Five-Year Incidence of Progression to Osteoarthritis and Total Joint Arthroplasty in Patients Prescribed Glucagon-Like Peptide 1 Receptor Agonists.

BACKGROUND: Research has suggested that glucagon-like peptide-1 receptor agonists (GLP-1-RAs) may have therapeutic effects on osteoarthritis of the hip and knee, in addition to managing diabetes and obesity. However, there is a lack of understanding regarding the association between GLP-1-RA use and the diagnosis of osteoarthritis (OA) of the hip and knee. METHODS: A collaborative network analytics platform was queried for obese diabetic (n = 1,094,198), obese nondiabetic (n = 916,235), and nonobese diabetic (n = 157,305) patients who had an index visit between 2015 and 2017. Patients who had pre-existing hip and/or knee OA were excluded. A 1:1 propensity score matching was used to balance GLP-1-RA use in stratified cohorts for age, sex, race, body mass index, and hemoglobin A1c. The primary outcomes were rates of progression to hip OA, knee OA, major joint injections, total hip arthroplasty, and total knee arthroplasty. Cox proportional hazards models determined hazard ratios (HRs) between cohorts prescribed and not prescribed GLP-1-RAs. RESULTS: All patients had a five-year follow-up. Rates of progression to hip and knee OA were higher among the GLP-1-RA users in both obese diabetic (hip HR: 1.63, 95% confidence interval [CI]: 1.46 to 1.82; knee HR: 1.52, CI: 1.41 to 1.64) and nonobese diabetic (hip HR: 1.78, CI: 1.50 to 2.10; knee HR: 1.58, CI: 1.39 to 1.80) cohorts. These diabetic cohorts received higher rates of major joint injections, though there was no difference in rates of total hip arthroplasty or total knee arthroplasty. No differences in five-year outcomes were seen when comparing obese, nondiabetic patients who were prescribed GLP-1-RAs with obese, nondiabetic patients not exposed to GLP-1-RAs. CONCLUSIONS: This five-year analysis found a greater risk of progression to hip and knee OA among obese and non-obese diabetic GLP-1-RA users. Further studies should explore GLP-1-RA effects upon glucose management, weight loss, and lower extremity arthritis development. LEVEL OF EVIDENCE: III, retrospective cohort study.

Molecular Basis of Cardiomyopathies in Type 2 Diabetes.

Diabetic cardiomyopathy (DbCM) is a common complication in individuals with type 2 diabetes mellitus (T2DM), and its exact pathogenesis is still debated. It was hypothesized that chronic hyperglycemia and insulin resistance activate critical cellular pathways that are responsible for numerous functional and anatomical perturbations in the heart. Interstitial inflammation, oxidative stress, myocardial apoptosis, mitochondria dysfunction, defective cardiac metabolism, cardiac remodeling, hypertrophy and fibrosis with consequent impaired contractility are the most common mechanisms implicated. Epigenetic changes also have an emerging role in the regulation of these crucial pathways. The aim of this review was to highlight the increasing knowledge on the molecular mechanisms of DbCM and the new therapies targeting specific pathways.

Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets.

Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.

GLP-1 receptor agonists versus metformin in PCOS: a systematic review and meta-analysis.

This meta-analysis aimed to evaluate the efficacy and safety of glucagon-like peptide 1 (GLP-1) receptor agonists for women with polycystic ovary syndrome (PCOS) by comparing their effect with that of metformin. Electronic databases (PubMed, EMBASE, Cochrane Library, WanFang Database, CNKI) dating from their establishment to June 2018 were searched to find all randomized controlled trials (RCTs) reporting the efficacy of GLP-1 receptor agonists versus metformin for patients with PCOS. Therapeutic variables included menstrual cycle, sex hormone and clinical manifestations, glucose metabolism and other metabolic indexes. Eight RCTs among 462 related articles were included in the meta-analysis. Compared with metformin, GLP-1 receptor agonists were more effective in improving insulin sensitivity (standard mean difference [SMD] -0.40, 95% confidence interval [CI] -0.74 to -0.06, P = 0.02) and reducing body mass index (SMD -1.02, 95% CI -1.85 to -0.19, P = 0.02) and abdominal girth (SMD -0.45, 95% CI -0.89 to -0.00, P = 0.05). GLP-1 receptor agonists were associated with a higher incidence of nausea and headache than metformin, but there were no significant differences in other data. Therefore, compared with metformin, GLP-1 receptor agonists might be a good choice for obese patients with PCOS, especially those with insulin resistance. The available evidence is, however, inconclusive given its moderate to low quality. More high-quality research is needed to assess the efficacy of a GLP-1 receptor agonist on women with PCOS.

