An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria.

BACKGROUND: The FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany. METHODS: German patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2 OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared. RESULTS: Overall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT's albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible. CONCLUSIONS: Certain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.

iGlarLixi (insulin glargine 100 U/ml plus lixisenatide) is effective and well tolerated in people with uncontrolled type 2 diabetes regardless of age: A REALI pooled analysis of prospective real-world data.

AIM: To evaluate the effectiveness and safety in routine clinical practice of insulin glargine/lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) according to age. METHODS: Patient-level data were pooled from 1316 adults with T2D inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi for 24 weeks. Participants were classified into age subgroups of younger than 65 years (N = 806) and 65 years or older (N = 510). RESULTS: Compared with participants aged younger than 65 years, those aged 65 years or older had a numerically lower mean body mass index (31.6 vs. 32.6 kg/m2 ), a longer median diabetes duration (11.0 vs. 8.0 years), were more likely to receive prior basal insulin (48.4% vs. 43.5%) and had a lower mean HbA1c (8.93% [74.10 mmol/mol] vs. 9.22% [77.28 mmol/mol]). Similar and clinically relevant reductions in HbA1c and fasting plasma glucose from baseline to week 24 of iGlarLixi therapy were observed regardless of age. At 24 weeks, least-squares adjusted mean (95% confidence interval [CI]) change in HbA1c from baseline was -1.55% (-1.65% to -1.44%) in those aged 65 years or older and -1.42% (-1.50% to -1.33%) in those aged younger than 65 years (95% CI: -0.26% to 0.00%; P = .058 between subgroups). Low incidences of gastrointestinal adverse events and hypoglycaemic episodes were reported in both age subgroups. iGlarLixi decreased mean body weight from baseline to week 24 in both subgroups (-1.6 kg in those aged ≥ 65 years and -2.0 kg in those aged < 65 years). CONCLUSIONS: iGlarLixi is effective and well tolerated in both younger and older people with uncontrolled T2D.

Patient and physician perspectives and experiences of basal insulin titration in type 2 diabetes in the United States: Cross-sectional surveys.

AIM: Patient- and physician-associated barriers impact the effectiveness of basal insulin (BI) titration in the management of type 2 diabetes (T2D). We evaluated the experiences of patients with T2D and physicians with BI titration education. MATERIALS AND METHODS: In this observational, cross-sectional study, patients with T2D and physicians treating patients with T2D were identified by claims in the Optum Research Database and were invited to complete a survey. Eligible patients had 12 months of continuous health-plan enrolment with medical and pharmacy benefits during the baseline period, and recent initiation of BI therapy. Eligible physicians had initiated BI for ≥1 eligible patient with T2D during the past 6 months. RESULTS: In total, 416 patients and 386 physicians completed the survey. Ninety per cent of physicians reported treating ≥50 patients with T2D; 66% treated ≥25% of patients with BI. Whereas 74% of patients reported that BI titration was explained to them by a physician, 96% of physicians reported doing so. Furthermore, 20% of patients stated they were offered educational materials whereas 56% of physicians reported having provided materials. Physicians had higher expectations of glycaemic target achievement than were seen in the patient survey; their main concern was the patients' ability to titrate accurately (79%). CONCLUSIONS: There is a marked difference in patients' and physicians' experiences of BI titration education. Novel tools and strategies are required to enable effective BI titration, with more educational resources at the outset, and ongoing access to tools that provide clear, simple direction for self-titration with less reliance on physicians/health care providers.

Validation of a risk prediction model for early chronic kidney disease in patients with type 2 diabetes: Data from the German/Austrian Diabetes Prospective Follow-up registry.

