Glucose-lowering Treatment Research Articles

Effect of sodium-glucose transporter 2 inhibitors on sarcopenia in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

Sarcopenia has been recognized as the third category of disabling complications in patients with type 2 diabetes mellitus(T2DM), in addition to micro- and macrovascular complications. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are innovative glucose-lowering treatments that have been shown to reduce body weight and enhance cardiovascular and renal outcomes. However, there is vigilance that SGLT2 inhibitors should be taken cautiously because they target skeletal muscle and may raise the risk of sarcopenia. Herein, we conducted a meta-analysis of randomized controlled trials to evaluate the effects of SGLT2 inhibitors on sarcopenia in patients with T2DM. Relevant studies were obtained from PubMed, Embase, Medicine, Cochrane, and Web of Science databases to determine eligible studies until February 2023, without any language restrictions. A random effects model was utilized irrespective of heterogeneity, and the I2 statistic was used to evaluate study heterogeneity. The differences in results were measured using the weighted average difference (WMD) of the continuous data, along with a 95% confidence interval (CI). A total of 25 randomized controlled trials with 2,286 participants were included. SGLT2 inhibitors significantly reduced weight-related changes and fat-related changes, including body weight(BW) (WMD= -2.74, 95% CI: -3.26 to -2.23, P<0.01), body mass index(BMI) (WMD= -0.72, 95% CI: -0.95 to -0.49, P<0.01), waist circumference(WC) (WMD= -1.60, 95% CI: -2.99 to -0.22, P=0.02), fat mass(FM)(WMD= -1.49, 95% CI: -2.18 to -0.80, P<0.01), percentage body fat(PBF) (WMD= -1.28, 95% CI: -1.83 to -0.74, P<0.01), visceral fat area(VFA)(WMD= -19.52, 95% CI: -25.90 to -13.14, P<0.01), subcutaneous fat area(SFA)(WMD= -19.11, 95% CI: -31.18 to -7.03, P=0.002), In terms of muscle-related changes, lean mass(LM)(WMD= -0.80, 95% CI: -1.43 to -0.16, P=0.01), and skeletal muscle mass(SMM) (WMD= -0.38, 95% CI: -0.65 to -0.10, P=0.007), skeletal muscle index(SMI) (WMD= -0.12, 95% CI: -0.22 to -0.02, P=0.02)were also significantly reduced. In addition, body water likewise decreased significantly (WMD=-0.96, 95% CI: -1.68 to -0.23, P=0.009). As one of the most widely used hypoglycemic, SGLT2 inhibitors have beneficial effects on FM and BW weight loss in T2DM, such as BW, BMI, WC, FM, PBF, VFA, and SFA. However, the negative influence on muscle mass paralleled the reduction in FM and BW, and the consequent increased risk of sarcopenia warrants high attention, especially as patients are already predisposed to physical frailty. https://www.crd.york.ac.uk/prospero/#myprospero, identifier PROSPERO (No.CRD 42023396278).

Hyperglycaemic Metabolic Complications of Ischemic Brain: Current Therapeutics, Anti-Diabetics and Stem Cell Therapy.

Stroke is the leading cause of morbidity and mortality in diabetic patients. Diabetes alters the endothelial function and disrupts brain pathways, resulting in a variety of systemic metabolic complications. Diabetics not only have impaired neurotransmission, but also have progressive neurodegeneration, which leads to long-term neurological complications. Diabetes risk factors and physiology alter the frequency and severity of cardiovascular and cerebrovascular events, necessitating more hospitalizations. Stroke and diabetes have a mutually reinforcing relationship that worsens their outcomes. Diabetes has far-reaching systemic consequences for human physiology as a metabolic syndrome. As a result, diabetic stroke patients require dual-therapeutics with dual protection. Scientific researchers have made tremendous progress in diabetes-related stroke and its therapeutics over the last few decades. We have summarised diabetic brain and associated risk factors, co-morbidities, biomarkers, and hyperglycemia-associated neurovascular insult and cognitive demur. In addition to providing an overview of the effects of hyperglycaemia on brain physiology, this article aims to summarise the evidence from current glucose-lowering treatment, recent advances in stroke therapeutics as well as exploring stem cell therapy in the management of diabetes-associated stroke.