The Effect of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors in Patients Prescribed Regular U-500 Insulin.

Background: Only 2 small studies have examined the use of glucagon-like peptide-1 (GLP-1) receptor agonists with U-500 insulin, with mixed results. Moreover, there are no studies to our knowledge that have investigated use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors with U-500 insulin therapy. Objective: This research was designed to determine the effectiveness of GLP-1 agonists and SGLT-2 inhibitors in patients already taking U-500 insulin. Methods: A retrospective chart review was conducted on patients using U-500 insulin to which a GLP-1 agonist or SGLT-2 inhibitor was added as their treatment protocol. The primary outcome measure was change in glycosylated hemoglobin (A1C) after 3 to 6 months on the additional therapy. Secondary outcomes included A1C change at 12 months, changes in total daily dose (TDD) of U-500 insulin, body mass index (BMI) and body weight from baseline, and episodes of hypoglycemia. Results: A total of 17 patients were included in the review. The combination of a GLP-1 agonist and/or SGLT-2 inhibitor with U-500 insulin resulted in significant reductions in A1C (0.84%, P = 0.004) and TDD of U-500 insulin (33.5 units, P = 0.031) at the 3- to 6-month interval. Furthermore, statistically significant decreases in mean BMI and body weight were observed 12 months postbaseline. Hypoglycemia occurred in the majority of patients (64.7%). Conclusion and Relevance: This is the first study to examine SGLT-2 inhibitors in combination with U-500 insulin therapy. Clinically, the addition of a GLP-1 agonist and/or SGLT-2 inhibitor can improve A1C and decrease TDD, BMI, and body weight.

Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia).

BACKGROUND: This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin ± sulfonylurea. METHODS: In this 24-week, double-blind, placebo-controlled, multinational study, patients were randomized to lixisenatide 20 µg once daily or placebo. The primary endpoint was absolute change in glycated haemoglobin (HbA1c ) from baseline to week 24. RESULTS: A total of 391 patients were randomized. Lixisenatide significantly reduced HbA1c levels compared with placebo (LS mean difference: -0.36%, p = 0.0004). A significantly higher proportion of lixisenatide-treated patients achieved HbA1c targets of <7% (p = 0.003) and ≤6.5% (p = 0.001) versus placebo. Lixisenatide was associated with a statistically significant reduction in 2-h postprandial plasma glucose after a standardized breakfast versus placebo (LS mean difference: -4.28 mmol/L, p < 0.0001) and a significant reduction in fasting plasma glucose (p = 0.0109). There was no difference in weight loss versus placebo, with a modest reduction in body weight reported for both groups (lixisenatide: -1.50 kg, placebo: -1.24 kg; p = 0.296). The incidence of treatment-emergent adverse events (TEAEs) was 64.3% with lixisenatide versus 47.4% with placebo, with serious TEAEs reported in 1.5% versus 2.1% of patients, respectively. The most common TEAE in the lixisenatide group was nausea (16.3% vs 2.6% with placebo). The incidence of symptomatic hypoglycaemia was 5.6% with lixisenatide treatment and 2.6% with placebo (p = 0.1321), with no severe symptomatic hypoglycaemia events reported. CONCLUSIONS: In Asian patients with type 2 diabetes mellitus insufficiently controlled on metformin ± sulfonylurea, lixisenatide significantly improved glycaemic control and was well tolerated during the 24-week study.

Recent advances in the treatment of type 2 diabetes mellitus using new drug therapies.

Several recent advances provide multiple health benefits to individuals with type 2 diabetes mellitus (T2DM). Pharmacological therapy is governed by person-centered factors, including comorbidities and treatment goals. Adults with T2DM who have an established/high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, require a treatment regimen that includes agents that are proven to reduce cardiorenal risk. Weight management plays a key role in reducing glucose for patients with T2DM. A glucose-reduction treatment regimen must consider weight management. Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure, cardiovascular and renal events. Glucagon-like peptide-1 (GLP-1) receptor agonists allow better control of glycemia, promote weight loss and reduce the risk of cardiovascular events. Newer Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 dual agonist, which activate GIP and GLP-1 receptors improve glycemic control and promote greater weight loss than GLP-1 receptor agonists. Several novel drugs are in the clinical development phase. This review pertains to recent advances in pharmacological management of type 2 diabetes.

