Targeting PPARβ/δ for the treatment of type 2 diabetes mellitus

INTRODUCTION: The nuclear receptors Peroxisome Proliferator-Activated Receptors (PPAR)α and PPARγ are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively. Evidence is now emerging that the PPARβ/δ isotype is a potential pharmacological target for the treatment of insulin resistance and type 2 diabetes mellitus. AREAS COVERED: In this review, the capacity of PPARβ/δ to prevent the development of insulin resistance and type 2 diabetes mellitus is discussed. Special emphasis is placed on preclinical studies and the molecular mechanisms responsible for its actions in the main cell types involved in these pathologies: adipocytes, β-cells, skeletal muscle cells and hepatocytes. EXPERT OPINION: While several concerns remain for the development of PPARβ/δ agonists, these drugs have demonstrated their efficacy in the treatment of insulin resistance and type 2 diabetes mellitus in preclinical studies, as well as in a few short clinical studies in humans. Although this data is promising, additional studies must be performed to confirm the efficacy and safety of these drugs in the treatment of type 2 diabetes mellitus.     

Is exenatide advancing the treatment of type 2 diabetes?

Glucagon-like peptide 1 is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the glucagon-like peptide 1 receptor. Synthetic exendin-4 (exenatide) has recently been trialled in patients with Type 2 diabetes taking either metformin alone or a combination of metformin and a sulfonylurea. In both trials, exenatide 5 and 10 microg s.c. was shown to improve glycaemic control, with few adverse events. Exenatide represents a new and useful addition to the medicines used to treat Type 2 diabetes.     

Bromocriptine – unique formulation of a dopamine agonist for the treatment of type 2 diabetes

Importance to the field: There is a large unmet need for new therapies to treat type 2 diabetes (T2DM) which reduce fasting and postprandial glucose without increasing insulin levels and which are not associated with weight gain or hypoglycemia. The quick-release formulation of bromocriptine (bromocriptine-QR; Cycloset?) represents such a therapy.

Areas covered in the review: Bromocriptine-QR's proposed mechanism of action, unique formulation and clinical efficacy and safety will be discussed. A Medline search was conducted using the terms: bromocriptine quick-release, circadian rhythms, treatment type 2 diabetes, insulin resistance, beta-cell dysfunction (years 1985 – 2009).

What the reader will gain: The reader will gain an understanding of the importance of the brain as a target for the treatment of type 2 diabetes. In addition the safety, efficacy and indication for use of a first-in-class dopamine agonist as a treatment option for type 2 diabetes are discussed.

Take home message: Bromocriptine-QR is indicated to be used alone or in conjunction with all available treatments for type 2 diabetes. Although the mechanism of action is not fully understood, bromocriptine-QR's action points to a central target in the brain (hypothalamus) which may explain the observed peripheral improvements in metabolic parameters.     

Aleglitazar, a dual PPARα and PPARγ agonist for the potential oral treatment of type 2 diabetes mellitus

PPARγ and PPARα are nuclear receptors mainly involved in the regulation of glucose homeostasis and lipid levels, respectively. Aleglitazar, being developed by Roche Holding, is a dual agonist for PPARγ and PPARα for the potential simultaneous treatment of hyperglycemia and dyslipidemia in patients with type 2 diabetes mellitus (T2DM). In preclinical studies, aleglitazar decreased non-fasted glucose levels, increased glucose clearance and improved insulin resistance, while also increasing HDL-cholesterol and decreasing LDL-cholesterol levels in serum. In phase I and II clinical trials in patients with T2DM, aleglitazar demonstrated beneficial antidiabetic activities and had a higher antihyperglycemic efficacy than pioglitazone (a PPARγ agonist). Aleglitazar improved the lipid profile in patients and decreased levels of cardiovascular markers of inflammation and clotting. The observed adverse events were characteristic of either PPARγ or PPARα agonists; however, when compared to pioglitazone-PPARγ-mediated effects, such as edema and weight gain, these were less severe. PPARγ-mediated adverse events on bone have not been measured and should be addressed in the future. The PPARα-mediated adverse effects on renal function are of concern and are a primary endpoint of ongoing phase II clinical trials in patients with T2DM. A phase III clinical trial was also ongoing in patients with T2DM who had recently experienced a cardiac event.     