AIM: To validate a recently proposed risk prediction model for chronic kidney disease (CKD) in type 2 diabetes (T2D). MATERIALS AND METHODS: Subjects from the German/Austrian Diabetes Prospective Follow-up (DPV) registry with T2D, normoalbuminuria, an estimated glomerular filtration rate of 60 ml/min/1.73m2 or higher and aged 39-75 years were included. Prognostic factors included age, body mass index (BMI), smoking status and HbA1c. Subjects were categorized into low, moderate, high and very high-risk groups. Outcome was CKD occurrence. RESULTS: Subjects (n = 10 922) had a mean age of 61 years, diabetes duration of 6 years, BMI of 31.7 kg/m2 , HbA1c of 6.9% (52 mmol/mol); 9.1% had diabetic retinopathy and 16.3% were smokers. After the follow-up (~59 months), 37.4% subjects developed CKD. The area under the curve (AUC; unadjusted base model) was 0.58 (95% CI 0.57-0.59). After adjustment for diabetes and follow-up duration, the AUC was 0.69 (95% CI 0.68-0.70), indicating improved discrimination. After follow-up, 15.0%, 20.1%, 27.7% and 40.2% patients in the low, moderate, high and very high-risk groups, respectively, had developed CKD. Increasing risk score correlated with increasing cumulative risk of incident CKD over a median of 4.5 years of follow-up (P < .0001). CONCLUSIONS: The predictive model achieved moderate discrimination but good calibration in a German/Austrian T2D population, suggesting that the model may be relevant for determining CKD risk.

Identification of predictive factors of diabetic ketoacidosis in type 1 diabetes using a subgroup discovery algorithm.

AIM: To identify predictive factors for diabetic ketoacidosis (DKA) by retrospective analysis of registry data and the use of a subgroup discovery algorithm. MATERIALS AND METHODS: Data from adults and children with type 1 diabetes and more than two diabetes-related visits were analysed from the Diabetes Prospective Follow-up Registry. Q-Finder, a supervised non-parametric proprietary subgroup discovery algorithm, was used to identify subgroups with clinical characteristics associated with increased DKA risk. DKA was defined as pH less than 7.3 during a hospitalization event. RESULTS: Data for 108 223 adults and children, of whom 5609 (5.2%) had DKA, were studied. Q-Finder analysis identified 11 profiles associated with an increased risk of DKA: low body mass index standard deviation score; DKA at diagnosis; age 6-10 years; age 11-15 years; an HbA1c of 8.87% or higher (≥ 73 mmol/mol); no fast-acting insulin intake; age younger than 15 years and not using a continuous glucose monitoring system; physician diagnosis of nephrotic kidney disease; severe hypoglycaemia; hypoglycaemic coma; and autoimmune thyroiditis. Risk of DKA increased with the number of risk profiles matching patients' characteristics. CONCLUSIONS: Q-Finder confirmed common risk profiles identified by conventional statistical methods and allowed the generation of new profiles that may help predict patients with type 1 diabetes who are at a greater risk of experiencing DKA.

Local, collaborative, stepped, and personalized care management for older people with chronic diseases - results from the randomized controlled LoChro-trial.

BACKGROUND: In the aging population of Western societies, an increasing number of older adults have multiple chronic diseases. As multifaceted health problems imply the involvement of several healthcare professionals, multimorbid older people frequently face a fragmentation of health care. Addressing these challenges, we developed a local, collaborative, stepped, and personalized care management approach (LoChro-Care) and evaluated its effectiveness. METHODS: A two-group, parallel randomized controlled trial was conducted comparing LoChro-Care recipients (IG) to participants with usual care (CG). Patients aged 65 + with chronic conditions were recruited at inpatient and outpatient departments of the Medical Center, University of Freiburg. Participants were allocated using block randomization (nIG = 261, nCG = 263). LoChro-Care comprised individualized care provided by chronic care managers with 7 to 13 contacts over 12 months. Questionnaires were given at 3 time points (T0: baseline, T1: after 12 months, T2: after 18 months). The primary outcome was the physical, psychological, and social health status represented by a composite score of functional health and depressive symptoms. Secondary outcomes were the participants' evaluation of their health care situation, health-related quality of life (HRQL), and life-satisfaction (LS). The data were analyzed using linear mixed modelling. RESULTS: We analyzed N = 491 participants (nIG = 244, nCG = 247), aged M = 76.78 years (SD = 6.35). For the composite endpoint, neither a significant difference between IG and CG (p = .88) nor a group-time interaction (p = .52; p = .88) could be observed. Participants in both groups showed a significant decline on the primary outcome between T0 and T2 (p < .001). Post hoc analyses revealed a decline in both functional health (p < .001) and depressive symptoms (p = .02). Both groups did not differ in their evaluation of their health care situation (p = .93), HRQL (p = .44) or LS (p = .32). Relevant confounding variables were female gender and multimorbidity. CONCLUSION: Supporting patients' self-management in coordinating their individual care network through LoChro-Care did not result in any significant effect on the primary and secondary outcomes. A decline of functional health and depressive symptoms was observed among all participants. Potential future intervention adaptations are discussed, such as a more active case management through direct referral to (in-)formal support, an earlier treatment initiation, and the consideration of specific sociodemographic factors in care management planning. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00013904 (02.02.2018), https://drks.de/search/de/trial/DRKS00013904.

