Current EASD/ADA and KDIGO Guidelines for Treating Type 2 Diabetes with CKD

Wanner C, presented a session on “Current EASD/ADA and KDIGO Guidelines for Treating Type 2 Diabetes with CKD” at Virtual EASD Annual Meeting 2021 on 1st October 2021.

The guideline recommendations have various grading and level of evidence which are important to consider when applying the guideline recommendations. Grade A denotes that the true effect lies close to that of the estimate of the effect. Grade B denotes that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Grade C denotes that the true effect may be substantially different from the estimate of the effect. Grade D denotes that the estimate of effect is very uncertain, and often will be far from truth. The KDIGO defines five levels of glomerular filtration rate basis which the severity of kidney disease is assessed. The five levels are G1: ≤ 90 mL/min/1.73m2; G2: 60-89 mL/min/1.73m2; G3a: 45-59 mL/min/1.73m2: G3b: 30-44 mL/min/1.73m2; G4: 15-29 mL/min/1.73m2; G5: <15 mL/min/1.73m2.

Risk assessment of patients with CKD and without diabetes or ASCVD classifies patients into high risk and very high-risk patients. The kidney heart risk factor management pyramid is built on the foundation of lifestyle modifications which is common for all patient’s such as exercise, nutrition, smoking cessation, and management of co-morbidities like glycemic control, blood pressure control, and lipid management. Use of medications like SGLT2 inhibitors and RAS blockade is given in majority of patients whereas antiplatelet therapies is given in only some patients. It is recommended that patients with hyper-filtration and diabetes are treated in an individualized manner targeting a SBP to 130 mmHg and  <130 mmHg if tolerated, but not  <120 mmHg. In older people (aged <65 years) the SBP goal is to a range of 130-139 mmHg. A RAAS blocker is recommended for treatment of hypertension in patients with diabetes particularly in the presence of proteinuria, microalbuminuria, or LVH. Tight glucose control targeting HbA1c (<7.0% or < 53 mmol/mol) is recommended to decrease microvascular complications in patients with diabetes. Anti-hyperglycemic therapies in patients with diabetes and CKD includes metformin as the first-line treatement for hyperglycemia in patients with Type 2 diabetes and CKD and eGFR ≥ 30 mL/min/1.73m2. In patients with type 2 diabetes, CKD, and eGFR 30 including an SGLT-2 inhibitor in the antihyperglycemic treatment regimen is recommended. Treatment with an SGLT2 inhibitor (empagliflozin, canagliflozin or dapagliflozin) is associated with a lower risk of renal endpoints and is recommended if eGFR is 30 to < 90 mL/min/1.73m2.

The pillar of management of chronic kidney disease in type 2 diabetes currently stands on lifestyle modifications, reduction in salt intake, glucose and blood pressure control and use of drugs like ACE inhibitor, ARB, SGLT2-inhibitors and MRAs like Finerenone.


Treatment of Hyperglycaemia in ICU: Tight or Not Too Tight?

Van den Berghe G, presented a session on “Treatment of hyperglycaemia in icu: Tight or not too tight?” at Virtual EASD Annual Meeting 2021 on 1st October 2021.

Strict blood glucose control with intensive insulin therapy leads to improved leukocyte function, reduced inflammation, improved cardiac contractility, prevented dyslipidemia, improved liver, kidney mitochondrial ultrastructure and function, protection of central and peripheral nervous system. Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit. Other studies conducted in critically ill patients suggested use of intensive insulin therapy is associated with lower blood glucose levels causing reduced occurences of new kidney injury.

In a prospective, randomised controlled study, we enrolled 700 critically ill patients, 317 infants (aged <1 year) and 383 children (aged >or=1 year), who were admitted to the paediatric intensive care unit (PICU) it was seen that the mean blood glucose concentrations were lower in the intensive group than in the conventional group. Age-adjusted glucose control in PICY lead to shorter ICU stay, reduced inflammation, protection of the heart, and fewer ICU infections. In an another study, despite high incidence of hypoglycemia in PICU study the number of patients with hypoglycemia < 40 mg/dL were 1.4% in usual care and 24.9% in the tight glucose control group. In the NICE-sugar trial an international, randomized trial, it was seen that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. Moreover, no difference in organ function with more cardiovascular deaths and 13 times greater risk of hypoglycemia was noted. This has been attributed to lack of early parenteral nutrition in critically ill patients. Few studies have shown harm from early parenteral nutrition in critically ill patients. No blood glucose control plus early parenteral nutrition leads to reduced mortality and reduced organ failure. Early parenteral nutrition plus blood glucose < 110 mg/dL and late parenteral nutrition plus blood glucose < 110 mg/dL leads to enhanced recovery.

There is a need to redo the randomised clinical trials on strict blood glucose control (80-110 mg/dl vs. tolerating hyperglycemia upto 215 mg/dl) in multiple centers, in the context of no early parenteral nutrition with use of accurate sensors and guided by the LOGIC-insulin algorithm. The “TGC-fast” RCT is recruiting currently ± 8000 patients have been included, aiming for ± 9600 patients by next year.