A Complementary Therapy with Whey Protein in Diabetes: A Double-Blind Randomized Controlled Clinical Trial

Type 2 diabetes (T2DM) and its complications can cause severe morbidity and mortality. The researchers and clinicians’ attention has been toward finding an efficient treatment for T2DM to decrease its heavy burden on the people and countries. Whey protein (WP) is a known glucose-lowering treatment of traditional Persian medicine. This randomized controlled clinical trial aimed to evaluate the efficacy of the WP on the improvement of the glycemic index of the patients with T2DM in Fars, Fasa, Iran. A total of 58 patients with T2DM met the inclusion criteria and were randomly assigned to one of two groups: intervention or placebo. For 12 weeks, they were given 1 sachet of WP or 1 sachet of placebo. Before and after the trial, fasting blood sugar (FBS), lipid profile, and liver enzymes were tested. Finally, 35 patients completed the study (18 in the whey group and 17 in the placebo group). The mean ± standard deviation of age, BMI, and the disease duration in placebo group were 52.1±9.2 years, 26.8±3.9 kg/m2 and 102.9±67.7 months and in WP group were 51.2±8.2 years, 25.7±3.7 kg/m2 and 74.2±51.1 months. There were no significant differences among the study groups at the beginning (P&gt;0.05). Meanwhile, the WP and placebo groups were the same by means of the amount of anti-diabetic drugs that participants consumed (P=0.242). After 12 weeks FBS and hemoglobin A1C amounts showed remarkable decreases in the WP group compared to its starting point (P=0.011 and P=0.001 respectively); while in the placebo group, no significant difference was observed (P&gt;0.05). No severe complications were reported in the two groups. In conclusion, we found that whey protein would be a promising complementary therapy to control hyperglycemia in the patients with T2DM.

286-LB: A Trailblazing Approach to Target Mitochondrial Dysfunction in Diabetic Beta Cells

Rationale: Currently no curative treatment exists to reverse or prevent autoimmune destruction of pancreatic islets in type 1 diabetes (T1D), and the disease can only be managed with insulin replacement therapy. We propose to leverage the therapeutic properties of ketone bodies to prevent and/or improve diabetes-associated ailments of beta cells. Of note, although excessive production of ketones leads to life-threatening ketoacidosis in diabetic patients under glucose lowering treatment, emerging lines of evidence suggest that modest levels of ketone bodies play adaptive and beneficial roles. Specifically, a functional role as key signaling molecule is increasingly acknowledged for beta-hydroxybutyrate (BHB), the most abundant ketone circulating in the human body. However, therapeutic applications of BHB have never been considered in T1D. Results: In NOD mice BHB treatment significantly increased survival and delayed diabetes onset, protecting pancreatic islets from apoptosis, reducing insulitis, and decreasing serum levels of pro-inflammatory cytokines. Furthermore, islet yield and total pancreatic insulin were markedly higher in BHB treated mice compared to controls. In addition, in NOD pancreatic islets and in human islets isolated from healthy donors treated with a cocktail of pro-inflammatory cytokines (i.e. IL-1β, TNF-α, and IFN-γ) BHB had a protective effect on oxidative stress, significantly reducing the production of ROS. Finally, in both systems BHB significantly increased the mitophagy flux improving mitochondrial fitness and preserving mitochondrial functions. Conclusion: The proposed studies are highly significant and are attempting for the first time to dissect the role of ketones in pancreatic beta cell death and dysfunction during T1D. Indeed, if our preliminary studies are confirmed BHB might emerge as a glucose-lowering agent that, acting synergistically with pharmacotherapy, could be able to improve the quality of life in patients with T1D. Disclosure S. Jankauskas: None. U. Kansakar: None. C. Nieves garcia: None. J. Gambardella: None. P. Mone: None. Y. Tomer: None. G. Santulli: None. A. Lombardi: None.