Switching the basal insulin to insulin glargine 300 U/ml in people with type 2 diabetes under basal insulin supported oral therapy: Observational trial on effectiveness and safety.

AIMS: This study evaluated the effectiveness and safety of switching the basal insulin (BI) in a BI-supported oral therapy (BOT) to insulin glargine 300 U/ml (Gla-300) in adults with inadequately controlled type 2 diabetes (T2D). MATERIALS AND METHODS: This was a non-interventional, multicentre, prospective 12-month study, conducted in Germany, Austria and Switzerland. The study documented people with T2D with glycated haemoglobin (HbA1c) between 7.5% and 10.0%, currently treated by a non-Gla-300 BOT regimen, after the physician had decided to switch the BI to Gla-300. Primary endpoint was the proportion of patients achieving the fasting plasma glucose (FPG; ≤110 mg/dl) target. RESULTS: In total, 1194 participants comprised the full analysis set, of which 793 completed documentation of 12 months Gla-300 treatment (FAS-M12). The main previous BI was insulin glargine 100 U/ml (Gla-100; 47.2%). Twelve months after switching to Gla-300, 27.0% of FAS-M12 participants achieved the FPG target and 44.8% their individualized HbA1c target. The greatest FPG target achievements were seen in previous Gla-100 (29.3%), and greatest HbA1c target achievements in previous insulin detemir users (57.7%). The mean FPG decreased by -36.3 ± 51.2 mg/dl to 135.5 ± 36.9 mg/dl and mean HbA1c by -0.79 ± 1.01% to 7.45 ± 0.94%. Symptomatic and nocturnal hypoglycaemia incidence significantly decreased over 12 months of Gla-300 treatment. Body weight remained unchanged. CONCLUSIONS: Switching the BI to Gla-300 in a BOT regimen improved metabolic control and treatment satisfaction in a substantial proportion of patients with T2D and inadequate target achievement within 12 months in clinical practice with a decreased risk of symptomatic and nocturnal hypoglycaemia and without weight gain.

Elevated liver enzymes and comorbidities in type 2 diabetes: A multicentre analysis of 51 645 patients from the Diabetes Prospective Follow-up (DPV) database.

AIM: To assess the prevalence of elevated liver enzymes and associated diabetes-related comorbidities in type 2 diabetes (T2D). SUBJECTS AND METHODS: Between 2010 and 2019, 281 245 patients with T2D (aged 18-75 years) from 501 Diabetes Prospective Follow-up (DPV) centres were evaluated, resulting in analysis of 51 645 patients with complete data on demographics and liver enzymes. RESULTS: Elevated liver enzymes were found in 40.2% of all patients. However, only 8.6% of these patients had International Classification of Diseases-10 codes for nonalcoholic fatty liver disease and/or nonalcoholic steatohepatitis. Adjusted for age, sex, diabetes duration, body mass index and glycated haemoglobin, a higher prevalence of arterial hypertension (P < 0.0001), dyslipidaemia (P < 0.0001), peripheral artery disease (P = 0.0029), myocardial infarction (P = 0.0003), coronary artery disease (P = 0.0001), microalbuminuria (P < 0.0001) and chronic kidney disease (P < 0.0001) was seen in patients with elevated versus normal liver enzymes. The prevalence of elevated liver enzymes was lowest in patients receiving sodium-glucose cotransporter-2 (SGLT2) inhibitors or a combination of SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists. CONCLUSION: Elevated liver enzymes are common in patients with T2D and clearly correlate with a higher prevalence of clinically relevant comorbidities. Assessing liver enzymes should be standard clinical routine in T2D due to a possible predictive role for comorbidities and complications.

