Inter-relationships between cardiovascular, renal and metabolic diseases: Underlying evidence and implications for integrated interdisciplinary care and management.

Cardiovascular, renal and metabolic (CaReMe) diseases are individually among the leading global causes of death, and each is associated with substantial morbidity and mortality. However, as these conditions commonly coexist in the same patient, the individual risk of mortality and morbidity is further compounded, leading to a considerable healthcare burden. A number of pathophysiological pathways are common to diseases of the CaReMe spectrum, including neurohormonal dysfunction, visceral adiposity and insulin resistance, oxidative stress and systemic inflammation. Because of the shared pathology and common co-occurrence of the CaReMe diseases, the value of managing these conditions holistically is increasingly being realized. A number of pharmacological and non-pharmacological approaches have been shown to offer simultaneous metabolic, cardioprotective and renoprotective benefits, leading to improved patient outcomes across the CaReMe spectrum. In addition, increasing value is being placed on interdisciplinary team-based and coordinated care models built on greater integration between specialties to increase the rate of early diagnosis and adherence to practice guidelines, and improve clinical outcomes. This interdisciplinary approach also facilitates integration between primary and specialty care, improving the patient experience, optimizing resources, and leading to efficiencies and cost savings. As the burden of CaReMe diseases continues to increase, implementation of innovative and integrated care delivery models will be essential to achieve effective and efficient chronic disease management and to ensure that patients benefit from the best care available across all three disciplines.

First-in-human study of a pharmacological duodenal exclusion therapy shows reduced postprandial glucose and insulin and increased bile acid and gut hormone concentrations.

AIMS: To address the need for noninvasive alternatives to metabolic surgery or duodenal exclusion devices for the management of type 2 diabetes (T2D) and obesity by developing an orally administered therapeutic polymer, GLY-200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively. MATERIALS AND METHODS: A Phase 1, randomized, double-blind, placebo-controlled, single- (SAD) and multiple-ascending-dose (MAD) healthy volunteer study was conducted. In the SAD arm, four cohorts received a single dose of 0.5 g up to 6.0 g GLY-200 or placebo, while in the MAD arm, four cohorts received 5 days of twice-daily or three-times-daily dosing (total daily dose 2.0 g up to 6.0 g GLY-200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, including serum glucose, insulin, bile acids and gut hormones. RESULTS: No safety signals were observed; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. In the MAD arm (Day 5), reductions in glucose and insulin and increases in bile acids, glucagon-like peptide-1, peptide YY and glicentin, were observed following a nonstandardized meal in subjects receiving twice-daily dosing of 2.0 g GLY-200 (N = 9) versus those receiving placebo (N = 8). CONCLUSIONS: GLY-200 is safe and generally well tolerated at doses of ≤2.0 g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux-en-Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine. This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY-200 for the treatment of obesity and/or T2D.

Treatment patterns and glycated haemoglobin levels over 36 months in individuals with type 2 diabetes initiating second-line glucose-lowering therapy: The global DISCOVER study.

AIMS: To describe glucose-lowering treatment regimens and glycated haemoglobin (HbA1c) trajectories in individuals with type 2 diabetes (T2D) over 36 months of follow-up from the start of second-line therapy. MATERIALS AND METHODS: This data analysis from the 3-year, observational DISCOVER study programme included 14 687 participants from 37 countries with T2D initiating second-line glucose-lowering therapy. Treatment and HbA1c data were collected at baseline (start of second-line therapy) and at 6, 12, 24 and 36 months. Treatment regimen changes over follow-up were analysed using the McNemar test, with carry-forward imputation for intermediate missing values. RESULTS: A total of 11 592 participants had treatment data at baseline and 36 months, and 11 882 had HbA1c data at baseline. At baseline and 36 months, respectively, rates of oral monotherapy use were 12.1% and 12.4% (P = 0.22), rates of dual oral therapy use were 63.4% and 47.6% (P < 0.0001), rates of ≥ triple oral therapy use were 17.5% and 25.4% (P < 0.0001), and rates of injectable treatment use were 7.0% and 13.7% (P < 0.0001). Use of injectable drugs was most common among participants with an HbA1c level ≥64 mmol/mol (≥8.0%). Overall, 42.9% of participants changed treatment during follow-up. Mean HbA1c levels at baseline and 6 months were 67 mmol/mol (8.3%) and 55 mmol/mol (7.2%), respectively, remaining stable thereafter. CONCLUSIONS: Dual oral therapy was the most common treatment regimen at the start of second-line treatment, and over half of the participants remained on the same treatment during follow-up.

