Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Cardiovascular disease risk in people of African ancestry with HIV in the United Kingdom.

OBJECTIVES: Our objective was to describe the prevalence of cardiovascular disease (CVD) risk factors in people of African ancestry with HIV in the UK. METHODS: We conducted a cross-sectional analysis of CVD risk factors in Black people with HIV aged ≥40 years and estimated the 10-year CVD risk using QRISK®3-2018. Correlations between body mass index (BMI) and CVD risk factors were described using Pearson correlation coefficients, and factors associated with 10-year CVD risk ≥5% were described using logistic regression. RESULTS: We included 833 Black people with HIV and a median age of 54 years; 54% were female, 50% were living with obesity (BMI ≥30 kg/m2), 61% had hypertension, and 19% had diabetes mellitus. CVD risk >5% ranged from 2% in female participants aged 40-49 years to 99% in men aged ≥60 years, and use of statins ranged from 7% in those with CVD risk <2.5% to 64% in those with CVD risk ≥20%. BMI was correlated (R2 0.1-0.2) with triglycerides and diastolic blood pressure in women and with glycated haemoglobin, systolic and diastolic blood pressure, and total:high-density lipoprotein (HDL) cholesterol ratio in men. In both female and male participants, older age, blood pressure, diabetes mellitus, and kidney disease were strongly associated with CVD risk ≥5%, whereas obesity, total:HDL cholesterol, triglycerides, and smoking status were variably associated with CVD risk ≥5%. CONCLUSIONS: We report a high burden of CVD risk factors, including obesity, hypertension, and diabetes mellitus, in people of African ancestry with HIV in the UK. BMI-focused interventions in these populations may improve CVD risk while also addressing other important health issues.

Thyroid cancer and insulin resistance.

Thyroid cancer has shown a parallel increase with diabetes in the last few years. This narrative review aims to explain the association between these two entities, focusing on insulin resistance as the mediator and exploring the effects of antidiabetic agents on thyroid cancer incidence and progression.We searched Pubmed for English-written articles on insulin resistance, diabetes, antidiabetic treatments, and thyroid cancer reported from January 2019 to April 2023. Exclusion criteria were preclinical and clinical studies involving a population with thyroid dysfunction, benign nodular goiter, or those that only analyzed thyroid cancer's association with obesity.The results of the narrative literature review revealed 96 articles. Additionally, four studies from a manual search were retrieved. After the exclusion criteria were applied, we included 20 studies. Out of 8 studies on insulin-resistant or Metabolic Syndrome patients, all suggest a positive association with thyroid cancer. At the same time, for diabetes, four out of five publications support a link with thyroid cancer. The seven remaining studies on antidiabetics suggest that metformin might benefit thyroid cancer. In contrast, the evidence for an association between Glucagon-like peptide-1 receptor agonists (GLP-1 RA) and increased thyroid cancer findings is limited.In conclusion, the association between thyroid cancer and diabetes may be explained by insulin resistance, as shown in observational studies. However, the causal role is yet to be defined. Although the wide use of different antidiabetic agents has been related to thyroid cancer prevalence and progression, future research with drugs such as metformin or GLP-1 RA is still needed.

Use of Cardioprotective Antidiabetic Medications in Adults With and Without Cardiovascular Disease, 2015 to March 2020.

BACKGROUND: Certain glucagon-like peptide-1 receptor (GLP-1) agonists and sodium-glucose cotransporter-2 inhibitors (SGLT2-inhibitors) can reduce cardiovascular risk in individuals with type 2 diabetes and cardiovascular disease (CVD). However, these medications can be expensive, potentially limiting their use. Objectives: The primary objective was to characterize the use of cardioprotective GLP-1 agonists and SGLT2-inhibitors among adults with diabetes with and without CVD. The secondary objective was to investigate the association of socioeconomic factors and health care utilization with the use of these medications. METHODS: Adults aged ≥20 years old with self-reported diabetes, A1c ≥6.5%, or fasting glucose ≥126 mg/dL were identified using the 2015 to March 2020 National Health and Nutrition Examination Survey. The primary outcome was the use of cardioprotective GLP-1 agonists or SGLT2-inhibitors compared in individuals with and without CVD. Secondary analyses included identification of socioeconomic factors and health care utilization associated with the use of cardioprotective antidiabetic medications, stratified by CVD status. Weighted analyses were conducted to account for the complex survey design. RESULTS: Use of cardioprotective antidiabetic medications was higher in adults with CVD compared to those without CVD (7.8% vs. 4.6%, P = 0.02), which was driven by the use of cardioprotective SGLT2-inhibitors (4.6% versus 1.9%, P = 0.002). Lower income level and less frequent health care visits within the past year were associated with lower likelihood of using these medications. CONCLUSION AND RELEVANCE: Despite preferential use in individuals with diabetes and CVD, the prevalence of cardioprotective antidiabetic medication use remains relatively low. Disparities in use appear to exist based on income level and health care utilization.