Care of People with Diabetes Post COVID-19 in Primary Care

Khunti K, presented a session “Care of People with Diabetes Post COVID-19 in Primary Care” at Virtual EASD Annual Meeting 2021 on 1st October 2021. In individuals with COVID-19, the presence of co-morbidities, such as diabetes is associated with increased risk of severe COVID-19. Meta-analyses results for prevalence of co-morbidities and increased risk mortality and severity of disease by co-morbidities in COVID-19 patients. The most common co-occurring chronic diseases were diabetes, cardiovascular disease and stroke with multimorbidity and tested positive for COVID-19. In the practical recommendations for the management of diabetes in patients with COVID-19, outpatient care recommendations states caution of discontinuation of established therapy and utilisation of telemedicine and connected health models if possible to maintain maximal self-containment. A meta-analysis revealed a significantly reduced odd for mortality with the use of metformin in patients with diabetes and COVID-19. A nationwide observational study in England, several glucose lowering treatments such as DPP4I, GLP-1RAs, Metformin, SGLT2i, showed significant effects in decreasing risk of COVID-19 mortality in T2DM patients. DARE-19 trial, a phase 3 trial showed that Dapagliflozin had significant reduction in cardiometabolic risk factors in hospitalised patients with COVID-19. A population based study of England states that risk of COVID-19 related mortality risk was significantly associated with preceding levels of hyperglycemia in T1D and T2D patients. During COVID-19 pandemic, people with diabetes have perceived physical and psychological problems. For the chronic disease management during the pandemic, regular contact with primary care is important, to ensure that comorbidities are actively treated and risk factors are controlled, and to improve adherence to medical therapies. COVID and infection control measures necessitated new models of care mean that remote consultations (online, telephone or video) have replaced face-to-face consultations with primary health care professional. The proportion of newly diagnosed diabetes is also significantly increased in COVID-19 patients indicated by review and meta-analysis studies.

The specific consideration such as inpatient/outpatient services, routine diabetes care, foot and pregnancy services for people with disabilities, etc. should be implemented in the routine care of people with diabetes post-pandemic. Vaccine induces a weaker immunity response in people with poor glycemic control as compared to normal glycemic control.


Associations of Hypoglycaemia and Glycaemic Variability with Cardiac Arrhythmias Using a Long-term Monitoring Approach in Insulin-treated Patients with Type 2 Diabetes

Hyperglycaemic episodes are frequent in insulin treated patients with type 2 diabetes, leading to increased risk of cardiovascular disease and mortality. Andersen A, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting using a long-term monitoring approach.

In the one-year observational study, a total of 71 insulin-treated patients and microvascular complications ([mean±SD] age 66.8±9.6 years, BMI 30.1±4.5 kg/m2, HbA1c 6.8±0.4% [51.0±4.8 mmol/mol]) were included. In these patients, continuous glucose monitoring (118±6 days) and implantable cardiac monitors (ICMs) were employed.

It was observed that time spend in hypoglycaemia was higher during night-time than during day-time. In 12 patients, the ICMs detected 724 episodes of clinically relevant arrhythmias. Out of 724 episodes, atrial fibrillation and pauses accounted for 99% of cases. No association between hypoglycaemia and cardiac arrhythmia was found during daytime. Subject-specific hourly incidence of cardiac arrhythmias tented to increase with the occurrence of hypoglycaemia but only slightly with increasing time in hypoglycaemia during night time.

In insulin-treated patients with T2D, cardiac arrhythmias were common and were associated with glycaemic variability, whereas arrhythmias were not strongly associated with hypoglycaemia.


Prevalence of and Factors Associated with Undiagnosed Stage 3 Chronic Kidney Disease in Patient with Type 2 Diabetes: A Report from REVEAL-CKD

Chronic kidney disease (CKD) is a serious condition which affects 10% of the world’s population but it remains largely under recognized problem in among patients with pre-existing comorbidities. As large number of CKD patients have T2D, Wittbrodt E, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which investigated prevalence and factors associated with undiagnosed stage 3 CKD in patients with T2D.

REVEAL-CKD is a multinational initiative to assess early stage undiagnosed CKD. A total of 66,815 patients with eGFR values indicating stage 3 CKD and pre-existing T2D with mean age of 70 years were included in this study. With increasing age, prevalence of undiagnosed CKD increases and ranged between 38% and 48% in patients with other pre-existing comorbidities.

In comparison to patients with diagnosed CKD, undiagnosed group had more female (46% versus 63%) and a had higher proportion of patients >75 years: 33% versus 38%

The results of the given study suggest that a large proportion of older or female patients with baseline T2D have undiagnosed CKD. These results suggest that an opportunity exists for more proactive CKD diagnosis and monitoring of patients with pre-existing comorbidities.