Is there a role for alpha-glucosidase inhibitors in the prevention of type 2 diabetes mellitus?

Type 2 diabetes mellitus is a major health problem associated with excess morbidity and mortality. As the prevalence of this metabolic disorder is rapidly increasing and current treatment fails to stabilise the disease in most patients, prevention should be considered as a key objective in the near future. People who develop type 2 diabetes pass through a phase of impaired glucose tolerance (IGT). Defects in the action and/or secretion of insulin are the two major abnormalities leading to development of glucose intolerance. Any intervention in the impaired glucose tolerance phase that reduces resistance to insulin or protects the beta-cells, or both, should prevent or delay progression to diabetes.Acarbose, miglitol and voglibose act by competitively inhibiting the alpha-glucosidases, a group of key intestinal enzymes involved in the digestion of carbohydrates. They decrease both postprandial hyperglycaemia and hyperinsulinaemia, and thereby may improve sensitivity to insulin and release the stress on beta-cells. These compounds do not induce hypoglycaemia and have a good safety profile, although gastrointestinal adverse effects may limit long-term compliance to therapy.The recent placebo-controlled prospective STOP-noninsulin-dependent diabetes mellitus (STOP-NIDDM) trial demonstrated that acarbose 100mg three times daily reduces the risk of developing type 2 diabetes in patients with IGT (relative risk reduction of 25% after a mean follow-up of 3.3 years). The 6-year Early Diabetes Intervention Trial (EDIT), comparing the effect of acarbose 50mg three times daily to that of metformin, showed a trend to a positive effect of acarbose compared with placebo, in a mid-term 3-year analysis, which should be confirmed in the final analysis.To our knowledge, no such prevention intervention trials have been or are currently being performed with miglitol or voglibose. In conclusion, because of its absence of toxicity and its particular mechanism of action on gastrointestinal tract and indirect consequences on both insulin action and beta-cell function, acarbose may be used to prevent type 2 diabetes. If the ongoing EDIT trial confirms the positive results of the recent STOP-NIDDM trial, acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of diabetes in patients with IGT. However, the best dosage of acarbose for this specific indication remains to be specified, especially when all three important parameters, efficacy, tolerance and cost, are taken into consideration.     

Pharmacotherapy of ‘treatment resistant’ type 2 diabetes

Introduction: Despite type 2 diabetes (T2D) management offers a variety of pharmacological interventions targeting different defects, numerous patients remain with persistent hyperglycaemia responsible for severe complications. Unlike resistant hypertension, treatment resistant T2D is not a classical concept although it is a rather common observation in clinical practice.

Areas covered: This article proposes a definition for ‘treatment resistant diabetes’, analyses the causes of poor glucose control despite standard therapy, briefly considers the alternative approaches to glucose-lowering pharmacotherapy and finally describes how to overcome poor glycaemic control, using innovative oral or injectable combination therapies.

Expert opinion: Before considering intensifying the pharmacotherapy of a patient with poorly controlled T2D, it is important to verify treatment adherence, target obesity and consider various non pharmacological improvement quality interventions. If treatment resistant diabetes is defined as not achieving glycated haemoglobin target despite oral triple therapy with a third glucose-lowering agent added to metformin-sulfonylurea dual treatment, the combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor and a sodium glucose cotransporter type 2 (SGLT2) inhibitor may offer new opportunities before considering injectable therapies. Insulin basal therapy (± metformin) may be optimized by the addition of a SGLT2 inhibitor or a glucagon-like peptide-1 (GLP-1) receptor agonist.     

Practical considerations for the use of sodium–glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes

Sodium–glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term.     