Idiopathic Intracranial Hypertension After Abrupt Cessation of Medication: A Case Report of Abrupt Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Cessation and Review of the Literature.

PURPOSE OF REVIEW: The purpose of this review is two-fold: (1) to discuss a case report of idiopathic intracranial hypertension (IIH) after abrupt cessation of a glucagon-like peptide-1 (GLP-1) receptor agonist with resultant rapid weight gain and (2) to review the literature regarding the potential role of GLP-1 receptor agonists in the treatment of IIH as well as potential pitfalls. RECENT FINDINGS: GLP-1 receptor agonists have become widely used to treat obesity. Obesity is a known risk factor for the development of IIH, though the precise pathophysiology is unclear. GLP-1 receptor agonists may help treat IIH by promoting weight loss, lipolysis of adipose tissue, and potentially decreasing the secretion of CSF, as was seen in rat models. Abrupt cessation of GLP-1 receptor agonists can result in regaining lost weight rapidly. In the case that we present, the patient stopped duraglutide abruptly due to lack of insurance coverage and regained the weight she had lost within a month. She subsequently developed IIH. GLP-1 receptor agonists have the potential to help treat IIH; however, this class of medication needs to be used carefully, as cessation of the medication and resultant rapid weight gain can result in IIH.

Glucagon-Like Peptide-1 Agonists for Treating Obesity in Patients With Immune-Mediated Skin Diseases. / Agonistas del receptor de GLP-1 para el tratamiento de la obesidad en pacientes con dermatosis inmunomediadas.

Psoriasis and hidradenitis suppurativa are often associated with obesity. Because chronic low-grade inflammation underlies these 2 diseases, they can progress to more severe forms in patients with obesity if weight-reduction measures are not taken. This review covers pharmacologic alternatives for treating obesity, with emphasis on the benefits associated with the novel use of glucagon-like peptide-1 (GLP-1) agonists that act on satiety receptors. These drugs have led to greater weight loss in clinical trials and real-world settings than orlistat, which until recently was the only drug approved for treating obesity in the European Union. Although experience with GLP-1 agonists in patients with obesity and inflammatory skin diseases is currently scarce, the promising results reported suggest they may offer a useful tool for managing obesity.

[Translated article] Glucagon-Like Peptide-1 Agonists for Treating Obesity in Patients With Immune-Mediated Skin Diseases.

Psoriasis and hidradenitis suppurativa are often associated with obesity. Because chronic low-grade inflammation underlies these 2 diseases, they can progress to more severe forms in patients with obesity if weight-reduction measures are not taken. This review covers pharmacologic alternatives for treating obesity, with emphasis on the benefits associated with the novel use of glucagon-like peptide-1 (GLP-1) agonists that act on satiety receptors. These drugs have led to greater weight loss in clinical trials and real-world settings than orlistat, which until recently was the only drug approved for treating obesity in the European Union. Although experience with GLP-1 agonists in patients with obesity and inflammatory skin diseases is currently scarce, the promising results reported suggest they may offer a useful tool for managing obesity.

Effects of new hypoglycemic drugs on cardiac remodeling: a systematic review and network meta-analysis.

