Renal effects of GLP-1 receptor agonists and tirzepatide in individuals with type 2 diabetes: seeds of a promising future.

PURPOSE: Chronic kidney disease (CKD) is one of the most common complications of type 2 diabetes (T2D), and CKD-related disability and mortality are increasing despite the recent advances in diabetes management. The dual GIP/GLP-1 receptor agonist tirzepatide is among the furthest developed multi-agonists for diabetes care and has so far displayed promising nephroprotective effects. This review aims to summarize the evidence regarding the nephroprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RA) and tirzepatide and the putative mechanisms underlying the favorable renal profile of tirzepatide. METHODS: A comprehensive literature search was performed from inception to July 31st 2023 to select research papers addressing the renal effects of GLP-1RA and tirzepatide. RESULTS: The pathogenesis of CKD in patients with T2D likely involves many contributors besides hyperglycemia, such as hypertension, obesity, insulin resistance and glomerular atherosclerosis, exerting kidney damage through metabolic, fibrotic, inflammatory, and hemodynamic mechanisms. Tirzepatide displayed an unprecedented glucose and body weight lowering potential, presenting also with the ability to increase insulin sensitivity, reduce systolic blood pressure and inflammation and ameliorate dyslipidemia, particularly by reducing triglycerides levels. CONCLUSION: Tirzepatide is likely to counteract most of the pathogenetic factors contributing to CKD in T2D, potentially representing a step forward in incretin-based therapy towards nephroprotection. Further evidence is needed to understand its role in renal hemodynamics, fibrosis, cell damage and atherosclerosis, as well as to conclusively show reduction of hard renal outcomes.

Glucometabolic outcomes of GLP-1 receptor agonist-based therapies in patients with type 2 diabetes: a systematic review and network meta-analysis.

Background: Innovative GLP-1 receptor agonist (GLP-1RA)-based treatment strategies-such as tirzepatide, GLP-1RA plus basal insulin fixed-ratio combinations [FRC], GLP-1RA plus sodium glucose cotransporter-2 inhibitors [SGLT-2i] combinations, and high-dose GLP-1RA-have been listed among the most efficacious options for type 2 diabetes management. However, differences in their glucometabolic effects have not been assessed in dedicated head-to-head trials. In the absence of such trials, we aimed to provide a useful comparison among these treatment strategies to guide clinical practice. Methods: In this network meta-analysis, we searched PubMed, MEDLINE, and Web of Science (from database inception to June 24, 2023) for randomised controlled studies, published in English, that enrolled individuals with type 2 diabetes treated with tirzepatide, iGlarLixi, iDegLira, GLP-1RA plus SGLT-2i combination, or high-dose GLP-1RA (dulaglutide 3 mg and 4.5 mg, semaglutide 2 mg) compared with placebo or active comparators. Eligible studies reported change from baseline in HbA1c as an outcome, which was the primary outcome of this analysis. Secondary outcomes were changes in fasting and post-prandial glucose, bodyweight, LDL-cholesterol, blood pressure and risk of hypoglycaemia. We assessed risk of bias through the Cochrane Collaboration's tool (RoB2 tool), publication bias through visual inspection of funnel plots and Egger's test, and heterogeneity by comparing the magnitude of the common between-study variance (τ2) for each outcome with empirical distributions of heterogeneity variances. This network meta-analysis was registered in PROSPERO (CRD42022329878). Findings: 40 trials were included. Tirzepatide 15 mg ranked first in terms of HbA1c reduction compared to other GLP-1RA-based strategies, even those including insulin (vs. iDegLira MD -0.40%, 95% CI [-0.66; -0.14], low certainty; vs. iGlarLixi MD -0.48%, 95% CI [-0.75; -0.21], low certainty), without increasing the risk of hypoglycaemia (vs. iDegLira OR 0.35, 95% CI [0.16; 0.79], high certainty; vs. iGlarLixi OR 0.31, 95% CI [0.20; 0.48], high certainty). Tirzepatide 15 mg was also the most efficacious on weight lowering, even compared to high-dose GLP-1RA (eg, semaglutide 2 mg MD -6.56 kg, 95% CI [-7.38; -5.73], low certainty) and GLP-1RA plus SGLT-2i combination (MD -4.61 kg, 95% CI [-5.29; -3.93], low certainty). Risk of bias and publication bias were generally low throughout studies, while high levels of heterogeneity were detected for most outcomes. Interpretation: Aiming to support clinicians in tailoring treatment to patients' needs, we suggest that a hierarchy among treatment strategies be devised considering the best options for type 2 diabetes. Tirzepatide, followed by GLP-1RA plus basal insulin FRC and GLP-1RA plus SGLT-2i combination, was associated with greater benefit on HbA1c than high-dose GLP-1RA. Funding: Fondazione per la Ricerca Biomedica "Saverio e Isabella Cianciola" and Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8-Project Age-It: Ageing Well in an Ageing Society.

