebo group, and the difference between groups was not significant (p=0.065). However, key secondary endpoints were met: the mean 4 h C-peptide AUC was significantly higher (mean increase of 0.015 nmol/L [95% CI -0.076 to 0.106] vs decrease of -0.156 nmol/L [-0.305 to -0.006]; p=0.019), and daily insulin use (0.48 units per kg per day for placebo vs 0.36 units per kg per day for alefacept; p=0.02) and the rate of hypoglycaemic events (mean of 10.9 events per person per year for alefacept vs 17.3 events for placebo; p<0.0001) was significantly lower at 12 months in the alefacept group than in the placebo group. Mean HbA1c concentrations at week 52 were not different between treatment groups (p=0.75). So far, no serious adverse events were reported and all patients had at least one adverse event. In the alefacept group, 29 (88%) participants had an adverse event related to study drug versus 15 (94%) participants in the placebo group. In the alefacept group, 14 (42%) participants had grade 3 or 4 adverse events compared with nine (56%) participants in the placebo group; no deaths occurred. INTERPRETATION: Although the primary outcome was not met, at 12 months, alefacept preserved the 4 h C-peptide AUC, lowered insulin use, and reduced hypoglycaemic events, suggesting efficacy. Safety and tolerability were similar in the alefacept and placebo groups. Alefacept could be useful to preserve ß-cell function in patients with new-onset type 1 diabetes.