Association of country economy and socioeconomic factors on risk factor control for primary prevention of cardiovascular disease in patients with diabetes mellitus: Insights from the DISCOVER study.

BACKGROUND: We sought to describe global patterns in achievement of risk factor control for primary prevention in patients with T2D and explore the association of country's GNI/capita with risk factor control. METHODS: The DISCOVER study is a prospective, observational study of patients with T2D from 38 countries enrolled at initiation of second-line glucose-lowering therapy. We examined achievement of risk factor control (glycosylated hemoglobin <7%, blood pressure <140/90 mmHg, prescription of a statin) at 3 years among those without optimal control at baseline. Countries were stratified by gross national income (GNI)/capita, from 2017). We examined the impact of country GNI/capita with achievement of risk factor control. FINDINGS: Our cohort included 9613 patients with T2D and without baseline cardiovascular disease (mean age 57.2 ± 8.7 years, 47.9% women). At baseline, 6354/7646 patients (83.1%) had suboptimal glucose control, 3449/9200 patients (37.5%) had suboptimal BP control, and 2800/4221 patients (66.7%) were not on an appropriate statin (sample sizes differed due to missing covariate data). Optimal control at 3 years of follow-up was achieved in 41% (glucose), 56% (blood pressure), and 29% (statins) of patients. There was significant variability in achievement of risk factor control across countries but no association between country GNI/capita with achievement of risk factor control (p > 0.08 for all). INTERPRETATION: In a global, prospective study of patients with T2D, we found that cardiovascular risk factor control achievement was suboptimal despite 3 years of follow-up in specialized health care systems. Neither country-level nor patient-level socioeconomic factors fully explained this finding.

Factors associated with weight loss in people with overweight or obesity living with type 2 diabetes mellitus: Insights from the global DISCOVER study.

AIMS: To estimate real-world change in weight over 3 years and the factors influencing it in participants who are overweight and live with type 2 diabetes. MATERIALS AND METHODS: DISCOVER is a multinational prospective observational study that enrolled participants with type 2 diabetes between December 2014 and June 2016 at the time of initiation of a second-line glucose-lowering medication (GLM). Demographic, anthropometric, and quality-of-life data were collected at baseline, and after 6, 12, 24 and 36 months of follow-up. Using a hierarchical, repeated-measures linear regression model, we examined factors associated with weight change over time. RESULTS: Of 10 675 participants with type 2 diabetes who were overweight/obese (mean age 57.1 ± 11.1 years, 46% women), 21% lost ≥5% weight over 3 years, which was associated with modestly improved physical and mental health. Advancing age, female sex, and higher baseline weight were associated with weight loss. Most importantly, the type of GLM prescribed at previous visit had the strongest impact on weight change over time independent of participant factors, with use of a sodium-glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist associated with 1.0% weight loss versus a 0.6% weight gain with sulphonylureas, thiazolidinediones, meglitinides or insulin. CONCLUSION: In this large contemporary prospective study, approximately one in five participants with early-stage type 2 diabetes and overweight/obesity lost ≥5% weight over 3 years. The type of GLM has the most impact on weight loss over time, highlighting the need for a careful selection of agents that takes baseline weight into consideration.

Global use of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes. Results from DISCOVER.