Professional continuous glucose monitoring in patients with diabetes mellitus: A systematic review and meta-analysis.

AIM: To evaluate the effect on glucose control of professional continuous glucose monitoring (p-CGM)-based care as compared with standard care in the management of patients with type 1 and type 2 diabetes. MATERIALS AND METHODS: The PubMed database was searched comprehensively to identify prospective or retrospective studies evaluating p-CGM as a diagnostic tool for subsequent implementation of lifestyle and/or medication changes and reporting glycated haemoglobin (HbA1c) as an outcome measure. RESULTS: We found 872 articles, 22 of which were included in the meta-analysis. Overall, the use of p-CGM was associated with greater HbA1c reduction from baseline (-0.28%, 95% confidence interval [CI] -0.36% to -0.21%, I2  = 0%, P < 0.00001) than usual care, irrespective of type of diabetes, length of follow-up, frequency of continuous glucose monitoring (CGM) use and duration of CGM recording. In the few studies describing CGM-derived glucose metrics, p-CGM showed a beneficial effect on change in time in range from baseline (5.59%, 95% CI 0.12 to 11.06, I2  = 0%, P = 0.05) and a neutral effect on change in time below the target range from baseline (-0.11%, 95% CI -1.76% to 1.55%, I2  = 33%, P = 0.90). CONCLUSIONS: In patients with type 1 and type 2 diabetes, p-CGM-driven care is superior to usual care in improving glucose control without increasing hypoglycaemia.

Glucagon in type 2 diabetes: Friend or foe?

Hyperglucagonemia is one of the 'ominous' eight factors underlying the pathogenesis of type 2 diabetes (T2D). Glucagon is a peptide hormone involved in maintaining glucose homoeostasis by increasing hepatic glucose output to counterbalance insulin action. Long neglected, the introduction of dual and triple agonists exploiting glucagon signalling pathways has rekindled the interest in this hormone beyond its classic effect on glycaemia. Glucagon can promote weight loss by regulating food intake, energy expenditure, and brown and white adipose tissue functions through mechanisms still to be fully elucidated, thus its role in T2D pathogenesis should be further investigated. Moreover, the role of glucagon in the development of T2D micro- and macro-vascular complications is elusive. Mounting evidence suggests its beneficial effect in non-alcoholic fatty liver disease, while few studies postulated its favourable role in peripheral neuropathy and retinopathy. Contrarily, glucagon receptor agonism might induce renal changes resembling diabetic nephropathy, and data concerning glucagon actions on the cardiovascular system are conflicting. This review aims to summarise the available findings on the role of glucagon in the pathogenesis of T2D and its complications. Further experimental and clinical data are warranted to better understand the implications of glucagon signalling modulation with new antidiabetic drugs.

Effectiveness and safety of GLP-1 receptor agonists versus SGLT-2 inhibitors in type 2 diabetes: an Italian cohort study.