Cardiovascular Implications of Semaglutide in Obesity Management: Redefining Cardiovascular Health Strategies.

Semaglutide is a glucagon-l ike peptide 1 receptor agonist that has been noted to have a significant role in the reduction of body weight and glycaemic control. An increasing body of evidence from recent trials (SUSTAIN-6, SELECT and STEP HF) has shown significant cardiovascular benefits of semaglutide in both patients with and without diabetes and in people who are obese or overweight. Additional studies in a more diverse patient population and safety assessment are warranted prior to adding semaglutide to the increasing pool of guideline-directed medical therapy for the treatment and prevention of cardiac diseases.

Clinical insights into the cross-link between mood disorders and type 2 diabetes: A review of longitudinal studies and Mendelian randomisation analyses.

Mood disorders and type 2 diabetes mellitus (T2DM) are prevalent conditions that often co-occur. We reviewed the available evidence from longitudinal and Mendelian randomisation (MR) studies on the relationship between major depressive disorder (MDD), bipolar disorder and T2DM. The clinical implications of this comorbidity on the course of either condition and the impact of antidepressants, mood stabilisers, and antidiabetic drugs were examined. Consistent evidence indicates a bidirectional association between mood disorders and T2DM. T2DM leads to more severe depression, whereas depression is associated with more complications and higher mortality in T2DM. MR studies demonstrated a causal effect of MDD on T2DM in Europeans, while a suggestive causal association in the opposite direction was found in East Asians. Antidepressants, but not lithium, were associated with a higher T2DM risk in the long-term, but confounders cannot be excluded. Some oral antidiabetics, such as pioglitazone and liraglutide, may be effective on depressive and cognitive symptoms. Studies in multi-ethnic populations, with a more careful assessment of confounders and appropriate power, would be important.

Glucagon-like peptide 1(GLP-1) receptor agonists in the management of the patient with type 2diabetes mellitus and chronic kidney disease: an approach for the nephrologist.

Diabetic kidney disease, a common complication in patients with type 2 diabetes mellitus, is associated with a markedly increased morbidity and mortality, especially of cardiovascular origin, and faster progression to end-stage renal disease. To date, reducing cardiovascular and renal risk in this population was based on strict control of cardiovascular risk factors and the renin-angiotensin system blockade. More recently, sodium-glucose cotransporter type 2 inhibitors have demonstrated to offer cardiovascular and renal protection, but the residual risk remains high and their antihyperglycemic efficacy is limited in moderate-severe CKD. Therefore, drugs with a potent antihyperglycemic effect, independent of the glomerular filtration rate, with a low risk of hypoglycemia, that reduce weight in overweight/obese patients and that provide cardiovascular and renal protection, such as GLP-1 receptor agonists, are needed. However, these drugs require subcutaneous administration, which may limit their early use. The recent availability of oral semaglutide may facilitate the early introduction of this family with proven cardiovascular and renal benefits and excellent safety profile. In this review the family is analyzed as well as their cardiovascular and renal effects.

Acute Kidney Injury Associated With Semaglutide.

Case reports of acute kidney injury in patients taking the glucagon-like peptide 1 (GLP-1) receptor agonists exenatide and liraglutide have been reported. We report 2 patients with chronic kidney disease due to diabetic kidney disease who experienced rapid worsening of kidney function and increased proteinuria after being prescribed the GLP-1 receptor agonist semaglutide. In 1 patient, kidney biopsy showed advanced diffuse and nodular glomerulosclerosis accompanied by interstitial lymphoplasmacytic and eosinophilic infiltrate and evidence of acute tubular injury. At this time, the long-term outcomes of patients who experience acute kidney injury associated with GLP-1 receptor agonists is not known. We recommend that caution be used with these agents in patients with moderate to severe chronic kidney disease due to limited kidney reserve in the event of an adverse kidney event. Because most adverse kidney events have occurred in patients who experience adverse gastrointestinal symptoms, such patients should have laboratory tests and discontinuation of the medication if there is acute worsening of kidney function.