Disease heterogeneity of adult diabetes based on routine clinical variables at diagnosis: Results from the German/Austrian Diabetes Follow-up Registry.

AIM: To cluster adults with diabetes using variables from real-world clinical care at manifestation. MATERIALS AND METHODS: We applied hierarchical clustering using Ward's method to 56 869 adults documented in the prospective Diabetes Follow-up Registry (DPV). Clustering variables included age, sex, body mass index (BMI), HbA1c, diabetic ketoacidosis (DKA), components of the metabolic syndrome (hypertension/dyslipidaemia/hyperuricaemia) and beta-cell antibody status. Time until use of oral antidiabetic drugs (OADs), use of insulin, chronic kidney disease (CKD), cardiovascular disease (CVD), retinopathy or neuropathy were assessed using Kaplan-Meier analysis and Cox regression models. RESULTS: We identified eight clusters: four clusters comprised early diabetes onset (median age 40-50 years) but differed with regard to BMI, HbA1c, DKA and antibody positivity. Two clusters included adults with diabetes onset aged in their early 60s who met target HbA1c, but differed in BMI and sex distribution. Two clusters were characterized by late diabetes onset (median age 69 and 77 years) and comparatively low BMI, but differences in HbA1c. Earlier insulin use was observed in adults with high HbA1c, and earlier OAD use was observed in those with high BMI. Time until CKD or CVD was shorter in those with late onset, whereas retinopathy occurred earlier in adults with late onset and high HbA1c, and in adults with early onset, but high HbA1c and high percentage of antibody positivity. CONCLUSIONS: Adult diabetes is heterogeneous beyond classical type 1/type 2 diabetes, based on easily available variables in clinical practice using an automated clustering algorithm that allows both continuous and binary variables.

PCSK9 inhibition and cholesterol homeostasis in insulin producing ß-cells.

Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathology of atherosclerotic cardiovascular disease. For decades, the gold standard for LDL-C lowering have been statins, although these drugs carry a moderate risk for the development of new-onset diabetes. The inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged in the last years as potential alternatives to statins due to their high efficiency and safety without indications for a diabetes risk so far. Both approaches finally eliminate LDL-C from bloodstream by upregulation of LDL receptor surface expression. Due to their low antioxidant capacity, insulin producing pancreatic ß-cells are sensitive to increased lipid oxidation and related generation of reactive oxygen species. Thus, PCSK9 inhibition has been argued to promote diabetes like statins. Potentially, the remaining patients at risk will be identified in the future. Otherwise, there is increasing evidence that loss of circulating PCSK9 does not worsen glycaemia since it is compensated by local PCSK9 expression in ß-cells and other islet cells. This review explores the situation in ß-cells. We evaluated the relevant biology of PCSK9 and the effects of its functional loss in rodent knockout models, carriers of LDL-lowering gene variants and PCSK9 inhibitor-treated patients.

[Complaints and clinical findings six months after COVID-19: outpatient follow-up at the University Medical Center Freiburg]. / Persistierende Beschwerden 6 Monate nach COVID-19 ­ Erfahrungen aus der COVID-19-Nachsorgeambulanz des Universitätsklinikums Freiburg.