BACKGROUND: Despite strong evidence of benefit, uptake of newer glucose-lowering medications that reduce cardiovascular risk has been low. We sought to examine global trends and predictors of use of SGLT2i and GLP-1 RA in patients with type 2 diabetes. METHODS: DISCOVER is a global, prospective, observational study of patients with diabetes enrolled from 2014-16 at initiation of second-line glucose-lowering therapy and followed for 3 years. We used hierarchical logistic regression to examine factors associated with use of either an SGLT2i or GLP-1 RA at last follow-up and to assess country-level variability. RESULTS: Among 14,576 patients from 37 countries, 1579 (10.8%) were started on an SGLT2i (1275; 8.7%) or GLP-1 RA (318; 2.2%) at enrollment, increasing to 16.1% at end of follow-up, with large variability across countries (range 0-62.7%). Use was highest in patients treated by cardiologists (26.1%) versus primary care physicians (10.4%), endocrinologists (16.9%), and other specialists (22.0%; p < 0.001). Coronary artery disease (OR 1.29, 95% CI 1.08-1.54) was associated with greater use of SGLT2i or GLP-1 RA while peripheral artery disease (OR 0.73, 95% CI 0.54-1.00) and chronic kidney disease (OR 0.73, 95% CI 0.58-0.94) were associated with lower use (OR 0.73, 95% CI 0.54-1.00). The country-level median odds ratio was 3.48, indicating a very large amount of variability in the use of SGLT2i or GLP-1 RA independent of patient demographic and clinical factors. CONCLUSIONS: Global use of glucose-lowering medications with established cardiovascular benefits has increased over time but remains suboptimal, particularly in sub-groups most likely to benefit. Substantial country-level variability exists independent of patient factors, suggesting structural barriers may limit more widespread use of these medications.

Quality of life in people with type 2 diabetes in the 3 years following initiation of second-line therapy: The DISCOVER study.

AIMS: To assess changes in health-related quality of life (HRQoL) in DISCOVER, a 3-year, longitudinal, observational study of patients with type 2 diabetes initiating a second-line glucose-lowering therapy. METHODS: HRQoL was assessed using the physical and mental component summary (PCS and MCS) scores of the 36-item Short-Form Health Survey version 2 (score ranges: 0-100; higher denotes better HRQoL) and the Hypoglycaemia Fear Survey II (HFS-II; score range: 0-132 scale; higher indicates greater fear of hypoglycaemia). Latent class growth modelling (LCGM) was used to identify patients with similar score trajectories. RESULTS: Mean baseline PCS (n = 7428), MCS (n = 7453), and HFS-II (n = 5005) scores were 48.0, 45.4, and 15.4, respectively, and remained stable during follow-up. LCGM revealed subgroups with low or decreasing HRQoL. Patients in these subgroups tended to be older, had more comorbidities, and a lower socioeconomic status than in other subgroups. Use of insulin and sulfonylureas was highest in the subgroup with the highest fear of hypoglycaemia. CONCLUSIONS: Overall, HRQoL remained stable in DISCOVER patients during follow-up. However, LCGM suggests that some patient characteristics and use of sulfonylureas or insulin are associated with low or decreasing HRQoL, potentially warranting the use of alternative therapies.

Incidence rates and predictors of microvascular and macrovascular complications in patients with type 2 diabetes: Results from the longitudinal global discover study.

BACKGROUND: Micro- and macrovascular complications are a major cause of morbidity and mortality in people with type 2 diabetes (T2D). We sought to understand the global incidence rates and predictors of these complications. METHODS: We examined the incidence of vascular complications over 3 years of follow-up in the DISCOVER study-a global, observational study of people with T2D initiating second-line glucose-lowering therapy. Hierarchical Cox proportional hazards regression models examined factors associated with development of micro- and macrovascular complications during follow-up. RESULTS: Among 11,357 people with T2D from 33 countries (mean age 56.9 ± 11.7 years, T2D duration 5.7 ± 5.1 years, HbA1c 8.4 ± 1.7%), 19.0% had a microvascular complication at enrolment (most commonly neuropathy), and 13.2% had a macrovascular complication (most commonly coronary disease). Over 3 years of follow-up, 16.0% developed an incident microvascular complication, and 6.6% had an incident macrovascular complication. At the end of 3 years of follow-up, 31.5% of patients had at least one microvascular complication, and 16.6% had at least one macrovascular complication. Higher HbA1c and smoking were associated with greater risk of both incident micro- and macrovascular complications. Known macrovascular complications at baseline was the strongest predictor for development of new microvascular complications (HR 1.40, 95% CI 1.21 -1.61) and new macrovascular complications (HR 3.39, 95% CI 2.84 -4.06). CONCLUSIONS: In this global study, both the prevalence and 3-year incidence of vascular complications were high in patients with relatively short T2D duration, highlighting the need for early risk-factor modification.

What are the factors associated with long-term glycaemic control in patients with type 2 diabetes and elevated glycated haemoglobin (≥7.0%) at initiation of second-line therapy? Results from the DISCOVER study.

