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The VA NEPHRON-D trial tackled an important question about the combination therapy of ACEi and ARBs. We know from the RENAAL trial that losartan has significant benefits in diabetic nephropathy. The authors of the VA NEPHRON-D tiral aimed to assess if the addition of an ACE inhibitor to ARB therapy prevent eGFR reduction, ESRD, or death in patients with T2DM, CKD stage 2-3, and elevated urine albumin: creatinine. The trial included a reasonable number of 1448 patients who were randomized to losartan + placebo group and combination group of losartan and lisinopril. The trial was ended earlier due to inconclusive results. The authors of VA NEPHRON-D trial concluded that combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. Source: NEJM
|ACCORD Trial Summary: Gerstein et al randomized 10,251 patients with type 2 diabetes mellitus, hemoglobin A1c ≥7.5% with CAD or ≥2 cardiovascular risk factors (dyslipidemia, HTN, current smoking, obesity) to either standard glycemic control HbA1c 7-7.9% (n=5,123) or intensive glycemic control HbA1c <6% (n=5,128). The primary objective was to assess if intensive glycemic control targeting a HbA1c <6% versus standard glycemic control targeting a HbA1c 7-7.9% reduce the risk of CV events in patients with type II diabetes. The primary outcome of nonfatal MI or nonfatal stroke or CV death was non-significant among both groups. However, |
Source: 2008, Effects of Intensive Glucose Lowering in Type 2 Diabetes, NEJM
2012, Percutaneous Coronary Intervention (PCI) vs CABG in Patients with Diabetes and multivessel CAD
2018, Aspirin for primary prevention in patients with Diabetes mellitus, NEJM
2007, Basal insulin for DM2, Diabetes Care
Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care
Summarized by: Tabinda Saleem, MBBS
Reviewed by: Usama bin Nasir, MD
Contribution to literature
This trial revealed that the use of the fully automated closed-loop insulin system can help physicians achieve a better glycemic control among hospitalized patients with type 2 diabetes without rendering them at risk of hypoglycemia.
Description of the trail
The goal of this trial was to compare the fully automated closed-loop insulin delivery system (artificial pancreas) with the conventional subcutaneous insulin therapy among thehospitalized type 2 diabetic patients receiving non-critical care, and assess the overall difference among the targeted glycemic control, variability of glucose levels and rate of hypoglycemia.
It was a randomized, open-label trial that recruited patients From August 2, 2016 to December 11, 2017 from the general wards at the University Hospital in Bern, Switzerland, and at Addenbrooke’s Hospital in Cambridge, United Kingdom.
Patients were randomly assigned to either closed-loopinsulin delivery (70 patients) or to the control group with standard insulin therapy (66 patients). The treatment group received the rapid-acting insulin analogue (Humalog, Eli Lilly, or NovoRapid, NovoNordisk) by means of a trial pump (Dana Diabecare R, Sooil) through a cannula inserted into the abdomen. And the control group received the conventional subcutaneous insulin and other anti-hyperglycemic therapies according to the local clinical practice.
- Total number of patients: 136
- Duration of follow up: 15 days or until hospital discharge.
- Mean patient age: 67 years
- Percentage male: 50%
- Mean BMI: 32
- Mean HbA1c: 8%
- 18 years and older
- Type 2 diabetics only
- In-patient hyperglycemia requiring subcutaneous insulin therapy.
- Type 1 diabetes
- Any physical or psychological disease
- Use of any such medication that can interfere with the conduct of the trial or the interpretation of the results
Other salient features
- Randomization was ensured on the basis of age, sex, glycated hemoglobin level, body-mass index (kg/m2), duration of diabetes and pretrial total daily insulin dose to balance the two groups.
- Throughout the trial patients were allowed to have standard hospital meals at usual mealtimes, according to local practice.
- Sepsis was the predominant reason for admission in approximately 43% of the patients.
- Safety end points included clinically significant hyperglycemia (>360 mg per deciliter) with ketonemia and severe hypoglycemia (<40 mg/dl) along with other adverse events.
- The mean (±SD) percentage of time that the sensor glucose measurement was in the target glucose range was 65.8±16.8% inthe closed-loop group and 41.5±16.9% in the control group, for a difference of 24.3±2.9 percentagepoints (95% confidence interval [CI], 18.6 to 30.0; P<0.001).