1765-P: Direct ß-Cell Effects of miR-6727-3p, an miRNA Related to Improved ß-Cell Function in Humans

Most people with type 2 diabetes (T2D) have limited improvement in β-cell function with glucose-lowering treatment; but we know little about contributing factors. Plasma miRNAs may reflect or predict treatment response at the level of the β cell. In youth treated with insulin glargine followed by metformin in the Restoring Insulin Secretion Study, we found that miR-6727-3p was positively associated with treatment response. Thus, we sought to determine whether miR-6727-3p has a direct effect on islets to improve insulin secretion and decrease cell death under T2D conditions. C57BL/6 mouse islets were treated for 48 h with 11.1 mM glucose (considered “normal” for mouse islets) or 25 mM glucose + 0.5 mM palmitate (“T2D”) in the presence of 5 nM miR-6727-3p mimic or miR-scramble. Thereafter, we assessed glucose-stimulated insulin secretion (GSIS) and islet cell death. T2D conditions resulted in elevated basal and reduced GSIS (Table). Regardless of condition, miR-6727-3p had no effect to change basal or GSIS. As expected, cell death increased in islets cultured in T2D vs normal conditions, but surprisingly, miR-6727-3p further exacerbated cell death under both conditions. Together, these data suggest miR-6727-3p may not alter β-cell function but that it may be deleterious to β-cell survival. Moreover, higher levels of plasma miR-6727-3p in responders are likely unrelated to treatment response. Disclosure S.Zraika: None. P.Wander: None. B.Barrow: None. D.Enquobahrie: None. T.K.Bammler: None. J.Macdonald: None. S.Srinouanprachanh: None. K.Chan: None. E.J.Boyko: None. S.E.Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Other Relationship; Novo Nordisk. Funding National Institutes of Health (R01DK132355)

Duration and effectiveness of glucose-lowering regimens in the real world management of diabetes: Data from the Australian EXTEND45 Linked Cohort Study

BackgroundDiabetes is a common condition that often requires increasing intensity of glucose lowering regimens. We describe the population trends in the intensity of regimens, and associations of achieved HbA1c and treatment persistence. MethodsWe performed an episode-based analysis of the EXTEND-45 dataset, assessing trends in glucose lowering therapy and the associated outcomes of HbA1c and treatment persistence. Trends from 2009 to 2014 were assessed for each intensity level of a glucose lowering therapy regimen, according to the year prescribed. Episodes were defined as the length of time that an individual adhered to a regimen through ongoing prescription, and this was used as to define persistence. Mean HbA1c were calculated for each episode. Persistence and HbA1c were compared across the different regimens of treatment intensity. ResultsThe intensity of glucose lowering therapy remained stable over time with around one third of episodes utilising a single glucose lowering agent. Mean HbA1c was higher for insulin-based treatment (mean 7.9 % SD = 1.3 %), and lowest for episodes of no glucose lowering treatment (mean 6.3 % (SD = 0.8 %). Around half of participants achieved glycemic targets of 7 %. While there was considerable variation in persistence, the median persistence was around 3 months (94 days, IQR 51–201 days). ConclusionsTherapeutic intensity for diabetes has remained stable over 9 years. Whilst there was considerable variability in persistence with glucose lowering regimens, the mean duration of all regimens was less than a year. Requirement for higher intensity treatment with insulin was related to poorer glycemic control.

Predicting the HbA1c level following glucose-lowering interventions in individuals with HbA1c-defined prediabetes: a post-hoc analysis from the randomized controlled PRE-D trial.

