The global increase in the prevalence of type 2 diabetes has led to the development and implementation of new classes of antidiabetic medications, introducing advanced therapeutic options for the management of the disease. These new medications, though primarily designed to regulate blood glucose levels, also have applications in weight management, potentially transforming the current approaches to diabetes treatment. Newer medications, however, have ophthalmic side effects with controversies in trials and real-life data. We comprehensively assessed the ocular benefits and adverse effects of traditional and newer-generation anti-diabetic drugs. Our primary focus is on how these newer medications affect the stage of diabetic retinopathy. Additionally, we explore the associations between these medications and other ocular conditions, including age-related macular degeneration, glaucoma, orbital conditions, and diseases impacting the ocular surface. Furthermore, we provide contextual background by discussing the ocular effects of traditional anti-diabetic drugs.

Worldwide, nearly 40% of adults are overweight and 13% are obese. Health consequences of excess weight include cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality. Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. Their mode of action is to mimic the endogenous GLP-1, an intestinal hormone that regulates glucose metabolism and satiety. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. They carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Gastrointestinal adverse events (nausea, vomiting, diarrhea) are fairly common while pancreatitis and intestinal obstruction are rarer. There may be a loss of lean body mass as well as premature facial aging. A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued. Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal.

To evaluate the risk of diabetic retinopathy progression and systemic vascular events, including death, in patients with nonproliferative diabetic retinopathy (NPDR) with obstructive sleep apnea (OSA).

Retrospective cohort study.

Electronic chart query using TriNetX, an electronic health records network comprising data from over 124 million patients. Patients with NPDR with and without OSA were identified. Patients were excluded if they had a history of proliferative disease (proliferative diabetic retinopathy), diabetic macular edema, or prior ocular intervention (intravitreal injection, laser, or pars plana vitrectomy). Propensity score matching was performed to control for baseline demographics and comorbidities. The rate of progression to vision-threatening complications, need for ocular intervention, and systemic events was measured at 1, 3, and 5 years.

A total of 11 931 patients in each group were analyzed after propensity score matching. There was an elevated risk of proliferative diabetic retinopathy in the OSA cohort at 1 (risk ratio [RR]: 1.34, P < .001), 3 (RR: 1.31, P < .001), and 5 years (RR: 1.28, P < .001). There was an elevated risk of diabetic macular edema in the OSA group at all time points: 1 (RR: 1.31, P < .001), 3 (RR: 1.19, P<.001), and 5 years (RR: 1.18, P < .001). With respect to ocular interventions, there was an increased risk of intravitreal injection in patients with OSA at 1 (RR: 1.59, P < .001), 3 (RR: 1.58, P < .001), and 5 years (RR: 1.54, P < .001), and similar trends were noted with laser photocoagulation, but not vitrectomy. Regarding systemic events, patients with NPDR with OSA had a greater risk of stroke (1 year RR: 1.80, P < .001; 3 years RR: 1.56, P < .001; and 5 years RR: 1.49, P < .001), myocardial infarction (1 year RR: 1.51, P < .001; 3 years RR: 1.46, P < .001; and 5 years RR: 1.43, P < .001), and death (1 year RR: 1.31, P < .001; 3 years RR: 1.19, P < .001; and 5 years RR: 1.15, P < .001).

There is an increased rate of diabetic retinopathy progression to vision-threatening complications, need for ocular intervention, and systemic complications, including death, for patients with OSA. We emphasize the need for improved screening measures of patients with NPDR and potential OSA.

With increasing prevalence of obesity and cardiovascular diseases, there is a growing interest in the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as an adjunct therapy in type 1 diabetes (T1D). The GLP-1RAs are currently not approved by the US Food and Drug Administration for the treatment of T1D in the absence of randomized controlled trials documenting efficacy and safety of these agents in this population. The Diabetes Technology Society convened a series of three consensus meetings of clinicians and researchers with expertise in diabetes technology, GLP-1RA therapy, and T1D management. The project was aimed at synthesizing current literature and providing conclusions on the use of GLP-1RA therapy as an adjunct to automated insulin delivery (AID) systems in adults with T1D. The expert panel members met virtually three times on January 17, 2024, and April 24, 2024, and August 14, 2024, to discuss topics ranging from physiology and outcomes of GLP-1RAs in T1D to limitations of current sensors, algorithms, and insulin for AID systems. The panelists also identified research gaps and future directions for research. The panelists voted to in favor of 31 recommendations. This report presents the consensus opinions of the participants that, in adults with T1D using AID systems, GLP-1RAs have the potential to (1) provide effective adjunct therapy and (2) improve glycemic and metabolic outcomes without increasing the risk of severe hypoglycemia or diabetic ketoacidosis.