BACKGROUND: In recent years, the incidence of diabetes mellitus has been increasing annually, and cardiovascular complications secondary to diabetes mellitus have become the leading cause of death in diabetic patients. Considering the high incidence of type 2 diabetes (T2DM) combined with cardiovascular disease (CVD), some new hypoglycemic agents with cardiovascular protective effects have attracted extensive attention. However, the specific role of these regimens in ventricular remodeling remains unknown. The purpose of this network meta-analysis was to compare the effects of sodium glucose cotransporter type 2 inhibitor (SGLT-2i), glucagon-like peptide 1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) on ventricular remodeling in patients with T2DM and/or CVD. METHODS: Articles published prior to 24 August 2022 were retrieved in four electronic databases: the Cochrane Library, Embase, PubMed, and Web of Science. This meta-analysis included randomized controlled trials (RCTs) and a small number of cohort studies. The differences in mean changes of left ventricular ultrasonic parameters between the treatment and control groups were compared. RESULTS: A total of 31 RCTs and 4 cohort studies involving 4322 patients were analyzed. GLP-1RA was more significantly associated with improvement in left ventricular end-systolic diameter (LVESD) [MD = -0.38 mm, 95% CI (-0.66, -0.10)] and LV mass index (LVMI) [MD = -1.07 g/m2, 95% CI (-1.71, -0.42)], but significantly decreased e' [MD = -0.43 cm/s 95% CI (-0.81, -0.04)]. DPP-4i was more strongly associated with improvement in e' [MD = 3.82 cm/s, 95% CI (2.92,4.7)] and E/e'[MD = -5.97 95% CI (-10.35, -1.59)], but significantly inhibited LV ejection fraction (LVEF) [MD = -0.89% 95% CI (-1.76, -0.03)]. SGLT-2i significantly improved LVMI [MD = -0.28 g/m2, 95% CI (-0.43, -0.12)] and LV end-diastolic diameter (LVEDD) [MD = -0.72 ml, 95% CI (-1.30, -0.14)] in the overall population, as well as E/e' and SBP in T2DM patients combined with CVD, without showing any negative effect on left ventricular function. CONCLUSION: The results of the network meta-analysis provided high certainty to suggest that SGLT-2i may be more effective in cardiac remodeling compared to GLP-1RA and DPP-4i. While GLP-1RA and DPP-4i may have a tendency to improve cardiac systolic and diastolic function respectively. SGLT-2i is the most recommended drug for reversing ventricular remodeling in this meta-analysis.

Endothelial Function in Patients with Multiple Sclerosis: The Role of GLP-1 Agonists, Lipoprotein Subfractions, and Redox Balance.

INTRODUCTION: Epidemiological studies have suggested an increased vascular risk in patients with multiple sclerosis (MS). There is increasing evidence of the beneficial effects of GLP-1 agonists (GLP-1a) in preventing vascular complications and slowing the progression of neurodegeneration. Our objective was to explore the changes in the endothelial function of MS patients after 12 months of GLP-1a therapy. We also explored the role of lipoprotein subfractions and the antioxidant capacity of plasma. METHODS: MS patients were enrolled in a prospective, unicentric study. GLP-1a (dulaglutide) was administered to 13 patients. The control population consisted of 12 subjects. Endothelial function was determined by peripheral arterial tonometry and expressed as reperfusion hyperemia index (RHI). Trolox equivalent antioxidant capacity (TEAC) was used to assess the total antioxidant capacity of the plasma. The levels of lipoprotein subfractions were evaluated. RESULTS: The GLP-1a group did not have a significant change in their RHIs after 12 months (2.1 ± 0.6 vs. 2.1 ± 0.7; p = 0.807). However, a significant increase in their TEACs was observed (4.1 ± 1.4 vs. 5.2 ± 0.5 mmol/L, p = 0.010). On the contrary, the subjects in the control group had a significant worsening of their RHIs (2.1 ± 0.5 vs. 1.8 ± 0.6; p = 0.030), without significant changes in their TEACs. Except for a significant decrease in very-low-density lipoprotein (VLDL) (30.8 ± 10.2 vs. 22.6 ± 8.3 mg/dL, p = 0.043), no other significant changes in the variables were observed in the control group. VLDL levels (beta = -0.637, p = 0.001), the use of GLP-1a therapy (beta = 0.560, p = 0.003), and small LDL (beta = 0.339, p = 0.043) were the only significant variables in the model that predicted the follow-up RHI. CONCLUSION: Our results suggest that the application of additional GLP-1a therapy may have atheroprotective and antioxidant effects in MS patients with high MS activity and thus may prospectively mitigate their vascular risk. However, the lipoprotein profile may also play an important role in the atherogenic risk of MS subjects.