BACKGROUND: GLP-1 receptor agonists (GLP-1 RA) and SGLT-2 inhibitors (SGLT-2i) have shown to reduce the risk of major adverse cardiovascular events (MACE), death and worsening nephropathy when added to standard of care. However, these two dug classes differ in efficacy and safety. We compared the effectiveness and safety profile of GLP-1 RA and SGLT-2i in a large and unselected cohort of patients with type 2 diabetes resident in Lombardy from 2015 to 2020. METHODS: Using linkable administrative health databases, we included patients aged 50 years and older initiating GLP-1 RA or SGLT-2i. Clinical events were: death, hospital admission for myocardial infarction (MI), stroke, heart failure (HF), and renal disease as individual and composite outcomes (MACE-3: all cause-death, non-fatal MI, non-fatal stroke; MACE-4: MACE-3 plus unstable angina). Outcomes were evaluated separately in subjects with and without previous cardiovascular (CV) diseases. Treatments were compared using Cox proportional hazards regression model after Propensity Score Matching (PSM) in both intention-to-treat (ITT) and per protocol (PP) analyses. Serious adverse events were also evaluated. RESULTS: The analysis comprised 20,762 patients per cohort. The ITT analysis showed a significant risk reduction for non-fatal MI (HR 0.77; CI 95% 0.66-0.90), MACE-3 (HR 0.91; CI 95% 0.84-0.98), and MACE-4 (HR 0.92; CI 95% 0.86-0.99) in GLP-1RA compared with SGLT-2i users, while no difference was reported in the incidence of HF hospitalization and stroke between the two cohorts. Similar benefits were found in the subgroup of patients without previous CV diseases only. PP analysis largely confirmed the main results. The incidence of serious adverse events was low in both cohorts (< 1%). CONCLUSIONS: GLP-1RA showed to be equally safe and more effective than SGLT-2i in reducing the risk of MACE-3, MACE-4 and MI. This study adds to the growing body of real-world evidence addressing the specific clinical properties of GLP-1RA and SGLT-2i in everyday practice to tailor treatment to the individual patient.

Mini Review: Effect of GLP-1 Receptor Agonists and SGLT-2 Inhibitors on the Growth Hormone/IGF Axis.

Accumulating evidence supports the early use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose transporter-2 inhibitors (SGLT-2is) for the treatment of type 2 diabetes. Indeed, these compounds exert numerous pleiotropic actions that favorably affect metabolism and diabetes comorbidities, showing an additional effect beyond glucose control. Although a substantial amount of knowledge has been generated regarding the mechanism of action of both drug classes, much remains to be understood. Growth hormone (GH) is an important driver for multiple endocrine responses involving changes in glucose and lipid metabolism, and affects several tissues and organs (e.g., bone, heart). It acts directly on several target tissues, including skeletal muscle and bone, but several effects are mediated indirectly by circulating (liver-derived) or locally produced IGF-1. In consideration of the multiple metabolic and cardiovascular effects seen in subjects treated with GLP-1RAs and SGLT-2is (e.g., reduction of hyperglycemia, weight loss, free/fat mass and bone remodeling, anti-atherosclerosis, natriuresis), it is reasonable to speculate that GH and IGF-1 may play a about a relevant role in this context. This narrative mini-review aims to describe the involvement of the GH/IGF-1/IGF-1R axis in either mediating or responding to the effects of each of the two drug classes.

Cardiovascular and Renal Effectiveness of GLP-1 Receptor Agonists vs. Other Glucose-Lowering Drugs in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Real-World Studies.