To determine if glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with the development and progression of diabetic retinopathy (DR).

A systematic search was conducted on PubMed, Cochrane Library, and Embase from inception to February 2024 to identify clinical studies reporting the development of and changes in DR as the primary outcome in patients with type 2 diabetes taking GLP-1RA, insulin, or oral antidiabetic medication (OAD). Two researchers independently completed the search and referred to a third as necessary. Data for meta-analysis was pooled using a random-effects model.

Analysis of seven studies representing 242 537 patients showed a significantly decreased risk of incidence of DR between GLP-1RA and insulin use (RR = 0.66, 95% CI (0.48, 0.91), p = 0.01). There was no difference in the risk of DR complications (e.g., vitreous haemorrhage, retinal detachment, or requiring treatment with intravitreal injections, lasers, vitrectomy). Between GLP-1RA and OAD use, there was no difference in the risk of incidence of DR, while there was a significantly increased risk of DR complications (RR = 1.39, 95% CI (1.07, 1.80), p = 0.01).

Our findings indicate no elevated risk of incidence of DR linked to GLP-1RA compared to insulin. In fact, GLP-1RA may offer potential advantages over insulin regarding the overall incidence of DR. The increased risk of DR requiring treatment and associated complications in the GLP-1RA group compared to OAD may be due to the transient progression of DR associated with a rapid decrease in HbA1c - a phenomenon not specific to GLP-1RA and warrants further investigation.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Nonarteritic anterior ischemic optic neuropathy (NAION) is an untreatable condition often causing severe and irreversible visual loss in the affected eye. As it has recently been implied that the use of semaglutide associates with NAION, the aim of the present study was to evaluate this risk prospectively in all persons with type 2 diabetes (T2D) in Denmark.

In a five-year longitudinal cohort study, we identified all persons with T2D in Denmark (n = 424,152) between 2018 and 2024. Patients were stratified according to exposure (n = 106,454) or non-exposure (n = 317,698) to once-weekly semaglutide, and incidence rates and hazard ratios (HR) of NAION were estimated in a multivariable Cox proportional hazard regression model.

At baseline, median age and hemoglobin A1c were 65 years and 50 mmol/mol, and 54·5% were male. During 1,915,120 person-years of observation, 218 persons developed NAION. Semaglutide exposure was associated with a higher incidence rate (0·228 vs. 0·093 per 1000 person-years, p < 0·001) and independently predicted a higher risk of upcoming NAION (HR 2·19, 95% confidence interval 1·54 - 3·12), even when multiple other factors were taken into account. Overall, 67 persons exposed to semaglutide developed NAION with a median time from first prescription to event of 22·2 months (interquartile range 10·2-37·8 months).

During five years of observation of all persons with T2D in Denmark, use of once-weekly semaglutide independently more than doubled the risk of NAION. Given the irreversible nature of NAION, it is important to acknowledge this risk, and upcoming studies should aim to identify high-risk subgroups.

Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon-like peptide-1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co-agonists.

The objective of this narrative review was to summarize the available data on approved and emerging incretin-based agents for the treatment of obesity.

In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction-associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation.

Many dual and triple co-agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin-based therapies; however, data are promising, and further results are eagerly awaited.

Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) are a group of relatively novel medications for the treatment of diabetes mellitus. These medications can mimic the naturally occurring incretins of the body, which promote the release of insulin in response to hyperglycaemia. The anti-glycaemic effects of these medications can be profound and carry other metabolic benefits such as promoting weight loss. Clinical trials have shown GLP-1 RAs are safe to use from a cardiovascular perspective. However, some trials have suggested a link between GLP-1 RA use and worsening diabetic retinopathy. The conclusions surrounding this link are poorly established as data is drawn primarily from cardiovascular outcome trials. If an association does exist, a possible explanation might be the observed phenomenon of early worsening diabetic retinopathy with rapid correction of hyperglycaemic states. Trials which look at diabetic retinopathy as a primary outcome in relation to use of GLP-1 RAs are sparse and warrant investigation given the growing use of this group of medications. Therefore currently, it is uncertain what effect, beneficial or adverse, GLP-1 RA use has on diabetic retinopathy. This article provides an overview of GLP-1 RA use as a treatment for diabetes mellitus and the current understanding of their relationship with diabetic retinopathy.

To compare the risk of vision-threatening retinopathy between glucagon-like peptide-1 receptor agonists (GLP-1 RA) use and no use in patients with type 2 diabetes.

Using propensity score matching, we identified 27,506 pairs of GLP-1 RA users and non-users, 3904 pairs of GLP-1 RA and dipeptidyl peptidase-4 inhibitors (DPP-4i) users, 10,985 pairs of GLP-1 RA and sodium-glucose cotransporter-2 inhibitors (SGLT2i) users, 2542 pairs of GLP-1 RA and sulfonylurea, respectively, from Taiwan's National Health Insurance Research Database from January 1, 2009 to December 31, 2018. We used Cox proportional hazards models to compare the risk of vision-threatening retinopathy between GLP-1 RA use and other matched groups.

In the matched cohorts, the time-varying exposure analysis showed that GLP-1 RA use was not associated with an increased risk of vision-threatening retinopathy compared to GLP-1 RA non-use (aHR 0.96, 95 % CI 0.89-1.03). New-user and active-comparator analyses showed that GLP-1 RA was associated with a significantly lower risk of vision-threatening retinopathy than DPP-4i (aHR 0.8, 95 % CI 0.66-0.97) but had no significant association with this risk compared to SGLT2i (aHR 1.09, 95 % CI 0.96-1.24) or sulfonylureas (aHR 0.79, 95 % CI 0.49-1.06).

This nationwide cohort study showed that GLP-1 RA use was not associated with an increased risk of vision-threatening retinopathy compared to non- GLP-1 RA use, and GLP-1 RA could significantly lower the risk of vision-threatening retinopathy than DPP-4i.

To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database.

We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack.

The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001).

Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.

The current obesity pandemic has given rise to associated comorbidities and complications, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). During the last decade, certain glucagon-like peptide 1 receptor agonists (GLP-1RA), originally developed as antihyperglycemic drugs, also demonstrated efficacy for weight loss.

To review shared pathophysiologic features of common metabolic diseases and compare therapeutic strategies to reduce body weight and related complications.

We performed an extensive literature research to describe the effects of lifestyle modification, first-generation anti-obesity drugs, and GLP-1RA on weight loss in humans with obesity, type 2 diabetes and MASLD.

Until recently, treatment of obesity has been limited to lifestyle modification, which offer moderate degree and sustainability of weight loss. The few approved first-generation anti-obesity drugs are either limited to short term use or to certain forms of obesity. Some GLP-1RA significantly decrease caloric intake and body weight. Liraglutide and semaglutide have therefore been approved for treating people with obesity. They also lead to a reduction of hepatic fat content and inflammation in people with biopsy-confirmed MASLD. Possible limitations comprise adverse effects, treatment adherence and persistence.

Certain GLP-1RA are superior to lifestyle modification and first-generation anti-obesity drugs in inducing weight loss. They have therefore markedly changed the portfolio of obesity treatment with additional beneficial effects on steatotic liver disease.

Diabetic retinopathy (DR) is a leading cause of visual impairment, and the increasing prevalence of diabetes and obesity will impact rates of visual impairment moving forward. Our review aims to synthesize the current body of evidence regarding the impact of lifestyle interventions, such as weight loss, bariatric surgery, and novel antidiabetic drugs, on DR.

Literature review revealed insufficient evidence regarding the impact of weight loss on DR. Preoperative DR patients undergoing bariatric surgery were found to have similar short-term chances of improvement or worsening DR. Progression of DR with glucagon-like peptide 1 receptor agonists treatments appears unrelated to specific drugs and was also observed with traditional antidiabetic medications.