Emerging Role of GLP-1 Agonists in Obesity: A Comprehensive Review of Randomised Controlled Trials.

Obesity is a chronic disease with high prevalence and associated comorbidities, making it a growing global concern. These comorbidities include type 2 diabetes, hypertension, ventilatory dysfunction, arthrosis, venous and lymphatic circulation diseases, depression, and others, which have a negative impact on health and increase morbidity and mortality. GLP-1 agonists, used to treat type 2 diabetes, have been shown to be effective in promoting weight loss in preclinical and clinical studies. This review summarizes numerous studies conducted on the main drugs in the GLP-1 agonists class, outlining the maximum achievable weight loss. Our aim is to emphasize the active role and main outcomes of GLP-1 agonists in promoting weight loss, as well as in improving hyperglycemia, insulin sensitivity, blood pressure, cardio-metabolic, and renal protection. We highlight the pleiotropic effects of these medications, along with their indications, contraindications, and precautions for both diabetic and non-diabetic patients, based on long-term follow-up studies.

Newer Diabetes Management Options and Physical Fitness to Promote Cardiovascular Benefits.

A plethora of diabetes studies and established clinical guidelines show the strong salutary benefit of aerobic, resistance, and/or combination exercise for improved glycemic and cardiovascular outcomes. Promotion of physical fitness is a cornerstone approach to improved diabetes management especially since subjects with diabetes have reduced baseline aerobic exercise capacity (i.e., reduced cardiorespiratory fitness) with associated increased risk for premature all-cause and cardiovascular mortality. Since medications are often used in conjunction with fitness promotion this can result in complex interaction between management modalities. More recently, newer options such as glucose transporter-2 inhibitors and incretin agonists have shown to improve cardiovascular disease (CVD) outcomes in cardiovascular outcomes trials. Indeed, both classes of agents have experimentally the potential to synergize with exercise training but clinical data vis-à-vis cardiorespiratory fitness is still preliminary. Review of the interaction of exercise and metformin shows no improvement in cardiorespiratory fitness. The use of glucose transporter-2 inhibitors may improve fitness performance in those with diabetes and heart failure. Although incretin agonists have physiological effects on the vasculature and heart, they lack similar clinical supportive data.

Depot-specific adipose tissue modulation by SGLT2 inhibitors and GLP1 agonists mediates their cardioprotective effects in metabolic disease.

Sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 (GLP-1) receptor agonists are newer antidiabetic drug classes, which were recently shown to decrease cardiovascular (CV) morbidity and mortality in diabetic patients. CV benefits of these drugs could not be directly attributed to their blood glucose lowering capacity possibly implicating a pleotropic effect as a mediator of their impact on cardiovascular disease (CVD). Particularly, preclinical and clinical studies indicate that SGLT-2i(s) and GLP-1 receptor agonists are capable of differentially modulating distinct adipose pools reducing the accumulation of fat in some depots, promoting the healthy expansion of others, and/or enhancing their browning, leading to the suppression of the metabolically induced inflammatory processes. These changes are accompanied with improvements in markers of cardiac structure and injury, coronary and vascular endothelial healing and function, vascular remodeling, as well as reduction of atherogenesis. Here, through a summary of the available evidence, we bring forth our view that the observed CV benefit in response to SGLT-2i or GLP-1 agonists therapy might be driven by their ameliorative impact on adipose tissue inflammation.

Real-world effectiveness of IDegLira compared with intensified conventional insulin therapy in adults with type 2 diabetes: a retrospective cohort study.