AIMS: Glycaemic control is a cornerstone of type 2 diabetes (T2D) management. We assessed factors associated with good long-term glycaemic control in patients with glycated haemoglobin (HbA1c) ≥7.0% at initiation of second-line glucose-lowering therapy, using data from DISCOVER, a global, prospective, 3-year observational study of patients with T2D. MATERIALS AND METHODS: This analysis included patients with HbA1c ≥7.0% at baseline (initiation of second-line therapy). Multivariable regression models assessed factors associated with having HbA1c <7.0% at 3 years in two distinct groups: patients with (a) HbA1c ≥7.0% and <9.0%, and (b) HbA1c ≥9.0% at baseline. RESULTS: In total, 7575 patients with baseline HbA1c ≥7.0% were included (2233 with baseline HbA1c ≥9.0%). At 6 months, 43.7% and 24.2% of patients had an HbA1c level <7.0% in groups a and b, respectively; the corresponding proportions at 3 years were 45.8% and 29.3%. Having HbA1c <7.0% at 6 months (vs. ≥7.0%) was the strongest predictor of having HbA1c <7.0% at 3 years in both group a and group b [odds ratio (95% confidence interval): 2.01 (1.77-2.27) and 2.68 (2.10-3.41), respectively]. Longer T2D duration was associated with a decreased likelihood of having HbA1c <7.0% at 3 years. CONCLUSIONS: In patients with poor glycaemic control at initiation of second-line therapy, early attainment of HbA1c <7.0% appears predictive of long-term glycaemic control, suggesting that timely modification of treatment strategies in patients with elevated HbA1c after 6 months is important to minimize therapeutic inertia.

Incidence of sight-threatening diabetic retinopathy in an established urban screening programme: An 11-year cohort study.

AIMS: Systematic annual screening to detect sight-threatening diabetic retinopathy (STDR) is established in the United Kingdom. We designed an observational cohort study to provide up-to-date data for policy makers and clinical researchers on incidence of key screening endpoints in people with diabetes attending one screening programme running for over 30 years. METHODS: All people with diabetes aged ≥12 years registered with general practices in the Liverpool health district were offered inclusion. Data sources comprised: primary care (demographics, systemic risk factors), Liverpool Diabetes Eye Screening Programme (retinopathy grading), Hospital Eye Services (slit lamp biomicroscopy assessment of screen positives). RESULTS: 133,366 screening episodes occurred in 28,384 people over 11 years. Overall incidences were: screen positive 6.7% (95% CI 6.5-6.8), screen positive for retinopathy 3.1% (3.0-3.1), unassessable images 2.6% (2.5-2.7), other significant eye diseases 1.0% (1.0-1.1). 1.6% (1.6-1.7) had sight-threatening retinopathy confirmed by slit lamp biomicroscopy. The annual incidence of screen positive and screen positive for retinopathy showed consistent declines from 8.8%-10.6% and 4.4%-4.6% in 2007/09 to 4.4%-6.8% and 2.3%-2.9% in 2013/17, respectively. Rates of STDR (true positive) were consistently below 2% after 2008/09. Screen positive rates were higher in first time attenders (9.9% [9.4-10.2] vs. 6.1% [6.0-6.2]) in part due to ungradeable images (4.1% vs. 2.3%) and other eye disease (2.4% vs. 0.8%). 4.5% (3.9-5.2) of previous non-attenders had sight-threatening retinopathy. Compared with people with type 2 diabetes, those with type 1 disease demonstrated higher rates of screen positive (11.9% vs. 6.0%) and STDR (6.4% vs. 1.2%). Overall prevalence of any retinopathy was 27.2% (27.0-27.4). CONCLUSIONS: In an established screening programme with a stable population screen, positive rates show a consistent fall over time to a low level. Of those who are screen positive, fewer than 50% are screen positive for diabetic retinopathy. Most are due to sight threatening maculopathy. The annual incidence of STDR is under 2% suggesting future work on redefining screen positive and supporting extended intervals for people at low risk. Higher rates of screen positive and STDR are seen in first time attenders. Those who have never attended for screening should be specifically targeted.

Type 2 diabetes and heart failure: insights from the global DISCOVER study.