BACKGROUND: Increasing evidence suggests that some patients suffer from persistent symptoms for months after recovery from acute COVID-19. However, the clinical phenotype and its pathogenesis remain unclear. We here present data on complaints and results of a diagnostic workup of patients presenting to the post-COVID clinic at the University Medical Center Freiburg. METHODS: Retrospective data analysis of persistently symptomatic patients presenting to our clinic at least 6 months after onset of acute COVID-19. All patients were assessed by a doctor and routine laboratory analysis was carried out. Quality of life was assessed using SF-36 questionnaire. In case of specific persisting symptoms, further organ-specific diagnostic evaluation was performed, and patients were referred to respective departments/specialists. FINDINGS: 132 Patients (58 male, 74 female; mean age 53.8 years) presented to our clinic at least 6 months after COVID-19. 79 (60 %) had been treated as outpatients and 53 (40 %) as inpatients. Most common complaints were persistent fatigue (82 %) and dyspnea on exertion (61 %). Further common complaints were impairments of concentration (54 %), insomnia (43 %), and impairments of smell or taste (35 %). Quality of life was reduced in all sections of the SF-36 questionnaire, yielding a reduced working capacity. Significant pathological findings in laboratory, echocardiographic and radiological work-up were rare. Impairments in lung function tests were more common in previously hospitalized patients. CONCLUSION: Patients presenting 6 months after onset of acute COVID-19 suffer from a diverse spectrum of symptoms with impaired quality of life, also referred to as Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Further research is needed to determine the frequency of these post-COVID syndromes and their pathogenesis, natural course and treatment options. Evaluation and management should be multi-disciplinary.

The SAGE study: Global observational analysis of glycaemic control, hypoglycaemia and diabetes management in T1DM.

AIMS: To describe glycaemic control and diabetes management in adults with type 1 diabetes (T1DM), in a real-life global setting. MATERIALS AND METHODS: Study of Adults' GlycEmia (SAGE) was a multinational, multicentre, single visit, noninterventional, cross-sectional study in adult patients with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64 and ≥65 years) and reported across different regions. The primary endpoint was the proportion of participants achieving HbA1c  less than 7.0 % in each age group. Secondary endpoints included incidence of hypoglycaemia, severe hypoglycaemia and severe hyperglycaemia leading to diabetic ketoacidosis (DKA) and therapeutic management of T1DM. RESULTS: Of 3903 included participants, 3858 (98.8%) were eligible for the study. Overall, 24.3% (95% confidence interval [CI]: 22.9-25.6) of participants achieved the glycaemic target of HbA1c  less than 7.0 %, with more participants achieving this target in the 26-44 years group (27.6% [95% CI: 25.5-29.8]). Target achievement was highest in Eastern and Western Europe, and lowest in the Middle East. The incidence of hypoglycaemia and of severe hyperglycaemia leading to DKA tended to decrease with age, and varied across regions. Age and regional differences were observed in therapeutic management, including types of device/insulin usage, frequency of insulin dose adjustment and technology usage. CONCLUSIONS: Glycaemic control remains poor in adults with T1DM globally. Several areas of treatment may be optimised to improve outcomes, including supporting patient self-management of insulin therapy, increasing use of technologies such as CGM, and greater provision of healthcare support.

Licogliflozin versus placebo in women with polycystic ovary syndrome: A randomized, double-blind, phase 2 trial.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and insulin resistance. The dual sodium-glucose co-transporter 1/2 inhibitor (SGLT1/2i) licogliflozin (LIK066) ameliorates hyperinsulinism in patients with diabetes and obesity. This study examines the effect of licogliflozin on androgens in women with PCOS. In a multicentre, randomized, placebo-controlled, double-blind, 2-week trial, patients with PCOS received licogliflozin 50 mg or placebo three times a day (TID). Changes in free testosterone (FT), other androgens and variables of insulin resistance were analysed. Concentration of FT did not change (TRLIK066 :TRPCB [FT]: 0.88; 90% CI: 0.70-1.11; P = .353). Licogliflozin reduced androstendione (A4) by 19% (TRLIK066 :TRPCB [A4]: 0.81; 90% CI: 0.68-0.99; P = .089) and dehydroepiandrosteron sulphate (DHEAS) by 24% (TRLIK066 :TRPCB [DHEAS]: 0.76; 90% CI: 0.65-0.89; P = .008). Hyperinsulinaemia was reduced by 70% by licogliflozin (highest insulin concentration [MAXI]; TRLIK066 :TRPCB [MAXI]: 0·26; 90% CI:0.20-0.34; P < .001 and area under the curve insulin [AUCI]; TRLIK066 :TRPCB [AUCI]: 0.32; 90% CI: 0.25-0.41; P < .001). Diarrhoea and nausea occurred as common adverse events. Dual inhibition of SGLT1/2 ameliorates hyperinsulinaemia and hyperandrogenaemia in women with PCOS. Licogliflozin may represent a promising novel treatment option for PCOS.