To investigate whether the prediction of post-treatment HbA1c levels can be improved by adding an additional biomarker of the glucose metabolism in addition to baseline HbA1c. We performed an exploratory analysis based on data from 112 individuals with prediabetes (HbA1c 39-47 mmol) and overweight/obesity (BMI ≥ 25 kg/m2), who completed 13 weeks of glucose-lowering interventions (exercise, dapagliflozin, or metformin) or control (habitual living) in the PRE-D trial. Seven prediction models were tested; one basic model with baseline HbA1c as the sole glucometabolic marker and six models each containing one additional glucometabolic biomarker in addition to baseline HbA1c. The additional glucometabolic biomarkers included: 1) plasma fructosamine, 2) fasting plasma glucose, 3) fasting plasma glucose × fasting serum insulin, 4) mean glucose during a 6-day free-living period measured by a continuous glucose monitor 5) mean glucose during an oral glucose tolerance test, and 6) mean plasma glucose × mean serum insulin during the oral glucose tolerance test. The primary outcome was overall goodness of fit (R2) from the internal validation step in bootstrap-based analysis using general linear models. The prediction models explained 46-50% of the variation (R2) in post-treatment HbA1c with standard deviations of the estimates of ~2 mmol/mol. R2 was not statistically significantly different in the models containing an additional glucometabolic biomarker when compared to the basic model. Adding an additional biomarker of the glucose metabolism did not improve the prediction of post-treatment HbA1c in individuals with HbA1c-defined prediabetes.

Modern glucose-lowering treatment effect on bone remodeling in experimental diabetes mellitus and surgical menopause

BACKGROUND: Diabetes mellitus (DM) is an independent risk factor for low-traumatic fractures. On the other hand, hypoglycemic drugs can have both positive and negative effects on bone remodeling.THE AIM: Тo investigate bone metabolism parameters during surgical menopause and experimental DM under the treatment with glucagon-like peptide receptor agonist type 1 (arGLP-1) liraglutide (LIRA) and sodium-glucose cotransporter type 2 inhibitor (iSGLT-2) canagliflozin (CANA).MATERIALS AND METHODS: Female Wistar rats have been subjected to bilateral ovariectomy at the beginning of the experiment. Diabetes mellitus (DM) was modelled using a high-fat diet and streptozotocin+nicotinamide. Four weeks after the following groups were formed: “OE+DM” (females after ovariectomy with DM and without any therapy, n=4) «OE+DM+CANA» (females after ovariectomy with DM under treatment with CANA, n=4), «OE+DM+LIRA» (females after ovariectomy with DM under treatment LIRA, n=5). The treatment or observation period were continuing for 8 weeks. Calcium, phosphorus and bone turnover markers (fibroblast growth factor-23 (FGF-23), osteocalcin, sclerostin, osteoprotegerin (OPG), nuclear factor-kappa-B receptor activator ligand (RANKL), were measured in the end of experiment. Bone histomorphometry was performed after euthanasia.RESULTS: Treatment with both CANA and LIRA did not significantly affect the phosphorus-calcium metabolism, sclerostin and osteocalcin concentrations. At the same time, the level of OPG was the highest in «OE+DM ‘’ group (9.1 [7.81; 10.045] pmol/l). The differences were significant compared with «OE+DM+CANA’’ (2, 33 [1.84; 5.84] pmol/l, p = 0.003) and «OE+DM+LIRA» (1.7 [1; 2] pmol/l, p = 0.003) groups. There were no differences in OPG levels between animals treated with different drugs. Similarly, the OPG/RANKL ratio was similarly reduced with both types of treatment. In “OE+DM+CANA’’ group the bone trabeculae number of the femur epiphysis (p=0.042) were decreased in comparison to «OE+DM» group. LIRA did not change the histoarchitectonic parameters.CONCLUSION: Bone metabolism markers did not differ when using as canagliflozin as liraglutide. Besides, canagliflosin can lead to the activation of bone resorption, which is expressed in the femur epiphyseal trabeculae number decreasing.

Abstract #1394296: The First Reported Case of Lorlatinib-Associated Diabetic Ketoacidosis

Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient’s DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient’s oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.