AIMS: Heart failure (HF) is increasingly recognized as a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), but the global epidemiology and treatment of HF in T2D are not well defined. This study aimed to examine the global prevalence of HF and the incidence of HF over 3 years of follow-up in patients with T2D [by presence and absence of co-existing coronary artery disease (CAD)]. METHODS AND RESULTS: DISCOVER was a 3 year, prospective, observational study of T2D patients enrolled at initiation of second-line glucose-lowering therapy. Among 14 057 patients with T2D from 36 countries, 289 (2.1%) had a diagnosis of HF at enrolment; median prevalence across countries was 2.0% (inter-quartile range 1.0-3.1%). Patients with HF at baseline were more likely to be older [HF vs. no HF: 67 ± 12 vs. 57 ± 12 years, standardized difference (StDiff) = 84%] and have longer duration of T2D (8.1 ± 7.2 vs. 5.6 ± 5.2 years, StDiff = 40%), CAD (44% vs. 6%, StDiff = 97%), atrial fibrillation (21% vs. 1%, StDiff = 66%), and kidney disease (23% vs. 4%, StDiff = 55%). Patients with HF were less likely to be on metformin (66% vs. 79%, StDiff = 28%) and thiazolidinediones (5.5% vs. 10.6%, StDiff = 19%) but had similar use of other glucose-lowering medications. Among 9313 patients with follow-up data, there were 70 incident cases of HF, which translates to an incidence of 2.6 cases per 1000 person years. Of these incident HF cases, 60% occurred in the absence of pre-existing or concomitant CAD, and 73% were diagnosed in the outpatient setting. CONCLUSIONS: In a large, global cohort of patients with T2D, the majority of incident cases of HF occurred in outpatients and in the absence of known CAD. These findings highlight the need for greater awareness of HF risk in patients with T2D.

Cardiovascular and renal safety of metformin in patients with diabetes and moderate or severe chronic kidney disease: Observations from the EXSCEL and SAVOR-TIMI 53 cardiovascular outcomes trials.

AIM: To provide evidence on the cardiovascular and renal safety of metformin in chronic kidney disease (CKD) stages 3 to 4. MATERIALS AND METHODS: This post hoc analysis compared participants with an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73m2 in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (SAVOR-TIMI 53) trials taking metformin, with those not exposed to metformin during these trials, using a propensity-matching approach. Adjusted Cox proportional hazards models were used to assess risk of major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Metformin effect on eGFR slope was calculated using a mixed-model repeated measures analysis, and the number of lactic acidosis events was tabulated. RESULTS: No strong trend for lower metformin doses with lower eGFR values was observed in either the EXSCEL or SAVOR-TIMI 53 trials. In the 1745 metformin-using participants matched to non-metformin users, metformin had neutral effects on MACE (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.76-1.08; P = 0.28) and ACM (HR 0.86, 95% CI 0.70-1.07; P = 0.18), with no interaction by CKD stage, or with use of exenatide or saxagliptin. An improvement in eGFR slope was observed with metformin in the CKD stage 3B cohort in SAVOR-TIMI 53, but not in other groups. CONCLUSIONS: This analysis of participants with CKD stages 3 to 4 from two cardiovascular outcomes trials supports the cardiorenal safety of metformin, but does not suggest a consistent benefit on MACE, ACM, or eGFR slope across this population.

Safety and cost-effectiveness of individualised screening for diabetic retinopathy: the ISDR open-label, equivalence RCT.

