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REWIND Trial: Dulaglutide and cardiovascular outcomes in type 2 diabetes

The REWIND trial aimed to assess the cardiovascular (CV) safety of dulaglutide, a glucagon-like peptide-1 (GLP-1) agonist, in patients with type 2 diabetes mellitus at higher risk for CV events. The trial involved 9,901 patients and randomized them to dulaglutide and compared outcomes with placebo. The results of the REWIND trial indicated that once-weekly dulaglutide administered via subcutaneous injection is superior to placebo in improving glycemic control and reducing CV events in patients with type 2 diabetes and higher CV risk. There was also a significant reduction in nonfatal strokes and improvement in the composite renal outcomes. Source: Lancet

VADT Trial: Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes

VADT Trial:

2009, VADT Trial: Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes, Source

CREDENCE Trial: Canagliflozin and renal outcomes in type II diabetes and nephropathy

CREDENCE Trial Visual Abstract

In CREDENCE trial, the authors objective was to assess the effect of canagliflozin on renal outcomes in patients with type 2 DM and CKD. 4,401 patients with CKD and DM2 were enrolled to be treated with either 100 mg canagliflozin daily or matched placebo. The primary outcome of ESRD, worsening CKD or CV death was significantly lower in patients on canagliflozin (P=0.0001). The authors concluded that canagliflozin can significantly protect kidney in patients with diabetes. Take a look and share the visual abstract for quick learning.

Source: NEJM

TABLET Trial (2019): Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception

TABLET trial levothyroxine

TABLET Trial Summary: Dhillon-Smith R et al. randomized 952 women with positive testing for thyroid peroxidase antibodies and normal thyroid function and a history of miscarriage or infertility to either levothyroxine 50 μg once daily (n=476) or placebo (n=476). The primary objective was to assess if levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. No difference was noted among the primary outcome of live birth at >34 weeks gestation (RR 0.97; 95% CI, 0.83 to 1.14, P=0.74). There were no difference in adverse events. The authors of the TABLET trial concluded that the use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo.

Source: NEJM

IDNT Trial (2001): Irbesartan in diabetic nephropathy

Source: NEJM

LEADER Trial (2016): Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Source: NEJM

Algorithm: Diagnostic Workup of Primary Aldosteronism

algorithm for diagnosing primary aldosteronism

Primary Aldosteronism Diagnosis Algorithm

Primary aldosteronism is characterized by elevated plasma aldosterone levels that leads potassium loss, hypertension secondary to sodium reabsorption and volume expansion and at times metabolic alkalosis.

In order to discuss the diagnostic approach for primary aldosteronism in terms of both blood tests and imaging tests, I have designed this algorithm after reading the society of endocrine guidelines and indications of each test.

Feel free to contact me in case there’s any discrepancy between this algorithmic approach versus standard approach of diagnosing primary aldosteronism.

ACCORD Trial (2008): Effects of Intensive Glucose Lowering in Type 2 Diabetes

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, intesive glucose control was associated with higher all-cause and CV mortality. The authors of ACCORD trial concluded that in patients with T2DM, intensive glycemic control (target HbA1c <6%) increases mortality compared to standard control (target A1c 7-7.9%).

Source: 2008, Effects of Intensive Glucose Lowering in Type 2 Diabetes, NEJM

ASCEND: Aspirin for primary prevention in patients with Diabetes

2018, Aspirin for primary prevention in patients with Diabetes mellitus, NEJM

RABBIT 2 Trial: Basal-bolus insulin in inpatients with DM

2007, Basal insulin for DM2, Diabetes Care

ANGIE02 Trial: Closed-Loop Insulin Delivery for Type II Diabetes Mellitus Trial Visual Absract

angie02 trial visual abstract of closed  loop insulin delivery in type 2 diabetes

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.

Study Design

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%

Inclusion criteria

  • 18 years and older
  • Type 2 diabetics only
  • In-patient hyperglycemia requiring subcutaneous insulin therapy.

Exclusion criteria

  • Type 1 diabetes
  • Pregnancy
  • Breast-feeding
  • 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.

Primary outcomes

  • 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).

Secondary Outcomes

  • 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.

Interpretation (discussion)

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

Algorithm for Management of Adult Patients with DKA

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.

Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function

Visual Abstract: Metformin use based on kidney function. Over ~1 million patients are not on guideline-directed therapy of metformin due to abnormal kidney function. Thee present study studies the relationship of metformin with lactic acidosis over a wide range of eGFR in patients. Patients were followed up for years and were assesed for decline in kidney function via eGFR calculation and risk of development of lactic acidosis due to metformin use. The results were consistent with previously stated guidelines as to which metformin is safe to use in eGFR > 30 over all ranges while risk of lactic acidosis doubles once eGFR drops below 30  mL/min/1.73 m2

Source: JAMA Intern Med

STAMPEDE Trial: Bariatric Surgery versus Intensive Medical Therapy in Obese Patients with Diabetes

stampede trial visual abstract graphical summary on bariatric surgery versus medical therapy in obese patients with diabetes

Source: NEJM

CANVAS Trial: Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

Source: NEJM

NICE-SUGAR Trial: Intensive Glucose Control in Critically Ill Patients

nice sugar trial visual abstract

NICE-SUGAR Trial: 2009, Intensive versus Conventional Glucose Control in Critically Ill Patients | NEJM

Key Point

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.


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