Rapidly correcting HbA1c levels (≥2%) can paradoxically lead to early worsening DR. Patients considering weight loss, bariatric surgery, and novel antidiabetic drugs should be aware of the potential for DR progression, but they should not be discouraged, as achieving glycemic control is essential for reducing long-term morbidity and mortality from other diabetes-related complications. It is advisable to conduct a baseline retinal examination before treatment and continue monitoring during therapy. Further research is needed to understand the long-term effects of these treatments on DR.

Myeloid cells including microglia and macrophages play crucial roles in retinal homeostasis by clearing cellular debris and regulating inflammation. These cells are activated in several blinding ischemic retinal diseases including diabetic retinopathy, where they may exert both beneficial and detrimental effects on neurovascular function and angiogenesis. Myeloid cells impact the progression of retinal pathologies and recent studies suggest that targeting myeloid cells is a promising therapeutic strategy to mitigate diabetic retinopathy and other ischemic retinal diseases. This review summarizes the recent advances in our understanding of the role of microglia and macrophages in retinal diseases and focuses on the effects of myeloid cells on neurovascular injury and angiogenesis in ischemic retinopathies. We highlight gaps in knowledge and advocate for a more detailed understanding of the role of myeloid cells in retinal ischemic injury to fully unlock the potential of targeting myeloid cells as a therapeutic strategy for retinal ischemia.

Diabetic retinopathy (DR) is the leading etiology of blindness in the working population of the USA. Its long-term management relies on effective glycemic control. Seven anti-diabetic classes have been introduced for patients with type 2 diabetes (T2D) in the past two decades, with different glucose-lowering and cardiovascular benefits. Yet, their effects specifically on DR have not been studied in detail. A systematic review of the literature was conducted to investigate this topic, focusing on the available clinical data for T2D. Published studies were evaluated based on their level of statistical evidence, as long as they incorporated at least one endpoint or adverse event pertaining to retinal health. Fifty nine articles met our inclusion criteria and were grouped per anti-diabetic class as follows: alpha-glucosidase inhibitors (1), peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists (8), amylin analogs (1), glucagon-like peptide-1 (GLP-1) receptor agonists (28), dipeptidyl peptidase 4 (DPP-4) inhibitors (9), and sodium glucose co-transporter-2 (SGLT-2) inhibitors (9), plus one retrospective study and two meta-analyses evaluating more than one of the aforementioned anti-diabetic categories. We also reviewed publicly-announced results of trials for the recently-introduced class of twincretins. The available data indicates that most drugs in the newer anti-diabetic classes are neutral to DR progression; however, there are subclasses differences in specific drugs and T2D populations. In particular, there is evidence suggesting there may be worse diabetic macular edema with PPAR-gamma agonists, potential slight DR worsening with semaglutide (GLP-1 receptor agonist), and potential slight increase in the incidence of retinal vein occlusion in elderly and patients with advanced kidney disease receiving SGLT-2 inhibitors. All these warrant further investigation. Longer follow-up and systematic assessment of at least one DR-related endpoint are highly recommended for all future trials in the T2D field, to ultimately address this topic.

The results from the SUSTAIN-6 trial generated some uncertainty regarding the association between incretin-based drugs [dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)] and the risk of diabetic retinopathy. Our objective was to synthesize the available evidence from observational studies regarding the use of incretin-based drugs and the risk of diabetic retinopathy among individuals with type 2 diabetes.

We systemically searched Cochrane Library, Embase and Medline to identify observational studies of interest. Risk of bias was assessed using the ROBINS-I tool. Data from included studies were pooled using the DerSimonian and Laird random-effect model with the Hartung-Knapp extension.

We included 14 studies in the systematic review, with 10 examining DPP-4 inhibitors and seven examining GLP-1 RAs. Nine studies investigated incident diabetic retinopathy, six investigated diabetic retinopathy progression and two investigated both outcomes. Seven studies were at moderate risk of bias, four at serious risk of bias and three at critical risk of bias. Data pooled across studies showed no association between the use of DPP-4 inhibitors (risk ratio: 0.98, 95% confidence interval: 0.83, 1.17) or GLP-1 RAs (risk ratio: 0.87, 95% confidence interval: 0.56, 1.34) and the risk of diabetic retinopathy.