AIMS/HYPOTHESIS: Using variable diabetic retinopathy screening intervals, informed by personal risk levels, offers improved engagement of people with diabetes and reallocation of resources to high-risk groups, while addressing the increasing prevalence of diabetes. However, safety data on extending screening intervals are minimal. The aim of this study was to evaluate the safety and cost-effectiveness of individualised, variable-interval, risk-based population screening compared with usual care, with wide-ranging input from individuals with diabetes. METHODS: This was a two-arm, parallel-assignment, equivalence RCT (minimum 2 year follow-up) in individuals with diabetes aged 12 years or older registered with a single English screening programme. Participants were randomly allocated 1:1 at baseline to individualised screening at 6, 12 or 24 months for those at high, medium and low risk, respectively, as determined at each screening episode by a risk-calculation engine using local demographic, screening and clinical data, or to annual screening (control group). Screening staff and investigators were observer-masked to allocation and interval. Data were collected within the screening programme. The primary outcome was attendance (safety). A secondary safety outcome was the development of sight-threatening diabetic retinopathy. Cost-effectiveness was evaluated within a 2 year time horizon from National Health Service and societal perspectives. RESULTS: A total of 4534 participants were randomised. After withdrawals, there were 2097 participants in the individualised screening arm and 2224 in the control arm. Attendance rates at first follow-up were equivalent between the two arms (individualised screening 83.6%; control arm 84.7%; difference -1.0 [95% CI -3.2, 1.2]), while sight-threatening diabetic retinopathy detection rates were non-inferior in the individualised screening arm (individualised screening 1.4%, control arm 1.7%; difference -0.3 [95% CI -1.1, 0.5]). Sensitivity analyses confirmed these findings. No important adverse events were observed. Mean differences in complete case quality-adjusted life-years (EuroQol Five-Dimension Questionnaire, Health Utilities Index Mark 3) did not significantly differ from zero; multiple imputation supported the dominance of individualised screening. Incremental cost savings per person with individualised screening were £17.34 (95% CI 17.02, 17.67) from the National Health Service perspective and £23.11 (95% CI 22.73, 23.53) from the societal perspective, representing a 21% reduction in overall programme costs. Overall, 43.2% fewer screening appointments were required in the individualised arm. CONCLUSIONS/INTERPRETATION: Stakeholders involved in diabetes care can be reassured by this study, which is the largest ophthalmic RCT in diabetic retinopathy screening to date, that extended and individualised, variable-interval, risk-based screening is feasible and can be safely and cost-effectively introduced in established systematic programmes. Because of the 2 year time horizon of the trial and the long time frame of the disease, robust monitoring of attendance and retinopathy rates should be included in any future implementation. TRIAL REGISTRATION: ISRCTN 87561257 FUNDING: The study was funded by the UK National Institute for Health Research. Graphical abstract.

Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk.

Approximately half of all patients with type 2 diabetes (T2D) develop a certain degree of renal impairment. In many of them, chronic kidney disease (CKD) progresses over time, eventually leading to end-stage kidney disease (ESKD) requiring dialysis and conveying a substantially increased risk of cardiovascular morbidity and mortality. Even with widespread use of renin-angiotensin system blockers and tight glycemic control, a substantial residual risk of nephropathy progression remains. Recent cardiovascular outcomes trials investigating sodium-glucose cotransporter 2 (SGLT2) inhibitors have suggested that these therapies have renoprotective effects distinct from their glucose-lowering action, including the potential to reduce the rates of ESKD and acute kidney injury. Although patients in most cardiovascular outcomes trials had higher prevalence of existing cardiovascular disease compared with those normally seen in clinical practice, the proportion of patients with renal impairment was similar to that observed in a real-world context. Patient cardiovascular risk profiles did not relevantly impact the renoprotective benefits observed in these studies. Benefits were observed in patients across a spectrum of renal risk, but were evident also in those without renal damage, suggesting a role for SGLT2 inhibition in the prevention of CKD in people with T2D. In addition, recent studies such as CREDENCE and DAPA-CKD offer a greater insight into the renoprotective effects of SGLT2 inhibitors in patients with moderate-to-severe CKD. This review outlines the evidence that SGLT2 inhibitors may prevent the development of CKD and prevent and delay the worsening of CKD in people with T2D at different levels of renal risk.

Cardiovascular protection with sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: Does it apply to all patients?

Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease (CVD). Cardiovascular risk in these patients should be considered as a continuum, and comprehensive treatment strategies should aim to target multiple disease risk factors. Large-scale clinical trials of sodium-glucose co-transporter-2 (SGLT2) inhibitors have shown an impact on cardiovascular outcomes, including heart failure hospitalization and cardiovascular death, which appears to be independent of their glucose-lowering efficacy. Reductions in major cardiovascular events appear to be greatest in patients with established CVD, particularly those with prior myocardial infarction, but are independent of heart failure or renal risk. Most large-scale trials of SGLT2 inhibitors predominantly include patients with T2D with pre-existing CVD and high cardiovascular risk at baseline, limiting their applicability to patients typically observed in clinical practice. Real-world evidence from observational studies suggests that there might also be beneficial effects of SGLT2 inhibitors on heart failure hospitalization and all-cause mortality in various cohorts of lower risk patients. The most common adverse events reported in clinical and observational studies are genital infections; however, the overall risk of these events appears to be low and easily managed. Similar safety profiles have been reported for elderly and younger patients. There is still some debate regarding the safety of canagliflozin in patients at high risk of fracture and amputation. Outstanding questions include specific patterns of cardiovascular protection according to baseline risk.