Cardiovascular outcome trials (CVOT) showed that treatment with glucagon-like peptide-1 receptor agonists (GLP-1RA) is associated with significant cardiovascular benefits. However, CVOT are scarcely representative of everyday clinical practice, and real-world studies could provide clinicians with more relatable evidence. Here, literature was thoroughly searched to retrieve real-world studies investigating the cardiovascular and renal outcomes of GLP-1RA vs. other glucose-lowering drugs and carry out relevant meta-analyses thereof. Most real-world studies were conducted in populations at low cardiovascular and renal risk. Of note, real-world studies investigating cardio-renal outcomes of GLP-1RA suggested that initiation of GLP-1RA was associated with a greater benefit on composite cardiovascular outcomes, MACE (major adverse cardiovascular events), all-cause mortality, myocardial infarction, stroke, cardiovascular death, peripheral artery disease, and heart failure compared to other glucose-lowering drugs with the exception of sodium-glucose transporter-2 inhibitors (SGLT-2i). Initiation of SGLT-2i and GLP-1RA yielded similar effects on composite cardiovascular outcomes, MACE, stroke, and myocardial infarction. Conversely, GLP-1RA were less effective on heart failure prevention compared to SGLT-2i. Finally, the few real-world studies addressing renal outcomes suggested a significant benefit of GLP-1RA on estimated glomerular filtration rate (eGFR) reduction and hard renal outcomes vs. active comparators except SGLT-2i. Further real-world evidence is needed to clarify the role of GLP-1RA in cardio-renal protection among available glucose-lowering drugs.

SGLT-2 inhibitors as cardio-renal protective agents.

Despite remarkable advances in diabetes care, patients with type 2 diabetes are still burdened by higher morbidity and mortality than non-diabetic individuals. Atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease represent the most relevant causes of morbidity and mortality and sustain each other in a vicious circle. Cardiovascular diseases are the main cause of death in patients with chronic kidney disease, and, in turn, chronic kidney disease is a significant contributor to the risk of major cardiovascular events and hospitalization for heart failure. Cardiovascular outcome trials with SGLT-2 inhibitors in type 2 diabetes yielded unprecedented results on prevention of worsening heart failure and renal disease progression and mortality, further confirmed by randomized controlled trials in patients with baseline heart failure and chronic kidney disease, with or without diabetes, and observations from the real-world setting. However, the evidence regarding SGLT-2 inhibitors benefit on atherosclerotic cardiovascular events is conflicting. Hence, SGLT-2 inhibitors represent a remarkably valuable weapon in diabetes management, to be used in the context of a multi-targeted treatment strategy to address the many issues of this multifaceted disease.

Role of Glucose-Lowering Medications in Erectile Dysfunction.

Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.

Reduction of hypoglycaemia, lifestyle modifications and psychological distress during lockdown following SARS-CoV-2 outbreak in type 1 diabetes.

AIMS: To assess changes in glucose metrics and their association with psychological distress and lifestyle changes in patients with type 1 diabetes (T1D) using flash glucose monitoring (FGM) during lockdown following severe acute respiratory syndrome coronavirus 2 outbreak. MATERIALS AND METHODS: Single-centre, observational, retrospective study enrolling T1D patients who attended a remote visit on April 2020 at the Endocrinology division of the University Hospital Policlinico Consorziale, Bari, Italy. Lockdown-related changes in physical activity level and dietary habits were assessed on a semi-quantitative basis. Changes in general well-being were assessed by the General Health Questionnaire-12 items with a binary scoring system. Glucose metrics were obtained from the Libreview platform for the first 2 weeks of February 2020 (T0) and the last 2 weeks before the phone visit (T1). RESULTS: Out of 84 patients assessed for eligibility, 48 had sufficient FGM data to be included in the analysis. FGM data analysis revealed significant reductions in coefficient of variation, number of hypoglycaemic events, and time below range, while no changes were found in time in range, time above range, mean sensor glucose, and glucose management indicator. Moreover, the frequency of sweets consumption was inversely related to the occurrence of hypoglycaemic events during lockdown. CONCLUSIONS: Lockdown-related lifestyle changes, albeit unhealthy, may lead to reduction in FGM-derived measures of hypoglycaemia and glycaemic variability in patients with T1D.