Patient-reported outcomes in adults with type 1 diabetes in global real-world clinical practice: The SAGE study.

AIMS: To conduct a secondary analysis of the SAGE study to evaluate the association between glycaemic control and patient-reported outcomes (PROs), in adults with type 1 diabetes (T1DM) across different age groups and regions. MATERIALS AND METHODS: SAGE was a multinational, cross-sectional, observational study in adults with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64, and ≥65 years), and reported across different regions. PRO questionnaires were applied to assess hypoglycaemia fear (Hypoglycemia Fear Survey-II), diabetes-related distress (Problem Areas In Diabetes questionnaire), insulin treatment satisfaction (Insulin Treatment Satisfaction Questionnaire), and diabetes-specific quality of life (QoL; Audit of Diabetes-Dependent Quality of Life). Multivariable analysis was performed to evaluate the relationship between glycated haemoglobin (HbA1c) target achievement (<7% and individualised targets) with PRO scores. RESULTS: The PRO scores showed relatively low levels of diabetes-related emotional distress and fear of hypoglycaemia, moderate to high treatment satisfaction, and low diabetes-related impact on QoL. Results were generally comparable across age groups with some regional variability. Achievement of the HbA1c <7% target was associated with less worry about hypoglycaemia, lower diabetes-related emotional distress, higher insulin treatment satisfaction, and higher QoL. Achievement of individualised HbA1c targets was associated with lower diabetes-related emotional distress and higher insulin treatment satisfaction. CONCLUSIONS: Better glycaemic control was most closely associated with low emotional distress due to diabetes and high patient-reported insulin treatment satisfaction.

Guidelines adherence in the prevention and management of chronic kidney disease in patients with diabetes mellitus on the background of recent European recommendations - a registry-based analysis.

BACKGROUND: Recent European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) guidelines provide recommendations for detecting and treating chronic kidney disease (CKD) in diabetic patients. We compared clinical practice with guidelines to determine areas for improvement. METHODS: German database analysis of 675,628 patients with type 1 or type 2 diabetes, with 134,395 included in this analysis. Data were compared with ESC/EASD recommendations. RESULTS: This analysis included 17,649 and 116,747 patients with type 1 and type 2 diabetes, respectively. The analysis showed that 44.1 and 49.1 % patients with type 1 and type 2 diabetes, respectively, were annually screened for CKD. Despite anti-diabetic treatment, only 27.2 % patients with type 1 and 43.5 % patients with type 2 achieved a target HbA1c of < 7.0 %. Use of sodium-glucose transport protein 2 inhibitors (1.5 % type 1/8.7 % type 2 diabetes) and glucagon-like peptide-1 receptor agonists (0.6 % type 1/5.2 % type 2 diabetes) was limited. Hypertension was controlled according to guidelines in 41.1 and 67.7 % patients aged 18-65 years with type 1 and 2 diabetes, respectively, (62.4 vs. 68.4 % in patients > 65 years). Renin angiotensin aldosterone inhibitors were used in 24.0 and 40.9 % patients with type 1 diabetes (micro- vs. macroalbuminuria) and 39.9 and 47.7 %, respectively, in type 2 diabetes. CONCLUSIONS: Data indicate there is room for improvement in caring for diabetic patients with respect to renal disease diagnosis and treatment. While specific and potentially clinically justified reasons for non-compliance exist, the data may serve well for a critical appraisal of clinical practice decisions.

NUPR1 preserves insulin secretion of pancreatic ß-cells during inflammatory stress by multiple low-dose streptozotocin and high-fat diet.