- The mean sensor glucose measurement was significantly lower in the closed-loop group than in the control group (154±29 mgper deciliter vs. 188±43 mg per deciliter; difference, 35±6 mg per deciliter; 95% CI, 23 to 47;P<0.001).
- Values above the target range (>180 mgper deciliter) were found in 23.6±16.6% of the patients in the closed-loop group and in 49.5±22.8%of those in the control group, a difference of25.9±3.4 percentage points (95% CI, 19.2 to 32.7;P<0.001).
- Hypoglycemic episodes with capillary glucose measurement of less than 63 mg per deciliter, occurred three times in the closed-loop group (3 patients) and nine times in the control group (8 patients).
- Overnight (midnight to 8 a.m.) and daytime (8 a.m. to midnight) glycemic control was also significantly better in the closed-loop system compared to the control, with difference of 19.8±3.8 percentage points (95% CI, 12.2 to 27.4; P<0.001) and 26.9±3.2 percentage points (95% CI, 20.6 to 33.3; P<0.001) respectively.
This trial demonstrated that the hospitalized patients with type 2 diabetes who received insulin with a fully automated, closed-loop system had significantly better glucose control with lower rates of hyperglycemia and glucose variability than those who received standard subcutaneous insulin therapywithout changing the total daily insulin dose or increasing the risk of hypoglycemia.
The benefit of a closed-loop system is that the automated system instantaneously respond to the higher glucose level with insulin delivery and it continuously adapt to the changing insulin needs during the day and between days. In contrast conventional therapy are less responsive to glucose changes and insulin needs and are mainly dependent on the vigilance of the hospital staff, with tighter glycemic control increasing the risk of hypoglycemia with latterbeing a primary concern for many health care professionals and a reason to be reluctant to encourage tight glucose control.
The strength of this trial was that it had a longer follow up period (15 days) as compared to the previous randomized feasibility trial that evaluated the closed-loop system over a period of 72 hours. Also the sample size of this study was larger and included a diverse and complex inpatient population (including 19 patients on hemodialysis) from two different hospital settings from two different countries compared to the single hospital setting in the previous trail, increasing the utility of the current trial across different health care systems.
Though this trial has some limitations as well. The Sensor glucose measurements were more readily available for the closed-loop group than in the control group and the trial duration was also longer for the closed-loop group. The observed imbalance may be attributed to thedifferences in the burden of coexisting illnesses among the two groups (which was higher in the closed-loop group than in the control group) resulting in the collection of fewer sensor glucose data in the control group compared to the closed-loop group. That is why more work is required to determine the practical consideration of this system in the clinical practice and to facilitate its use by the health care professionals and to assess the costs.
In conclusion, in patients with type 2 diabetes who are receiving noncritical care, fully automated closed loop system can become an effective way of controlling glycemic levels compared to the standard insulin therapy withoutincreasing the risk of hypoglycemia in these patients.
Bally L, Thabit H, Hartnell S, Andereggen E, Ruan Y, Wilinska ME, et al. Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care. New England Journal of Medicine. 2018 Jun 25; Source
Diabetic ketoacidosis requires emergent intervention and treatment. The treatment of DKA requires careful monitoring of both acidosis as well as blood glucose levels. In order to streamline the treatment process, I have designed the following algorithm keeping in mind the complexity of the disease. This management algorithm is based on the American Diabetes association updated guidelines of 2009. Feel free to print this and share it without colleagues and students.
NICE-SUGAR Trial: 2009, Intensive versus Conventional Glucose Control in Critically Ill Patients | NEJM
The NICE trial tackled an important question of what should be the goal blood glucose levels in critically ill patients. The results of this trial were quiet significant and showed tighter or intensive blood glucose control was associated with highter 28 days and 90 days mortality. Additionally, it also led to an increase number of hypoglycemic episodes in these patients.
Guideline recommendations based on NICE-SUGAR Trial
The American Diabetes Association recommends starting insulin in patients with persistent hyperglycemia above 180 mg/dL in critically ill patients, and to maintain the glycemic range between 140-180 mg/dL.