This study suggests that the use of incretin-based drugs is not associated with the risk of diabetic retinopathy among individuals with type 2 diabetes. However, these findings should be interpreted with caution considering the limited quality of some of the available evidence.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) exhibit glucose-lowering, weight-reducing, and blood pressure-lowering effects. Nevertheless, a debate exists concerning the association between GLP-1RA treatment and the risk of diabetic retinopathy (DR) in patients diagnosed with type 2 diabetes mellitus (T2DM).

To ascertain the risk of DR in patients with T2DM undergoing GLP-1RA treatment, we conducted a meta-analysis utilizing data derived from randomized placebo-controlled studies (RCTs).

A comprehensive literature search was conducted using PubMed, Cochrane Library, Web of Science, and EMBASE. We focused on RCTs involving the use of GLP-1RAs in patients with T2DM. Utilizing R software, we compared the risk of DR among T2DM patients undergoing GLP-1RA treatment. The Cochrane risk of bias method was employed to assess the research quality.

The meta-analysis incorporated data from 20 RCTs, encompassing a total of 24,832 T2DM patients. Across all included trials, randomization to GLP-1 RA treatment did not demonstrate an increased risk of DR (odds ratio = 1.17; 95% CI 0.98-1.39). Furthermore, no significant heterogeneity or publication bias was detected in the analysis.

The results of this systematic review and meta-analysis indicate that the administration of GLP-1 RA is not associated with an increased risk of DR. PROSPERO REGISTRATION IDENTIFIER: CRD42023413199.

The glucagon-like peptide 1 (GLP-1) agonist showed anti-hyperglycemic and anti-inflammatory effects, which may retard the risk of external eye disease. The protective effect of GLP-1 agonist and dry eye disease (DED) was found, while the relationship between GLP-1 agonist and other corneal diseases was not clear. Herein, we aim to evaluate the association between the usage of GLP-1 agonists and the development of the following external eye disease in type 2 diabetes mellitus (T2DM) patients. A retrospective cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan was conducted. The T2DM patients were divided into those with GLP-1 treatment and those without GLP-1 treatment and matched with a 1:2 ratio. The main outcomes were the development of dry eye disease (DED), superficial keratitis, and infectious keratitis. The Cox proportional hazard regression was adopted to produce the adjusted hazard ratio (aHR) with a 95% confidence interval (CI) of external eye diseases between groups. There were 115, 54, and 11 episodes of DED, superficial keratitis, and infectious keratitis in the GLP-1 group. Another 280, 168, and 31 events of DED, superficial keratitis, and infectious keratitis were recorded in the control group. The GLP-1 group demonstrated a significantly lower incidence of DED (aHR: 0.853, 95% CI: 0.668-0.989, p = 0.0356) and superficial keratitis (aHR: 0.670, 95% CI: 0.475-0.945, p = 0.0107) compared to the control group. In the subgroup analyses, the correlation of GLP-1 agonist and DED development was more prominent in patients younger than 60 years old (p = 0.0018). In conclusion, the GLP-1 agonist treatments are significantly associated with a lower incidence of subsequent DED and superficial keratitis, while the relationship was not significant between GLP-1 agonist usage and infectious keratitis.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases.

Type 2 diabetes is a chronic and progressive cardiometabolic disorder that affects more than 10% of adults worldwide and is a major cause of morbidity, mortality, disability, and high costs. Over the past decade, the pattern of management of diabetes has shifted from a predominantly glucose centric approach, focused on lowering levels of haemoglobin A1c (HbA1c), to a directed complications centric approach, aimed at preventing short term and long term complications of diabetes, and a pathogenesis centric approach, which looks at the underlying metabolic dysfunction of excess adiposity that both causes and complicates the management of diabetes. In this review, we discuss the latest advances in patient centred care for type 2 diabetes, focusing on drug and non-drug approaches to reducing the risks of complications of diabetes in adults. We also discuss the effects of social determinants of health on the management of diabetes, particularly as they affect the treatment of hyperglycaemia in type 2 diabetes.

Early worsening of diabetic retinopathy (EWDR) due to the rapid decrease of blood glucose levels is a concern in diabetes treatment. The aim of the current study is to evaluate whether this is an important issue in subjects with type 2 diabetes with mild or moderate nonproliferative DR (NPDR), who represent the vast majority of subjects with DR attended in primary care.