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Different diabetes

Optimization of glucose control drives improvement of NAFLD independent of weight loss in people with T2D

Aim. The mainstays for the treatment of non-alcoholic fatty liver disease (NAFLD) are lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with both obesity and type 2 diabetes (T2D). In people with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD based on histological features. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. Methods. In a consecutively recruited population of 637 patients with T2D with HbA1c levels above treatment targets, DPP-IV inhibition, GLP-1RA therapy or SGLT2 inhibition was initiated, alongside lifestyle education with maintenance of exiting background glucose lowering treatment. We examined the longitudinal impact of the optimization of glycaemic control on fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Results. Change in HbA1c and change in FLI correlated significantly in a linear regression analysis after adjustment for change in BMI, age, sex, and drug class (R=0.467, p=0.031). The greatest reduction in FLI was observed in patients with the largest reduction in HbA1c (p&lt;0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. Conclusions. Significant reductions of HbA1c are associated with improvement in NAFLD independently from weight loss. These results suggest a prominent role for the optimization of glucose control in the management of coexistent NAFLD and T2D, especially in the ‘lean’ NAFLD and where significant weight loss may not be achieved.

Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin-But not through altered drug metabolism in patients with type 2 diabetes.

Drug metabolism might be altered in patients with type 2 diabetes. We aimed to evaluate if initiation of glucose-lowering drugs impacts warfarin efficacy and drug metabolism. First, we conducted a register-based self-controlled cohort study on Danish and Scottish warfarin users. Warfarin efficacy (international normalized ratio [INR]) was compared before and after initiation of glucose-lowering drugs. Second, we conducted a clinical pharmacokinetic trial comprising treatment-naïve type 2 diabetes patients. Patients ingested probe drugs for drug-metabolizing enzymes (the Basel Cocktail) before initiating glucose-lowering treatment, and after 3 and 12 weeks of treatment. Drug metabolism, glycaemic control, and inflammation were assessed on each visit. In the Danish and Scottish cohorts (n = 982 and n = 44, respectively), initiating glucose-lowering drugs reduced warfarin efficacy. INR decreased from 2.47 to 2.21 in the Danish cohort (mean difference -0.26; 95% CI -0.35; -0.17) and from 2.33 to 2.13 in the Scottish cohort (-0.21; 95% CI -0.52; 0.11) after initiation of glucose-lowering treatment. This impact on INR was more pronounced among individuals with stronger effects of glucose-lowering treatment. In the clinical pharmacokinetic trial (n = 10), initiating metformin did not affect drug metabolism after 3weeks (geometric mean ratio of CYP3A metabolic ratio: 1.12 [95% CI: 0.95; 1.32]) or 12 weeks of metformin treatment. Glycaemic control improved during treatment, while inflammation remained low and unchanged during treatment. In conclusion, initiation of glucose-lowering drugs among chronic warfarin users seems associated with a reduction in INR, particularly among individuals with a large decrease in HbA1c . This effect seems unrelated to CYP enzyme activity and warfarin drug metabolism.

Prognostic implications of stress hyperglycemia ratio in patients with myocardial infarction with nonobstructive coronary arteries