Type 2 Diabetes, Chronic Kidney Disease and Major Cardiovascular Events in Patients with Established Coronary Artery Disease

The conditions, type 2 diabetes and (T2DM) and chronic kidney disease (CKD) usually coincide which confers high risk of cardiovascular diseases. Saely C, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which assessed the single and joint effects of T2DM and CKD on major cardiovascular events (MACE) in a high-risk population of patients with established coronary artery disease (CAD).

A total of 1460 patients with angiographically proven CAD over 10.4±4.8 years, of whom 454 (30.8%) had T2DM and 251 (17.1%) had CKD were included in the study.

In comparison to non-diabetic subjects, MACE events occurred more frequently in T2DM patients (40.4% vs 28.7%, p<0.001) and in patients with CKD (eGFR < 60ml/min/1.73m2). While comparing the MACE incidence among patients with neither T2DM nor CKD (25.3%), patients with T2DM but who did not have CKD reported frequent MACE events (35.8%; p<0.001) as well as in non-diabetic patients with CKD (47.6%; p<0.001). MACE events happened most frequently in patients with both, T2DM and CKD (57.4%; p<0.001). In Cox regression analysis, T2DM (HR=1.46 [1.20-1.78]; p<0.001) and CKD (HR=1.81 [1.45-2.27]; p<0.001) were mutually independent predictors of MACE after multivariate adjustment.

T2DM and CKD are mutually independent risk factors for MACE patients in patients with established CAD. CAD patients with both CKD and T2DM are an extremely high risk for MACE.


Remission of Type 2 Diabetes Following a Short-term Intervention with Insulin Glargine and Metformin/Sitagliptin: Results of the REMIT-sita Randomised Controlled Trial

Non-surgical approaches have shown success in inducing remission of type 2 diabetes. However due to limited evidence diabetes remission was reported following a short-term intervention with insulin glargine, metformin/sitagliptin and lifestyle approaches. Gerstein H, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021.

102 patients with type 2 diabetes were segregated in 2 groups (i) a 12-week intensive treatment with insulin glargine and metformin/sitagliptin combined with lifestyle therapy or (ii) control group where the participants with HbA1C10 mmol/l on ≥50% of glucometer readings, re-initiation of diabetes medications ± abnormal FPG or 2-hour plasma glucose on OGTT were included in a randomised trial. To compare the treatment groups with and without FPG/OGTT relapse criteria time-to-relapse analysis was conducted.

In the intervention group, FPG/OGTT criteria included, hazard ratio of relapse was 0.72 (95% CI 0.47; 1.10) when compared to the control group. Hazard ratio of relapse was 0.60 (95% CI 0.39; 0.95), without the FPG/OGTT criteria (supplementary analysis). The results (HR 0.75, 95% CI 0.49; 1.15) were unaffected by the removal of the 2-hour plasma glucose from the relapse criteria.

A sustained diabetes remission may be induced using a short-term intervention with insulin glargine and metformin/sitagliptin. No additional information was obtained by using the 2-hour plasma glucose from OGTT in the relapse criteria.


Metformin Lowers Portal Pressure in Patients with Cirrhosis and Portal Hypertension: A Randomised Clinical Trial

Portal hypertension (PH) is the vital factor of clinical decompensation in patients with liver cirrhosis. In pre-clinical data, metformin decreases portal pressure, however there are no clinical data for this advantageous impact. Thus, Rittig N, presented a study in a session at Virtual EASD Annual Meeting 2021 on 1st October 2021 which aimed to analyse the acute impacts of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion in patients with cirrhosis.

A randomized, double-blinded, placebo-controlled parallel study design in which 32 β-blocker naive patients with cirrhosis were assessed before and 90 minutes following an oral single-dose of 1000 mg metformin (n=16) or placebo (n=16). Liver vein catherization was executed to analyse HVGP and indocyanine green (ICG) infusion for analysis of hepatic blood flow.

Metformin group showed higher mean relative change in HVPG as compared to placebo group (-16% vs. 4%) (95%CI: -28 to -4%) (95%CI:-6 to 14%) in the (time x group, p = 0.008). In patients with baseline HVPG ≥ 12 mmHg, metformin-treated group showed clinically substantial enhancements in HVPG (HVPG < 12 mmHg or a > 20% reduction in HVPG) than placebo-treated patients (46% (6/13) vs. 8% (1/13)) (p = 0.07). No changes or differences were seen in systemic blood pressure, heart rate, hepatic plasma- and blood flow, hepatic ICG clearance, hepatic O2 uptake, or inflammation markers among groups.

A single oral metformin dose significantly decreases HVPG in patients with cirrhosis and PH without impacting systemic or liver hemodynamics, or inflammatory biomarkers. This shows a promising view of a safe and inexpensive therapy option that should be analysed in larger scale clinical studies with long-term results in patients with cirrhosis and PH.