Impact of Cardio-Renal-Metabolic Comorbidities on Cardiovascular Outcomes and Mortality in Type 2 Diabetes Mellitus.

BACKGROUND: We evaluated the incremental contribution of chronic kidney disease (CKD) to the risk of major adverse cardiovascular (CV) events (MACE), heart failure (HF), and all-cause mortality (ACM) in type 2 diabetes mellitus (T2DM) patients and its importance relative to the presence of other cardio-renal-metabolic (CaReMe) comorbidities. METHODS: Patients (≥40 years) were identified at the time of T2DM diagnosis from US (Humedica/Optum) and UK (Clinical Practice Research Datalink) databases. Patients were monitored post-diagnosis for modified MACE (myocardial infarction, stroke, ACM), HF, and ACM. Adjusted hazard ratios were obtained using Cox proportional-hazards regression to evaluate the relative risk of modified MACE, HF, and ACM due to CKD. Patients were stratified by the presence or absence of atherosclerotic CV disease (ASCVD) and age. RESULTS: Between 2011 and 2015, of 227,224 patients identified with incident T2DM, 40,063 (17.64%) had CKD. Regardless of prior ASCVD, CKD was associated with higher risk of modified MACE, HF, and ACM; this excess hazard was more pronounced in older patients with prior ASCVD. In time-to-event analyses in the overall cohort, patients with T2DM + CKD or T2DM + CKD + hypertension + hyperlipidemia had increased risks for modified MACE, HF, and ACM versus patients with T2DM and no CaReMe comorbidities. Patients with CKD had higher risks for and shorter times to modified MACE, HF, and ACM than those without CKD. CONCLUSION: In T2DM patients, CKD presence was associated with higher risk of modified MACE, HF, and ACM. This may have risk-stratification implications for T2DM patients based on background CKD and highlights the potential importance of novel renoprotective strategies.

Personalized risk-based screening for diabetic retinopathy: A multivariate approach versus the use of stratification rules.

AIMS: To evaluate our proposed multivariate approach to identify patients who will develop sight-threatening diabetic retinopathy (STDR) within a 1-year screen interval, and explore the impact of simple stratification rules on prediction. MATERIALS AND METHODS: A 7-year dataset (2009-2016) from people with diabetes (PWD) was analysed using a novel multivariate longitudinal discriminant approach. Level of diabetic retinopathy, assessed from routine digital screening photographs of both eyes, was jointly modelled using clinical data collected over time. Simple stratification rules based on retinopathy level were also applied and compared with the multivariate discriminant approach. RESULTS: Data from 13 103 PWD (49 520 screening episodes) were analysed. The multivariate approach accurately predicted whether patients developed STDR or not within 1 year from the time of prediction in 84.0% of patients (95% confidence interval [CI] 80.4-89.7), compared with 56.7% (95% CI 55.5-58.0) and 79.7% (95% CI 78.8-80.6) achieved by the two stratification rules. While the stratification rules detected up to 95.2% (95% CI 92.2-97.6) of the STDR cases (sensitivity) only 55.6% (95% CI 54.5-56.7) of patients who did not develop STDR were correctly identified (specificity), compared with 85.4% (95% CI 80.4-89.7%) and 84.0% (95% CI 80.7-87.6%), respectively, achieved by the multivariate risk model. CONCLUSIONS: Accurate prediction of progression to STDR in PWD can be achieved using a multivariate risk model whilst also maintaining desirable specificity. While simple stratification rules can achieve good levels of sensitivity, the present study indicates that their lower specificity (high false-positive rate) would therefore necessitate a greater frequency of eye examinations.

MECHANISMS IN ENDOCRINOLOGY: SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism?