This is a retrospective nested case-control study of subjects with type 2 diabetes and previous mild or moderate NPDR. Using the SIDIAP ("Sistema d'informació pel Desenvolupament de la Recerca a Atenció Primària") database, we selected 1,150 individuals with EWDR and 1,150 matched control subjects (DR without EWDR). The main variable analyzed was the magnitude of the reduction of HbA1c in the previous 12 months. The reduction of HbA1c was categorized as rapid (>1.5% reduction in <12 months) or very rapid (>2% in <6 months).

We did not find any significant difference in HbA1c reduction between case and control subjects (0.13 ± 1.21 vs. 0.21 ± 1.18; P = 0.12). HbA1c reduction did not show significant association with worsening of DR, neither in the unadjusted analyses nor in adjusted statistical models that included the main confounding variables: duration of diabetes, baseline HbA1c, presence of hypertension, and antidiabetic drugs. In addition, when stratification by baseline HbA1c was performed, we did not find that those patients with higher levels of HbA1c presented a higher risk to EWDR.

Our results suggest that the rapid reduction of HbA1c is not associated with progression of mild or moderate NPDR.

The purpose of this case report is to describe a case of vitreous hemorrhage in a patient with a history of diabetic retinopathy and receiving dulaglutide for the management of type 2 diabetes mellitus (T2DM).

A 64-year-old African American male with a past medical history of T2DM and severe diabetic retinopathy for 4 years was restarted on dulaglutide 1.5 mg weekly after being off therapy for 3 months. Baseline laboratory test results included hemoglobin A1c (HbA1c) of 8.8% and random blood glucose (BG) of 280 mg/dL. In addition, the patient had an average fasting BG of 150 mg/dL. In absence of intolerance, the dulaglutide dose was gradually maximized to 4.5 mg weekly and HbA1c decreased to 7.3% and random BG to 121 mg/dL at week 12 since reinitiation. At week 17 of therapy, the patient presented to the emergency department with a 1-day history of vision loss in the left eye and was diagnosed as having vitreous hemorrhage. The etiology for vitreous hemorrhage is unclear and may be a spontaneous episode. In discussion with the patient and the ophthalmologist, dulaglutide was restarted at 1.5 mg once weekly. After 4 weeks of reinitiation, the patient denied any recurrent symptoms of vitreous hemorrhage or worsening diabetic retinopathy. The most recent ophthalmology evaluation indicated no change in diabetic retinopathy.

This case report adds to the limited body of evidence available for the incidence of vitreous hemorrhage in the setting of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) therapy and pre-existing diabetic retinopathy. The case report illustrates that a history of diabetic retinopathy should not automatically preclude the use of GLP-1 RAs.