Inhibitors of type 2 sodium glucose co-transporters – a new strategy for diabetes treatment

In the last few years, the type 2 sodium glucose co-transporters (SGLT2) have been the subject of particular attention as a new, potent group of anti-diabetic drugs.SGLT2 inhibitors block glucose reabsorption in the kidneys, which prompts urinary excretion of glucose and results in lowering of its plasma levels. Although this group of medications is still under investigation, their efficacy in the treatment of type 2 diabetes mellitus (T2D) is very promising, with some of these inhibitors currently undergoing clinical trials.     

Lead modification via computational studies: Synthesis of pyrazole-containing β-amino carbonyls for the treatment of type 2 diabetes

This article describes studies on the design, synthesis, and biological evaluation of pyrazole-containing β-amino carbonyl compounds ( 5a – 5q ) as DPP-4 inhibitors and anti-diabetic agents. In contrast, mannich reactions went smoothly with bismuth nitrate (Bi (NO₃)₃) catalyst in the presence of ethanol and produced pyrazole-containing β-amino carbonyl compounds in good yield. Molecular docking studies of designed derivatives with DPP-4 enzyme (PDB: 2OLE), compounds 5d , 5h , 5j , and 5k showed excellent interaction. 3D QSAR and pharmacophoric model studies were also carried out. ADMET parameters, pharmacokinetic properties, and in vivo toxicity studies further confirmed that all the designed compounds were found to have good bioavailability and were less toxic. Further, these compounds were evaluated as enzyme-based in vitro DPP-4 inhibitory activity, and 5d , 5h , 5i , 5j , and 5k exhibited IC₅₀ toward DPP-4 enzyme of 10.52, 10.41, 5.55, 4.16, and 7.5 nM, respectively. The most potent compound, 5j , was further selected for in vivo anti-diabetic activity using an STZ-induced diabetic mice model, and 5j showed a significant diabetic control effect.     

Reappraisal and perspectives of clinical drug–drug interaction potential of α-glucosidase inhibitors such as acarbose,voglibose and miglitol in the treatment of type 2 diabetes mellitus

1.?Amidst the new strategies being developed for the management of type 2 diabetes mellitus (T2DM) with both established and newer therapies, alpha glucosidase inhibitors (AGIs) have found a place in several treatment protocols.

2.?The objectives of the review were: (a) to compile and evaluate the various clinical pharmacokinetic drug interaction data for AGIs such as acarbose, miglitol and voglibose; (b) provide perspectives on the drug interaction data since it encompasses coadministered drugs in several key areas of comorbidity with T2DM.

3.?Critical evaluation of the interaction data suggested that the absorption and bioavailability of many coadministered drugs were not meaningfully affected from a clinical perspective. Therefore, on the basis of the current appraisal, none of the AGIs showed an alarming and/or overwhelming trend of interaction potential with several coadministered drugs. Hence, dosage adjustment is not warranted in the use of AGIs in T2DM patients in situations of comorbidity.

4.?The newly evolving fixed dose combination strategies with AGIs need to be carefully evaluated to ensure that the absorption and bioavailability of the added drug are not impaired due to concomitant food ingestion.     

Combination therapy for multiple sclerosis: the treatment strategy of the future?

Multiple sclerosis (MS) is an inflammatory autoimmune disease characterised by demyelination and axonal loss in the CNS. Although new immunomodulatory therapies including interferon-beta and glatiramer acetate became available during the last decade, these therapies are only partially effective. There is a continuing need to develop more effective treatment strategies to combat the chronic and progressive aspects of the disease. In view of the complex pathophysiology underlying the MS disease process, combination therapy offers a rational therapeutic approach. Combining immunomodulatory agents with different mechanisms of action that promote synergistic or additive effects represents an important objective in MS therapeutic research. Ultimately, the optimal therapies will likely include strategies that promote repair and limit tissue destruction in combination with anti-inflammatory interventions.     