Finerenone - are we there yet with a non-steroidal mineralocorticoid receptor antagonist for the treatment of diabetic chronic kidney disease?

Introduction: Chronic kidney disease occurs in 40% of subjects with diabetes and increases the risk of cardiovascular death three-fold, compared to having diabetes alone. The non-steroidal mineralocorticoid receptor antagonist finerenone protects against chronic kidney disease in animal models.Areas covered: This evaluation is of a phase 3 trial of finerenone; Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD). In FIDELIO-DKD, finerenone reduced the primary composite outcome of kidney failure, a sustained decrease of at least 40% in eGFR over four weeks, or death from renal causes, from 21.1% to 17.8%, with a good safety profile.Expert opinion: Finerenone is an effective mineralocorticoid receptor antagonist for the treatment of diabetic chronic kidney disease. Recently, glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporters 2 (SGLT-2) inhibitors have been added to the list of medicines for use in subjects with this condition. Although finerenone has a different mechanism of action to these medicines, it will need to be tested and shown to be effective in presence of these medicines in diabetic kidney disease, prior to widespread use.

Insulin Sensitizers for Improving the Endocrine and Metabolic Profile in Overweight Women With PCOS.

OBJECTIVE: To evaluate the efficacy of insulin sensitizers on menstrual frequency, sex hormone, and metabolic parameters in overweight women with polycystic ovary syndrome (PCOS). METHODS: We searched multiple databases from inception to September 2019 for randomized controlled trials. Network meta-analysis was conducted using multivariate random effects method. RESULTS: Fourteen trials reporting on 619 women were included. Compared with metformin, metformin + thiazolidinediones (TZDs) was more superior in menstrual recovery (weighted mean difference [WMD] 3.68; 95% credibility interval [CrI], 1.65 to 8.20), metformin +  glucagon-like peptide-1 (GLP-1) receptor agonists was more effective in decreasing androstenedione (WMD -2.53; 95% CrI, -3.96 to -1.09), both metformin + GLP-1 receptor agonists (WMD 9.22; 95% CrI, 5.46 to 12.98) and metformin + TZDs (WMD 4.30; 95% CrI, 0.78 to 7.82) were more effective in increasing sex hormone-binding globulin (SHBG), while TZDs were less effective in decreasing body mass index (BMI) (WMD 1.69; 95% CrI, 0.72 to 2.66). Compared with GLP-1 receptor agonists, metformin + GLP-1 receptor agonists was associated with higher SHBG (WMD 7.80; 95% CrI, 4.75 to 10.85), lower free testosterone (WMD -1.77; 95% CrI, -3.25 to -0.29), lower androstenedione (WMD -2.70; 95% CrI, -3.91 to -1.50) and lower fasting blood glucose (WMD -0.41; 95% CrI, -0.73 to -0.08). CONCLUSION: For overweight women with PCOS, both metformin combined with GLP-1 receptor agonists and metformin combined with TZDs appear superior to monotherapy in improving hyperandrogenemia. Metformin combined with TZDs could be particularly effective in promoting the recovery of menstruation. Metformin combined with GLP-1 receptor agonists has the additional advantage of improving fasting glucose when compared with GLP-1 receptor agonists alone. TZDs are inferior to metformin in decreasing BMI.

Old wines in new bottles: Repurposing opportunities for Parkinson's disease.

Parkinson's disease (PD) is a chronic progressive neurological disorder characterized by accumulation of Lewy bodies and profound loss of substantia nigra dopaminergic neurons. PD symptomatology is now recognized to include both cardinal motor as well as clinically significant non-motor symptoms. Despite intensive research, the current understanding of molecular mechanisms underlying neurodegeneration in PD is limited and has hampered the development of novel symptomatic and disease modifying therapies. The currently available treatment options are only partially or transiently effective and fail to restore the lost dopaminergic neurons or retard disease progression. Given the escalating drug development costs, lengthening timelines and declining R&D efficiency, industry and academia are increasingly focusing on ways to repurpose existing molecules as an accelerated route for drug discovery. The field of PD therapeutics is witnessing vigorous repurposing activity supported by big data analytics, computational models, and high-throughput drug screening systems. Here we review the mechanisms, efficacy, and safety of several emerging drugs currently aspiring to be repositioned for PD pharmacotherapy.