Obesity is associated with dyslipidemia and subclinical inflammation that promotes metabolic disturbances including insulin resistance and pancreatic ß-cell dysfunction. The nuclear protein, transcriptional regulator 1 (NUPR1) responds to cellular stresses and features tissue protective properties. To characterize the role of NUPR1 in endocrine pancreatic islets during inflammatory stress, we generated transgenic mice with ß-cell-specific Nupr1 overexpression (ßNUPR1). Under normal conditions, ßNUPR1 mice did not differ from wild type (WT) littermates and display normal glucose homeostasis and ß-cell mass. For induction of inflammatory conditions, mice were treated with multiple low-dose streptozotocin (mld-STZ) and/or fed a high-fat diet (HFD). All treatments significantly worsened glycaemia in WT mice, while ßNUPR1 mice substantially preserved insulin secretion and glucose tolerance. HFD increased ß-cell mass in all animals, with ßNUPR1 mice tending to show higher values. The improved outcome of ßNUPR1 mice was accompanied by decreased NF-κB activation and lymphocyte infiltration in response to mld-STZ. In vitro, isolated ßNUPR1 islets preserved insulin secretion and content with insignificantly low apoptosis during culture stress and IL-1ß exposure. These findings suggest that NUPR1 plays a vital role in the protection of ß-cells from apoptosis, related degradation of insulin storages and subsequent secretion during inflammatory and obesity-related tissue stress.

Effectiveness and safety of insulin glargine 300 U/mL in insulin-naïve patients with type 2 diabetes after failure of oral therapy in a real-world setting.

AIM: To evaluate the effectiveness and safety of initiating basal insulin-supported oral therapy (BOT) with insulin glargine 300 U/mL (Gla-300) in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs (OADs). MATERIALS AND METHODS: This non-interventional, multi-centre, prospective 52-week study, conducted in Germany and Switzerland, documented patients with type 2 diabetes with an HbA1c of between 7.5% and 10.0%, currently treated with OADs, after the physician had decided to start a BOT regimen with Gla-300. The primary endpoint was the rate of achievement of the individualized predefined HbA1c target. RESULTS: Of 1748 patients included, 1153 comprised the full analysis set, of whom 721 completed documentation of 12 months of Gla-300 treatment. Twelve months after starting Gla-300, 49.9% achieved their individualized HbA1c target, and 61.1% achieved either their HbA1c target or a fasting plasma glucose (FPG) of ≤110 mg/dL. Mean HbA1c decreased by -1.22% ± 1.05% to 7.28% ± 0.92% and mean FPG by -51.5 (±48.63) mg/dl to 132.9 ± 33.0 mg/dL. Median duration of HbA1c target achievement was 341 days and probability to remain on target after 6 months was 81%. Hypoglycaemia incidence and rates remained low after 12 months of Gla-300 treatment; no severe or severe nocturnal hypoglycaemia was observed. Body weight remained unchanged. CONCLUSIONS: Starting a BOT regimen with Gla-300 allowed about 60% of 721 German and Swiss patients with inadequately controlled type 2 diabetes to achieve glycaemic control within 12 months in daily clinical practice. Glycaemic control was achieved without weight gain or increased risk of nocturnal or severe hypoglycaemia.

Similar glycaemic control and less hypoglycaemia during active titration after insulin initiation with glargine 300 units/mL and degludec 100 units/mL: A subanalysis of the BRIGHT study.