Type 2 diabetes (T2D) is associated with inhibition of autophagic and lysosomal housekeeping processes that detrimentally affect key organ functioning; a process likely to be exacerbated by conventional insulin-driven anabolic therapies. We propose that the cardio-renal benefits demonstrated with sodium-glucose cotransporter-2 inhibitor (SGLT2i) treatment in T2D partly may be explained by their ability to drive consistent, overnight periods of increased catabolism brought about by constant glucosuria. Key steps driving this catabolic mechanism include: a raised glucagon/insulin ratio initially depleting glycogen in the liver and ultimately activating gluconeogenesis utilizing circulating amino acids (AAs); a general fuel switch from glucose to free fatty acids (accompanied by a change in mitochondrial morphology from a fission to a sustained fusion state driven by a decrease in AA levels); a decrease in circulating AAs and insulin driving inhibition of mammalian target of rapamycin complex 1 (mTORC1), which enhances autophagy/lysosomal degradation of dysfunctional organelles, eventually causing a change in mitochondrial morphology from a fission to a sustained fusion state. Resumption of eating in the morning restores anabolic biogenesis of new and fully functional organelles and proteins. Restoration of diurnal metabolic rhythms and flexibility by SGLT2is may have therapeutic implications beyond those already demonstrated for the cardio-renal axis and may therefore affect other non-diabetes disease states.

Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the EDITION clinical studies in people with type 2 diabetes.

AIMS: To investigate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) vs insulin glargine 100 U/mL (Gla-100) over 12 months in a patient-level meta-analysis, using data from the EDITION studies in people with type 2 diabetes (T2DM). METHODS: EDITION 1, 2 and 3 were multicentre, randomized, open-label, 2-arm, parallel-group, treat-to-target phase IIIa studies. Similar study designs and endpoints enabled a meta-analysis to be conducted. RESULTS: Reductions in glycated haemoglobin (HbA1c) were better sustained over 12 months with Gla-300 than with Gla-100 (least squares [LS] mean difference in change from baseline: -0.10 % [95% confidence interval {CI} -0.18 to -0.02] or -1.09 mmol/mol [95% CI -2.01 to -0.20]; P = .0174). Risk of confirmed (≤3.9 mmol/L) or severe hypoglycaemia was 15% lower with Gla-300 vs Gla-100 at night (relative risk 0.85 [95% CI 0.77-0.92]) and 6% lower at any time of day (relative risk 0.94 [95% CI 0.90-0.98]). Rates of hypoglycaemia were 18% lower with Gla-300 vs Gla-100 at night (rate ratio 0.82 [95% CI 0.67-0.99]), but comparable at any time of day. HbA1c <7.0 % without nocturnal hypoglycaemia was achieved by 24% more participants with Gla-300 than with Gla-100 (relative risk 1.24 [95% CI 1.03-1.50]). Severe hypoglycaemia was rare; in both treatment groups the incidence of events at any time of day was ≤3.6%, while rates were ≤0.08 events per participant-year. CONCLUSIONS: In a broad population of people with T2DM over 12 months, use of Gla-300 provided more sustained glycaemic control and significantly lower hypoglycaemia risk at night and at any time of day compared with Gla-100.

Cancer risks of anti-hyperglycemic drugs for type 2 diabetes treatment - a clinical appraisal.

AIM: A clinical appraisal of existing scientific literature sought to assess the need for long-term prospective epidemiological studies to investigate an increased cancer risk of anti-hyperglycemic medication in type 2 diabetes. METHOD: A focus statement was formulated as: "With a higher risk of cancers in patients with type 2 diabetes, all anti-hyperglycemic drugs should undergo long-term, prospective epidemiological studies for cancer risks." Field surveys were sent to practicing physicians and endocrinologists to identify the currently prevalent level of acceptance of this statement. Subsequently, a meeting with a six-member panel of key opinion leaders was held to discuss published evidence in support and against the statement. This publication reviews the publications and discussion points brought forth in this meeting and their effect on statement acceptance by the panel. RESULTS: Whereas the majority of field survey responders primarily agreed with the statement, panel members were divided in their statement support. This division remained intact after review of the literature. CONCLUSIONS: While there was evidence that type 2 diabetes is associated with an increased risk of cancer, existing studies seemed insufficient to definitively demonstrate a link between cancer risk and use of specific anti-hyperglycemic therapies.