Titratable fixed-ratio combination of insulin glargine plus lixisenatide: A simplified approach to glycemic control in type 2 diabetes mellitus.

Approximately 50% of patients with type 2 diabetes mellitus (T2DM) do not achieve glycemic targets and require treatment intensification. A fixed-ratio combination of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with basal insulin, such as lixisenatide with insulin glargine (iGlarLixi), exploits the complementary mechanisms of action of each component to address hyperglycemia while mitigating potential adverse events (AEs). The iGlarLixi dose is titrated considering the effect of basal insulin on fasting plasma glucose, and the fixed-ratio combination ensures that the lixisenatide dose never exceeds 20 µg/day. We describe the characteristics of iGlarLixi therapy, based on the LixiLan clinical program, and provide guidance on the characteristics of patients likely to benefit from such treatment in routine clinical practice. In the phase III LixiLan trials, iGlarLixi resulted in significantly greater reductions in glycated hemoglobin (HbA1c), better achievement of HbA1c targets, less glycemic variability versus insulin glargine, lixisenatide or GLP-1 RA alone, and was associated with weight control, less hypoglycemia versus insulin glargine, and fewer GI AEs versus lixisenatide. Findings were consistent regardless of age, diabetes duration, and baseline HbA1c. The efficacy, safety, and convenient once-daily administration schedule of iGlarLixi make it a valuable treatment option for patients with T2DM requiring treatment intensification.

Differential indication for SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with established atherosclerotic heart disease or at risk for congestive heart failure.

SGLT-2 inhibitors and most GLP-1 receptor agonists demonstrated cardiovascular superiority and reduction of cardiovascular and overall mortality. These results stand as a turning point in the management of diabetes, shifting the focus from controlling glucose levels to mastering the extra-glycemic effects of these new drugs. This narrative review will discuss recent CVOT with focus on SGLT-2 inhibitors and GLP-1 receptor agonists to distinguish relevant patients' characteristics as potential predictors for therapeutic efficacy. It will also examine their efficacy and safety, the differences in their cardiovascular and renal benefits, aiming to convey clinical suggestions for everyday practice.

Heterogeneity and Similarities in GLP-1 Receptor Agonist Cardiovascular Outcomes Trials.

The latest recommendations from the American Diabetes Association and the European Association for the Study of Diabetes prioritize the use of drugs with proven cardiovascular (CV) benefit in patients with established CV disease. Especially among the glucagon-like peptide (GLP)-1 receptor agonists (GLP-1RA) class, results of cardiovascular outcomes trials (CVOT) have been heterogeneous. Baseline characteristics of the population, study design, drugs in the control arm, modifications of CV risk factors, including glycemic control, reduction of hypoglycemia, and the GLP-1RA direct effects on CV cells and tissues, were considered. Ultimately, the time of exposure to the GLP-1RA appears to be the factor most prominently explaining trial heterogeneity. Thus, the CV benefit should be regarded as a class effect of GLP-1RA, as largely similar results are seen for drugs sharing a common mechanism of action.

Diabetes and cancer: Pathophysiological fundamentals of a 'dangerous affair'.

Diabetes and cancer are worldwide chronic diseases with a major impact on the quality and expectancy of life. Metabolic abnormalities observed during the onset and progression of diabetes may have a critical role on the initiation and progression of carcinogenesis. To date, there are no conclusive data on the mechanisms underlying the relationship between diabetes and any type of human cancer. However, recent evidence suggests that both hyperglycemia and hyperinsulinemia in diabetes could elicit cell damage responses, such as glucotoxicity, lipotoxicity and oxidative stress, which participate in the cell transformation process raising the risk of cancer development. In addition, clinical trials have revealed that several anti-diabetes therapies may potentially affect the risk of cancer though largely undefined mechanisms. In this review, we highlight epidemiological and pathophysiological aspects of diabetes, which may influence cancer initiation and progression.