Diabetic retinopathy (DR) is characterised by neurovascular degeneration as a result of chronic hyperglycaemia. Proliferative diabetic retinopathy (PDR) is the most serious complication of DR and can lead to total (central and peripheral) visual loss. PDR is characterised by the presence of abnormal new blood vessels, so-called "new vessels," at the optic disc (NVD) or elsewhere in the retina (NVE). PDR can progress to high-risk characteristics (HRC) PDR (HRC-PDR), which is defined by the presence of NVD more than one-fourth to one-third disc area in size plus vitreous haemorrhage or pre-retinal haemorrhage, or vitreous haemorrhage or pre-retinal haemorrhage obscuring more than one disc area. In severe cases, fibrovascular membranes grow over the retinal surface and tractional retinal detachment with sight loss can occur, despite treatment. Although most, if not all, individuals with diabetes will develop DR if they live long enough, only some progress to the sight-threatening PDR stage.  OBJECTIVES: To determine risk factors for the development of PDR and HRC-PDR in people with diabetes and DR.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5), Ovid MEDLINE, and Ovid Embase. The date of the search was 27 May 2022. Additionally, the search was supplemented by screening reference lists of eligible articles. There were no restrictions to language or year of publication.  SELECTION CRITERIA: We included prospective or retrospective cohort studies and case-control longitudinal studies evaluating prognostic factors for the development and progression of PDR, in people who have not had previous treatment for DR. The target population consisted of adults (≥18 years of age) of any gender, sexual orientation, ethnicity, socioeconomic status, and geographical location, with non-proliferative diabetic retinopathy (NPDR) or PDR with less than HRC-PDR, diagnosed as per standard clinical practice. Two review authors independently screened titles and abstracts, and full-text articles, to determine eligibility; discrepancies were resolved through discussion. We considered prognostic factors measured at baseline and any other time points during the study and in any clinical setting. Outcomes were evaluated at three and eight years (± two years) or lifelong.  DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from included studies using a data extraction form that we developed and piloted prior to the data collection stage. We resolved any discrepancies through discussion. We used the Quality in Prognosis Studies (QUIPS) tool to assess risk of bias. We conducted meta-analyses in clinically relevant groups using a random-effects approach. We reported hazard ratios (HR), odds ratios (OR), and risk ratios (RR) separately for each available prognostic factor and outcome, stratified by different time points. Where possible, we meta-analysed adjusted prognostic factors. We evaluated the certainty of the evidence with an adapted version of the GRADE framework.   MAIN RESULTS: We screened 6391 records. From these, we identified 59 studies (87 articles) as eligible for inclusion. Thirty-five were prospective cohort studies, 22 were retrospective studies, 18 of which were cohort and six were based on data from electronic registers, and two were retrospective case-control studies. Twenty-three studies evaluated participants with type 1 diabetes (T1D), 19 with type 2 diabetes (T2D), and 17 included mixed populations (T1D and T2D). Studies on T1D included between 39 and 3250 participants at baseline, followed up for one to 45 years. Studies on T2D included between 100 and 71,817 participants at baseline, followed up for one to 20 years. The studies on mixed populations of T1D and T2D ranged from 76 to 32,553 participants at baseline, followed up for four to 25 years.  We found evidence indicating that higher glycated haemoglobin (haemoglobin A1c (HbA1c)) levels (adjusted OR ranged from 1.11 (95% confidence interval (CI) 0.93 to 1.32) to 2.10 (95% CI 1.64 to 2.69) and more advanced stages of retinopathy (adjusted OR ranged from 1.38 (95% CI 1.29 to 1.48) to 12.40 (95% CI 5.31 to 28.98) are independent risk factors for the development of PDR in people with T1D and T2D. We rated the evidence for these factors as of moderate certainty because of moderate to high risk of bias in the studies.  There was also some evidence suggesting several markers for renal disease (for example, nephropathy (adjusted OR ranged from 1.58 (95% CI not reported) to 2.68 (2.09 to 3.42), and creatinine (adjusted meta-analysis HR 1.61 (95% CI 0.77 to 3.36)), and, in people with T1D, age at diagnosis of diabetes (< 12 years of age) (standardised regression estimate 1.62, 95% CI 1.06 to 2.48), increased triglyceride levels (adjusted RR 1.55, 95% CI 1.06 to 1.95), and larger retinal venular diameters (RR 4.28, 95% CI 1.50 to 12.19) may increase the risk of progression to PDR. The certainty of evidence for these factors, however, was low to very low, due to risk of bias in the included studies, inconsistency (lack of studies preventing the grading of consistency or variable outcomes), and imprecision (wide CIs). There was no substantial and consistent evidence to support duration of diabetes, systolic or diastolic blood pressure, total cholesterol, low- (LDL) and high- (HDL) density lipoproteins, gender, ethnicity, body mass index (BMI), socioeconomic status, or tobacco and alcohol consumption as being associated with incidence of PDR. There was insufficient evidence to evaluate prognostic factors associated with progression of PDR to HRC-PDR.  AUTHORS' CONCLUSIONS: Increased HbA1c is likely to be associated with progression to PDR; therefore, maintaining adequate glucose control throughout life, irrespective of stage of DR severity, may help to prevent progression to PDR and risk of its sight-threatening complications. Renal impairment in people with T1D or T2D, as well as younger age at diagnosis of diabetes mellitus (DM), increased triglyceride levels, and increased retinal venular diameters in people with T1D may also be associated with increased risk of progression to PDR. Given that more advanced DR severity is associated with higher risk of progression to PDR, the earlier the disease is identified, and the above systemic risk factors are controlled, the greater the chance of reducing the risk of PDR and saving sight.