BACKGROUND: IDegLira is a fixed-ratio combination of insulin degludec and liraglutide with proven efficacy against simpler regimens and non-inferiority against basal-bolus insulin therapy. However, the evaluation of its real-world effectiveness is hindered by technical issues and requires further exploration. Thus we aimed to compare effectiveness of insulin degludec/liraglutide (IDegLira) versus intensified conventional insulin therapy (ICT) for type 2 diabetes in a real-world setting. METHODS: This retrospective cohort study from an outpatient clinic in Hungary included people who initiated IDegLira due to inadequate glycaemic control (HbA1c > 7.0% [53.0 mmol/mol]) with oral and/or injectable antidiabetic drugs. Data were compared with a historical cohort who initiated ICT. Outcomes included HbA1c, body weight, and hypoglycaemia differences over 18 months of follow-up. RESULTS: Data were included from 227 and 72 people who initiated IDegLira and ICT, respectively. Estimated mean difference (MD) in HbA1c at 18 months favoured IDegLira versus ICT (MD 0.60, 95% CI 0.88-0.32 [MD 6.6 mmol/mol, 95% CI 9.6-3.5]). More people reached target HbA1c ≤7.0% (53.0 mmol/mol) with IDegLira than ICT (odds ratio 3.36, 95% CI 1.52-7.42). IDegLira treatment was associated with weight loss compared with gain for ICT (MD 6.7 kg, 95% CI 5.0-8.5). The hazard ratio for hypoglycaemia comparing IDegLira with ICT was 0.18 (95% CI 0.08-0.49). CONCLUSIONS: Treatment with IDegLira over 18 months resulted in greater HbA1c reductions, weight loss versus gain, and a lower rate of hypoglycaemia versus ICT in people with type 2 diabetes.

An overview of current therapy options of non-alcoholic fatty liver disease.

Finding an effective treatment of non-alcoholic fatty liver disease (NAFLD) remains one of main challenges in hepatological research for the 21st century, since there is no such a treatment yet. Lifestyle modifications leading to weight reduction are cheap and effective, however only a fraction of patients reaches significant weight loss goals. Current pharmacological treatment of NAFLD comprises screening and therapy of metabolic syndrome components and minimizing of alcohol intake. There are new substances being evaluated in clinical trials, the most promising ones are semaglutide and lanifibranor.

Medical and Surgical Obesity Treatments and Atherosclerosis: Mechanisms beyond Typical Risk Factors.

PURPOSE OF REVIEW: This study aims to discuss the mechanisms by which GLP-1 agonists and bariatric surgery improve cardiovascular outcomes in severely obese patients. RECENT FINDINGS: Recent studies have demonstrated that both GLP-1 agonist use and bariatric surgery reduce adverse cardiovascular outcomes. Improvements in traditional atherosclerosis risk factors in association with weight loss likely contribute, but weight loss-independent mechanisms are also suggested to have roles. We review the clinical and preclinical evidence base for cardiovascular benefit of LP-1 agonists and bariatric surgery beyond traditional risk factors, including improvements in endothelial function, direct impacts on atherosclerotic plaques, and anti-inflammatory effects.

Glycemic Control in Hospitalized Stroke Patients: A Review.

PURPOSE OF REVIEW: The purpose of this review is to discuss clinical trials involving glycemic control in hospitalized stroke patients and to review oral medications used in glycemic control. GLP-1 agonists, which have some preliminary studies in ischemic stroke, will also be reviewed. RECENT FINDINGS: Until recently, glycemic control targets in hospitalized stroke patients remained unclear. The SHINE (Stroke Hyperglycemia Insulin Network Effort) trial demonstrated no significant difference between aggressive versus standard of care glycemic control in the acute ischemic stroke patient. Although SHINE demonstrated a lack of statistical difference in glycemic control targets, many questions remain including glycemic control in patients with other stroke types (SAH, ICH). The role of non-insulin-based medications in glycemic control for hospitalized stroke patients remains unclear and presents an opportunity for further research. Finally, GLP-1 agonists present an interesting area of research for acute ischemic stroke.

Effects of antidiabetic drugs on left ventricular function/dysfunction: a systematic review and network meta-analysis.