Weight loss differences seen between glucagon-like peptide–1 receptor agonists and sodium–glucose cotransporter–2 inhibitors for treatment of type 2 diabetes

BackgroundWeight loss is an advantageous quality for diabetic medications because it can improve insulin sensitivity and glucose control and reduce cardiovascular risk factors and comorbidities. Glucagon-like peptide–1 (GLP-1) receptor agonists and sodium–glucose cotransporter–2 (SGLT-2) inhibitors are both preferred agents for use after metformin therapy, and both cause modest weight loss.ObjectiveThe aim of this study was to evaluate the difference in weight loss between GLP-1 receptor agonists and SGLT-2 inhibitors in patients with type 2 diabetes (T2D).MethodsThis was a retrospective study that was conducted at a level 3 patient-centered medical home in Buffalo, NY. The participants were adults with T2D treated with either a GLP-1 receptor agonist or an SGLT-2 inhibitor, in addition to background diabetes medications, between January 1, 2012, and September 20, 2017. The outcome measures included the median weight loss after 6 months of consecutive therapy compared between the 2 antidiabetic classes and the median differences in blood pressure, glycosylated hemoglobin (A1C) levels, and renal function markers compared between the 2 classes.ResultsA total of 73 patients were included in the final analysis, with 31 receiving SGLT-2 inhibitors and 42 receiving therapy with GLP-1 receptor agonists. The SGLT-2 inhibitor cohort presented a median weight loss of –2.80 kg (interquartile range [IQR] –5.40 to –1.50), and the GLP-1 receptor agonist cohort presented a median weight loss of –1.15 kg (IQR –3.38 to 0.975) (P = 0.014). There were no statistically significant differences in A1C levels, blood pressure, or renal function markers.ConclusionSGLT-2 inhibitors, when used in combination with background diabetes regimens, can lead to more statistically significant weight loss than GLP-1 receptor agonists without compromising renal function.     

Combination therapy: the Holy Grail for the treatment of postmenopausal osteoporosis?

Agents for the treatment of osteoporosis are divided into broad categories according to whether the predominant effect is to inhibit bone resorption (antiresorptive drugs) or stimulate bone formation (osteo-anabolic drugs). However, due to the coupling of these two components of bone remodeling, drugs that inhibit bone resorption generally also reduce bone formation, and those that stimulate bone formation also increase bone resorption. Since these synchronous changes may limit the beneficial effects of treatment, researchers have undertaken a search for combinations of antiresorptive and osteo-anabolic drugs given concurrently, sequentially, intermittently, or cyclically that could partially or totally uncouple bone resorption and bone formation. This offers the potential for greater increases in bone mineral density (BMD), restoration of lost structural elements, and perhaps greater reduction in fracture risk than monotherapy with currently approved drugs. While some methods of combining drugs have been shown to enhance BMD response and perhaps extend the duration of osteo-anabolic effects compared to monotherapy, none have been proven to provide greater reduction of fracture risk. Upon completion of a course of osteo-anabolic therapy with daily subcutaneous parathyroid hormone, antiresorptive therapy must be started in order to prevent subsequent loss of BMD.     

Vanadium compounds for the treatment of human diabetes mellitus: A scientific curiosity? A review of thirty years of research

In the second part of the 1980s, and in the 1990s, a number of investigators demonstrated –mainly in streptozotocin-induced (STZ) diabetic rats-that the vanadate and vanadyl forms of vanadium possessed a number of insulin-like effects in various cells. It was hypothesized that oral vanadium could be an alternative treatment to parenteral insulin in the therapy of diabetes mellitus. However, the long-term and/or chronic administration of vanadium compounds should also mean tissue vanadium accumulation and risks of toxicity. The purpose of this review was to revise the current-state-of-the-art on the use of vanadium in the treatment of human diabetes. It has been conducted more than three decades after the first report on the beneficial insulin-mimetic effects of oral vanadium administration in STZ-diabetic rats. Although the antidiabetic effects of vanadium in STZ-diabetic rodents are well supported, in the few studies on human patients with positive results, that are available in the literature, vanadium compounds were administered during very short periods. We conclude that vanadium administration for the treatment of human diabetes is misplaced.