Background The role of stress hyperglycemia in acute myocardial infarction (AMI) has long been emphasized. Recently, the stress hyperglycemia ratio (SHR), a novel index reflecting an acute glycemia rise, has shown a good predictive value in AMI. However, its prognostic power in myocardial infarction with nonobstructive coronary arteries (MINOCA) remains unclear. Methods In a prospective cohort of 1179 patients with MINOCA, relationships between SHR levels and outcomes were analyzed. SHR was defined as acute-to-chronic glycemic ratio using admission blood glucose (ABG) and glycated hemoglobin. The primary endpoint was defined as major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, stroke, revascularization, and hospitalization for unstable angina or heart failure. Survival analyses and receiver-operating characteristic (ROC) curve analyses were performed. Results Over the median follow-up of 3.5 years, the incidence of MACE markedly increased with higher SHR tertile levels (8.1%, 14.0%, 20.5%; p < 0.001). At multivariable Cox analysis, elevated SHR was independently associated with an increased risk of MACE (HR 2.30, 95% CI: 1.21–4.38, p = 0.011). Patients with rising tertiles of SHR also had a significantly higher risk of MACE (tertile 1 as reference; tertile 2: HR 1.77, 95% CI: 1.14–2.73, p = 0.010; tertile 3: HR 2.64, 95% CI: 1.75–3.98, p < 0.001). SHR remained a robust predictor of MACE in patients with and without diabetes; whereas ABG was no longer associated with the MACE risk in diabetic patients. SHR showed an area under the curve of 0.63 for MACE prediction. By incorporating SHR to TIMI risk score, the combined model further improved the discrimination for MACE. Conclusions The SHR independently confers the cardiovascular risk after MINOCA, and may serve as a better predictor than glycemia at admission alone, particularly in those with diabetes. KEY MESSAGES Stress hyperglycemia ratio (SHR) is independently associated with the prognosis in a distinct population with myocardial infarction with nonobstructive coronary arteries (MINOCA). SHR is a better predictor of prognosis than admission glycemia alone, especially in diabetic patients with MINOCA. SHR may serve as a prognostic marker for risk stratification as well as a potential target for tailored glucose-lowering treatment in MINOCA.

Changes in quantity plant-based protein intake on type 2 diabetes remission in coronary heart disease patients: from the CORDIOPREV study

PurposeDiabetes remission is a phenomenon described in the context of drastic weight loss due to bariatric surgery or low-calorie diets. Evidence suggests that increasing the intake of plant protein could reduce the risk of type 2 diabetes. We sought for association between changes in plant protein intake in the context of 2 healthy diets without weight loss nor glucose-lowering medication, and diabetes remission in coronary heart disease patients from the CORDIOPREV study.MethodsNewly diagnosed type 2 diabetes participants without glucose-lowering treatment were randomized to consume a Mediterranean or a low-fat diet. Type 2 diabetes remission was assessed with a median follow-up of 60 months according to the ADA recommendation. Information on patient's dietary intake was collected using food-frequency questionnaires. At first year of intervention, 177 patients were classified according to changes in plant protein consumption into those who increased or decreased its intake, in order to perform an observational analysis on the association between protein intake and diabetes remission.ResultsCox regression showed that patients increasing plant protein intake were more likely to remit from diabetes than those who decreased its intake (HR = 1.71(1.05–2.77)). The remission occurred mainly at first and second year of follow-up with diminished number of patients achieving remission in the third year onwards. The increase in plant protein was associated with lower intake of animal protein, cholesterol, saturated fatty acids, and fat, and with higher intake of whole grains, fibre, carbohydrates, legumes, and tree nuts.ConclusionThese results support the need to increase protein intake of vegetal origin as dietary therapy to reverse type 2 diabetes in the context of healthy diets without weight loss.

Individualizing treatment choices for patients with type 2 diabetes according to patient preference

Many patients with Type 2 diabetes will require additional glucose lowering treatment to achieve optimal glucose control. Ensuring treatment adherence is therefore crucial in order to reduce the long-term risks of complications. A study recently published in Nature Medicine, known as the TriMaster study is the first study to evaluate the effectiveness of allowing people with type 2 diabetes to choose their own second/third line medication to manage hyperglycaemia. This approach was thought to balance the potential efficacy with potential side effects profiles of the selected drugs. The study led by academics from the University of Exeter was a randomized double-blind, three-way cross over trial where patients received three different second- or third-line once-daily type 2 diabetes glucose-lowering drugs (pioglitazone 30 mg, sitagliptin 100 mg and canagliflozin 100 mg). As part of a prespecified secondary endpoint, patients' drug preference were examined after they had tried all three drugs. In total, 448 participants were treated with all three drugs which overall showed similar glucose lowering outcomes. In terms of preference, 115 patients (25%) preferred pioglitazone, 158 patients (35%) sitagliptin and 175 patients (38%) canagliflozin. The drug preferred by individual patients was associated with a lower HbA1c (mean: 4.6; 95% CI: 3.9, 5.3) mmol mol−1 lower versus nonpreferred) and was associated with fewer side effects (mean: 0.50; 95% CI: 0.35, 0.64) fewer side effects versus nonpreferred). This study showed that allocating therapy based on patients individually preferred drugs, rather than allocating all patients the overall most preferred drug (canagliflozin), would result in more patients achieving the lowest HbA1c for them (70% versus 30%) and the fewest side effects (67% versus 50%). Given the comparable glucose lowering ability of different drugs, allowing patients to try suitable medications before they choose long-term therapy according to their treatment preference could be a practical alternative to individualised treatment strategy for type 2 diabetes that would facilitate long-term treatment compliance.