BACKGROUND: Although a variety of antidiabetic drugs have significant protective action on the cardiovascular system, it is still unclear which antidiabetic drugs can improve ventricular remodeling and fundamentally delay the process of heart failure. The purpose of this network meta-analysis is to compare the efficacy of sodium glucose cotransporter type 2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, metformin (MET), sulfonylurea (SU) and thiazolidinediones (TZDs) in improving left ventricular (LV) remodeling in patients with type 2 diabetes (T2DM) and/or cardiovascular disease (CVD). METHODS: We searched articles published before October 18, 2019, regardless of language or data, in 4 electronic databases: PubMed, EMBASE, Cochrane Library and Web of Science. We included randomized controlled trials in this network meta-analysis, as well as a small number of cohort studies. The differences in the mean changes in left ventricular echocardiographic parameters between the treatment group and control group were evaluated. RESULTS: The difference in the mean change in LV ejection fraction (LVEF) between GLP-1 agonists and placebo in treatment effect was greater than zero (MD = 2.04% [0.64%, 3.43%]); similar results were observed for the difference in the mean change in LV end-diastolic diameter (LVEDD) between SGLT-2 inhibitors and placebo (MD = - 3.3 mm [5.31, - 5.29]), the difference in the mean change in LV end-systolic volume (LVESV) between GLP-1 agonists and placebo (MD = - 4.39 ml [- 8.09, - 0.7]); the difference in the mean change in E/e' between GLP-1 agonists and placebo (MD = - 1.05[- 1.78, - 0.32]); and the difference in the mean change in E/e' between SGLT-2 inhibitors and placebo (MD = - 1.91[- 3.39, - 0.43]). CONCLUSIONS: GLP-1 agonists are more significantly associated with improved LVEF, LVESV and E/e', SGLT-2 inhibitors are more significantly associated with improved LVEDD and E/e', and DPP-4 inhibitors are more strongly associated with a negative impact on LV end-diastolic volume (LVEDV) than are placebos. SGLT-2 inhibitors are superior to other drugs in pairwise comparisons.

Insight in the safety profile of antidiabetic agents glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors in daily practice from the patient perspective.

PURPOSE: The primary aim of this study was to gain insight in the safety profile of the new antidiabetic agents glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors in daily practice. The secondary aim was to compare reported adverse drug reactions (ADRs) with information described in the Summary of Product Characteristics (SPC) and to generate knowledge about characteristics, like time to onset and outcome of ADRs. This knowledge is important for drug regulators and clinical practice to understand and manage ADRs better. METHODS: A prospective, observational web-based cohort event monitoring study among first-time users of GLP-1 agonists and DPP-4 inhibitors. Patients were recruited through community pharmacies from 2008 to 2016. Participants were invited to complete six web-based questionnaires over a 1-year periods after start of the antidiabetic agent. Questions were posed about patient characteristics, drug use, and ADRs. Data were analyzed using descriptive statistics. RESULTS: Then, 743 patients were included. Also 62% of all GLP-1 agonist users (total n = 119) and 33% of DPP-4 inhibitor users (total n = 624) experienced an ADR. Of the 10 most reported ADRs, for GLP-1 agonist all, and for DPP-4 inhibitors 8 were described in the drug's SPC. For 45 (91%) ADRs, the patients recovered without discontinuation of the GLP-1 agonist and 79 (73%) ADRs without discontinuation of the DPP-4 inhibitor therapy. CONCLUSIONS: This study gives insight in the safety profile and ADR characteristics of the new antidiabetic agents. This study provides important knowledge for healthcare professionals in managing ADRs and can be directly applied in consultations in daily practice.

Why the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease.

Over the past 66 years, our knowledge of the role of the endothelium in the regulation of cardiovascular function and dysfunction has advanced from the assumption that it is a single layer of cells that serves as a barrier between the blood stream and vascular smooth muscle to an understanding of its role as an essential endocrine-like organ. In terms of historical contributions, we pay particular credit to (1) the Canadian scientist Dr. Rudolf Altschul who, based on pathological changes in the appearance of the endothelium, advanced the argument in 1954 that "one is only as old as one's endothelium" and (2) the American scientist Dr. Robert Furchgott, a 1998 Nobel Prize winner in Physiology or Medicine, who identified the importance of the endothelium in the regulation of blood flow. This review provides a brief history of how our knowledge of endothelial function has advanced and now recognize that the endothelium produces a plethora of signaling molecules possessing paracrine, autocrine, and, arguably, systemic hormone functions. In addition, the endothelium is a therapeutic target for the anti-diabetic drugs metformin, glucagon-like peptide I (GLP-1) receptor agonists, and inhibitors of the sodium-glucose cotransporter 2 (SGLT2) that offset the vascular disease associated with diabetes.

Diabetes pharmacotherapy and effects on the musculoskeletal system.

Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age-matched persons without diabetes, attributed to disease-specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin-based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall-related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo-anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium-dependent glucose co-transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes-related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.