AIM: To further investigate glycaemic control and hypoglycaemia in BRIGHT, focusing on the titration period. MATERIALS AND METHODS: BRIGHT was a multicentre, open-label, randomized, active-controlled, two-arm, parallel-group, 24-week study in insulin-naïve patients with uncontrolled type 2 diabetes initiated on glargine 300 U/mL (Gla-300) (N = 466) or degludec (IDeg-100) (N = 463). Predefined efficacy and safety outcomes were investigated during the initial 12-week titration period. In addition, patients' characteristics and clinical outcomes were assessed descriptively, stratified by confirmed (≤3.9 mmol/L) hypoglycaemia incidence during the initial titration period. RESULTS: At week 12, HbA1c was comparable between Gla-300 (7.32%) and IDeg-100 (7.23%), with similar least squares (LS) mean reductions from baseline (-1.37% and - 1.39%, respectively; LS mean difference of 0.02; 95% confidence interval: -0.08 to 0.12). Patients who experienced hypoglycaemia during the initial titration period had numerically greater HbA1c reductions by week 12 than patients who did not (-1.46% vs. -1.28%), and higher incidence of anytime (24 hours; 73.3% vs. 35.7%) and nocturnal (00:00-06:00 hours; 30.0% vs. 11.9%) hypoglycaemia between weeks 13-24. CONCLUSIONS: The use of Gla-300 resulted in similar glycaemic control as IDeg-100 during the initial 12-week titration period of the BRIGHT study, when less anytime (24 hours) hypoglycaemia with Gla-300 versus IDeg-100 has been reported. Experiencing hypoglycaemia shortly after initiating Gla-300 or IDeg-100 may be associated with hypoglycaemia incidence in the longer term, potentially impacting glycaemic management.

Renal function deterioration in adult patients with type-2 diabetes.

BACKGROUND: To explore, in a large group of patients with type-2 diabetes (T2DM), renal function decline in terms of the slope of the estimated glomerular filtration rate (eGFR) over time, and to find out how classical risk factors, such as the presence of hypertension, dyslipidemia and microalbuminuria, affect the renal function. METHODS: The analysis included 32,492 adult T2DM patients from the DIVE/DPV registries who had serial eGFR determinations and information on the presence of microalbuminuria, hypertension and dyslipidemia available. RESULTS: Patients had a mean age of 66.3 years, 52.6% were male with a mean BMI of 31.7 kg/m2. The mean eGFR was 78.4 ± 21.4 mL/min/1.73m2. The results showed that the prevalence of renal function impairment understood as chronic kidney disease (CKD) is considerable (53.0%) in a population of patients with T2DM and has a high incidence rate of 6.6% within a year. Serial determinations of the eGFR are, however, infrequent (7.8% of all patients) and these patients are characterised by the presence of a high-risk profile for CKD, such as hypertension (88.1%) and dyslipidemia (66.1%). Over a three-year time period, 30.9% of the patients had an eGFR slope of -12 mL/min/1.73m2 or more; and more than a doubled proportion of patients with an eGFR < 30 mL/min/1.73 m2 (3.8% vs. 1.8%; p < 0.001). Hypertension and albuminuria contributed to renal function decline while dyslipidemia did not negatively affect the slope. CONCLUSION: CKD is highly prevalent in patients with T2DM. Serial surveillance of the glomerular filtration rate is, however, not established in clinical practice, which would be necessary as indicated by a doubling of patients with an eGFR < 30 mL/min/1.73 m2 within 3 years. Moreover, the use of renin-angiotensin blocking agents was low, pointing at considerable room for improvement. Taken together we conclude that a closer surveillance of patients with diabetes based on the presence of further risk factors is mandatory combined with a mandatory prescription of RAS blocking agents once microalbuminuria and / or renal function deterioration develops.

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

BACKGROUND: Regulatory guidance specifies the need to establish cardiovascular safety of new diabetes therapies in patients with type 2 diabetes in order to rule out excess cardiovascular risk. The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown. METHODS: We randomly assigned 3297 patients with type 2 diabetes who were on a standard-care regimen to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary composite outcome was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. We hypothesized that semaglutide would be noninferior to placebo for the primary outcome. The noninferiority margin was 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio. RESULTS: At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both. The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority). Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12); nonfatal stroke occurred in 1.6% and 2.7%, respectively (hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P=0.04). Rates of death from cardiovascular causes were similar in the two groups. Rates of new or worsening nephropathy were lower in the semaglutide group, but rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher (hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P=0.02). Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal. CONCLUSIONS: In patients with type 2 diabetes who were at high cardiovascular risk, the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke was significantly lower among patients receiving semaglutide than among those receiving placebo, an outcome that confirmed the noninferiority of semaglutide. (Funded by Novo Nordisk; SUSTAIN-6 ClinicalTrials.gov number, NCT01720446 .).