Clinical trials with reno-vascular end points in patients with diabetes: Changing the scenario over the past 20 years

Major clinical advances over the last 20 years in the area of diabetic kidney disease (DKD) have been confirmed in large seminal clinical trials. These findings add to the previously identified benefits resulting from intensive glucose and blood pressure control therapies. Furthermore, newer glucose lowering treatments such as SGLT2 inhibitors and GLP-1 agonists appear very promising and are likely to transform the management and outlook of DKD over the next decade. In addition, novel mineralocorticoid receptor antagonists and a recently reported trial with an endothelin receptor blocker also have the potential to change clinical practice.

Abstract P140: Potential Mediators for Cardiovascular Benefits of Novel Diabetes Medications: A Meta-Regression Analysis

Background: Prior research suggests cardiovascular (CV) benefits of glucose-lowering interventions may be mediated by changes in hemoglobin A1c (HbA1c), bodyweight, systolic blood pressure (SBP), hematocrit, and urine albumin-creatinine ratio (uACR). We evaluated the heterogeneity of CV benefits by these potential mediators for sodium-glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) using a meta-analytic approach. Methods: We performed a systematic review and meta-regression analyses of 12 SGLT2i and 9 GLP-1RA CV outcome trials using linear mixed models of treatment efficacy measured as log hazard ratios (HRs) vs changes in potential mediators. We extracted follow-up mediator data for treatment and control, preferably at 12 months post randomization. Outcomes included MI, stroke, and MACE (a composite of MI, stroke, or CV death). We investigated slope differences between drug classes using interaction terms and likelihood-ratio tests. Results: Treatment efficacy for MACE improved with more HbA1c reduction among GLP-1RA (slope .26; P slope .02) but not among SGLT2i trials (slope -.22; P slope .39; P interaction .06), see Figure . Treatment efficacy for MACE, MI, and stroke decreased with more weight loss for SGLT2i (slope –.17, –.29, –.39; P slope &lt;.05) but not for GLP-1RA trials (slope .05, .03, .07; P slope .30, .62, .32). Slopes differed significantly between drug classes: P interaction &lt;.05. For stroke, we observed a trend of less treatment efficacy with increases in hematocrit among five SGLT2i trials with available data (slope .96; P slope .07). We did not find any indication of mediation effects by SBP and uACR for SGLT2i or GLP-1RAs (slopes -.11 -.07; P slopes ≥ .05). Conclusion: We confirm previous findings of increased CV benefits with reductions in HbA1c for GLP1-RAs. Further research is needed to investigate the potential loss of SGLT2i efficacy with greater weight loss and increase in hematocrit.