Pharmacological Treatment in Diabetes Mellitus Type 1 - Insulin and What Else?

The basis of treatment in autoimmune diabetes is insulin therapy; however, many clinical cases have proven that this method does not solve all problems. Trials of causal treatment including blocking the autoimmune processes and insulin-producing cells transplants were carried out. Those methods require more research to be concerned as efficient and safe ways of treatment in type 1 diabetes. The use of non-insulin adjunct treatment is a new trend. It has been successfully used in laboratories as well as clinical trials. Metformin is the most widely used drug, together with sodium-glucose co-transporters 2 (SGLT2) inhibitors, amylin analogues, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors. The results of administration of these medicaments give good outcomes in patients with diabetes mellitus type 1. Most likely, in the near future, they will progressively be used in both adult and adolescent patients with type 1 diabetes. Further multicenter, randomized studies are required to evaluate the efficacy of treatment and long term safety of these drugs.

Cardiovascular safety and benefits of GLP-1 receptor agonists.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) constitute a class of drugs for the treatment of type 2 diabetes, and currently, six different GLP-1RAs are approved. Besides improving glycemic control, the GLP-1RAs have other beneficial effects such as weight loss and a low risk of hypoglycemia. Treatment with the GLP-1RA lixisenatide has been shown to be safe in patients with type 2 diabetes and recent acute coronary syndrome. Furthermore, liraglutide and semaglutide have been shown to reduce cardiovascular (CV) disease (CVD) risk in type 2 diabetes patients with established and/or high risk of CVD. The CV safety of the remaining GLP-1RAs in type 2 diabetes patients with established and/or high risk of CVD remains uncertain, but ongoing CV outcome trials (CVOTs) will elucidate this within a few years. Areas covered: The aim of this review is to provide an overview of the existing GLP-1RAs with a particular focus on their clinical effects on CV risk factors and their CV safety and benefits. Expert opinion: Data on the CV risks and benefits associated with GLP-1RA treatment in patients with type 2 diabetes and high risk of CVD are emerging - and look promising (especially for liraglutide and semaglutide). Data from ongoing CVOTs will be crucial for the positioning of the individual GLP-1RAs in the treatment of patients with type 2 diabetes and high risk of CVD. However, the long-term CV safety and the potential of GLP-1RAs to prevent CVD in type 2 diabetes patients with less risk of CVD (e.g. newly diagnosed patients) remain uncertain.

Terapia complementaria a la insulina en el tratamiento de niños y adolescentes con diabetes mellitus tipo 1- (DM1) / Therapies complementaries to insulin in the treatment of children and adolescents with type 1 diabetes mellitus (T1DM)

La diabetes mellitus tipo 1 (DM1), es una enfermedad crónica caracterizada por la deficiencia de insulina debido a la pérdida de células ß pancreáticas, las alteraciones hormonales en la DM 1 no se limitan a la deficiencia de insulina; existiendo también secreción inadecuadada de glucagón en el período postprandial. Aunque el control glucémico con terapias intensivas con insulina ha reducido la incidencia de complicaciones microvascular y macrovasculares. La mayoría de las personas con DM1 tienen un control glucémico subóptimo; Por lo tanto, el uso de farmacoterapia adyuvante para mejorar el control ha sido de interés clínico. El uso de estos nuevos medicamentos brindaría la oportunidad de imitar más de cerca la fisiología pancreática normal, y contrarrestar otros mecanismos fisiopatológicos diferentes a Insulinopenia; contribuyendo a lograr un mejor control metabólico y expectativa de vida.

Type 1 diabetes mellitus (T1DM), is a chronic disease characterized by insulin deficiency due to the loss of pancreatic ß cells, the hormonal alterations in T1DM are not limited to insulin deficiency; there is also a deregulated glucagon secretion in the postprandial period. Although glycemic control with intensive therapies with insulin has reduced the incidence of microvascular and macrovascular complications, most people with T1DM1 glycemic control; therefore, the use of adjuvant pharmacotherapy to improve control has been of clinical interest. The use of these new drugs would offer the opportunity to imitate more closely the normal pancreatic physiology, and to counteract other physiopathological mechanisms different from insulinopenia; contributing to achieve better metabolic control and life expectancy.