Effect of Intensive Glycemic Control on Myocardial Infarction Outcome in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

The effect of intensive glucose-lowering treatment on the risk of cardiovascular events in type 2 diabetes remains uncertain, especially the effect on the occurrence of myocardial infarction in patients with type 2 diabetes is still unclear. The purpose of this study was to conduct a systematic review and meta-analysis of relevant RCTs. We performed a systematic review of randomized clinical trials (RCTS) and observational studies relevant to this study question. We searched the PubMed and Cochrane databases until June 2022. We included data on 14 RCTs and 144,334 patients, all of whom had type 2 diabetes. When all studies were considered, intensive glucose-lowering treatment significantly reduced the incidence of MI compared with conventional therapy and the total OR value is 0.90 (CI 0.84, 0.97; P = 0.004) when considering all the studies. When the target value of intensive glucose-lowering treatment was considered as HbA1c decrease of more than 0.5%, there was no significant protective effect on MI, the total OR value is 0.88 (CI 0.81, 0.96; P = 0.003). When considering all available RCTS, the intensive glucose-lowering treatment group had a protective effect for MACE compared to the conventional treatment group, and the total OR value is 0.92 (CI 0.88, 0.96; P < 0.00001). In the available RCTs, for the patients with a history of prior CAD, the total OR value is 0.94 (CI 0.89, 0.99; P = 0.002). And there was no difference in the incidence of hypoglycemic events between the intensive and conservative treatment groups. Our data support the positive protective effect of glucose-lowering therapy on MI in patients with T2DM, but there is no significant effect of intensive glucose-lowering. In addition, we found no greater protective effect of enhanced glucose control in the HbA1c reduction of more than 0.5%, and no difference in the incidence of adverse events compared with the HbA1c reduction of less than 0.5%.

Optimizing cardiovascular risk assessment and registration in a developing cardiovascular learning health care system: Women benefit most.

Since 2015 we organized a uniform, structured collection of a fixed set of cardiovascular risk factors according the (inter)national guidelines on cardiovascular risk management. We evaluated the current state of a developing cardiovascular towards learning healthcare system-the Utrecht Cardiovascular Cohort Cardiovascular Risk Management (UCC-CVRM)-and its potential effect on guideline adherence in cardiovascular risk management. We conducted a before-after study comparing data from patients included in UCC-CVRM (2015-2018) and patients treated in our center before UCC-CVRM (2013-2015) who would have been eligible for UCC-CVRM using the Utrecht Patient Oriented Database (UPOD). Proportions of cardiovascular risk factor measurement before and after UCC-CVRM initiation were compared, as were proportions of patients that required (change of) blood pressure, lipid, or blood glucose lowering treatment. We estimated the likelihood to miss patients with hypertension, dyslipidemia, and elevated HbA1c before UCC-CVRM for the whole cohort and stratified for sex. In the present study, patients included up to October 2018 (n = 1904) were matched with 7195 UPOD patients with similar age, sex, department of referral and diagnose description. Completeness of risk factor measurement increased, ranging from 0% -77% before to 82%-94% after UCC-CVRM initiation. Before UCC-CVRM, we found more unmeasured risk factors in women compared to men. This sex-gap resolved in UCC-CVRM. The likelihood to miss hypertension, dyslipidemia, and elevated HbA1c was reduced by 67%, 75% and 90%, respectively, after UCC-CVRM initiation. A finding more pronounced in women compared to men. In conclusion, a systematic registration of the cardiovascular risk profile substantially improves guideline adherent assessment and decreases the risk of missing patients with elevated levels with an indication for treatment. The sex-gap disappeared after UCC-CVRM initiation. Thus, an LHS approach contributes to a more inclusive insight into quality of care and prevention of cardiovascular disease (progression).

New guideline on diabetes management in chronic kidney disease

In autumn 2022, an update of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on diabetes management in chronic kidney disease (CKD) was published. This article presents in aclear manner and discusses the new aspects compared to the 2020 guideline. Innovations are seen in the area of general and all-encompassing treatment as well as in relation to blood glucose-lowering and organ-protective treatments with sodium-glucose cotransporter2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide‑1 receptor agonists. Anew feature is also the top 10 recommendations on diabetes management in CKD for both patients and physicians. The KDIGO guideline on diabetes management in CKD represents the current evidence-based standard of care for patients with diabetes mellitus and CKD. It is now important to implement the guideline in order to provide patients with the benefits of the treatments and thus improve their lives.