Journal Watch

Prepared for IDDT by Jim Young

December 2014

Benefits of timely basal insulin control in patients with type 2 diabetes
Dragana Lovre and Vivian Fonseca. Journal of Diabetes and Its Complications. Doi: 10.1016/j.jdiacomp.2014.11.018

This direct quotation from the abstract to this paper fully describes the reasoning expounded: “Early glucose control reduces the risk of both macrovascular and microvascular complications, while tight control late in diabetes has little or no macrovascular benefit. Insulin therapy offers the most potent antihyperglycemic effect of all diabetes agents, and has a unique ability to induce diabetes remission when used to normalize glycemia in newly diagnosed patients. When used as a second-line therapy, basal insulin is more likely to safely and durably maintain HbA1c levels than when insulin treatment is delayed. The use of basal insulin analogs is associated with a reduced risk of hypoglycemia and weight gain compared to NPH insulin and pre-mixed insulin. Patient self-titration algorithms can improve glucose control while decreasing the burden on office staff. Finally, recent data suggest that addition of incretin agents to basal insulin may improve glycemic control with very little, if any increased risk of hypoglycemia or weight gain.” I guess the invocation should be “Discus further”!


Glucose-lowering with exogenous insulin monotherapy in type 2 diabetes: dose association with all-cause mortality, cardiovascular events, and incident cancer
S. E. Holden et al. Diabetes, Obesity and Metabolism. Doi: 10.1111/dom.12412

This retrospective study set out to evaluate the association between insulin exposure and all-cause mortality, incident major adverse cardiovascular events (MACE) and incident cancer in people with type 2 diabetes treated with insulin monotherapy. It looked at 6,484 subjects who progressed to insulin monotherapy. The risks of progression to serious adverse outcomes were compared after they were followed for a mean of 3.3 years. It was found that there was an association between increasing exogenous insulin dose and increased risk of all-cause mortality, MACE and cancer in people with type 2 diabetes. The authors offer the caveat that the limitations of their observational studies mean that this should be further investigated using an interventional study design.


Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes
Kamlesh Khunti et al. Diabetes Care. Doi: 10.2337/dc14-0920

Because hypoglycemia has been associated with an increased risk of cardiovascular (CV) events and all-cause mortality, this retrospective study assessed whether, in a nationally representative population, there is an association between hypoglycemia, the risk of CV events, and all-cause mortality among insulin-treated people with type 1 diabetes (T1D) or type 2 diabetes (T2D). It found that hypoglycemia was associated with an increased risk of CV events and all-cause mortality in insulin-treated patients with diabetes. They also found that the relationship between hypoglycemia and CV outcomes and mortality exists over a long period.


Glycemic variability and diabetes retinopathy: a missing link
Cherng-Ru Hsu, Yu-Tsung Chen, Wayne H.-H. Sheu. Diabetes and Its Complications. Doi: 10.1016/j.jdiacomp.2014.11.013

Daily glucose variability, such as fasting plasma glucose fluctuation or postprandial hyperglycemia, has been proposed as contributors to diabetes-related macrovascular complications. However, its impacts on microvascular complications, such as diabetes retinopathy remain controversial. This study reviewed the current evidence of the relationship between glycemic variability and diabetes retinopathy in patients with type 1 or type 2 diabetes. It found that short-term glycemic fluctuation may contribute to the development or progression of diabetic retinopathy in patients with type 2 diabetes, whereas long-term glycemic fluctuation, reflected by variation of levels of HbA1c, appeared to show a stronger association with diabetes retinopathy both in patients with type 1 and type 2 diabetes. The authors suggest that their findings emphasize the need to reduce glycemic variability by various measures in order to reduce development and progression of diabetes retinopathy both in type 1 and type 2 diabetes patients.


The study of once- and twice-daily biphasic insulin aspart 30 (BIAsp 30) with sitagliptin, and twice-daily BIAsp 30 without sitagliptin, in patients with type 2 diabetes uncontrolled on sitagliptin and metformin
Sultan Linjawi et al. Primary Care Diabetes. Doi: 10.1016/j.pcd.2014.11.001

This study looked at the efficacy and tolerability of intensifying diabetes treatment with once- or twice-daily biphasic insulin aspart 30 (BIAsp 30) added to sitagliptin, and twice-daily BIAsp 30 without sitagliptin in patients with type 2 diabetes (T2D) inadequately controlled on sitagliptin. 582 insulin-naïve patients were randomized to twice-daily BIAsp 30 + sitagliptin (BIAsp BID + Sit), once-daily BIAsp 30 + sitagliptin (BIAsp QD + Sit) or twice-daily BIAsp 30 without sitagliptin (BIAsp BID), all with metformin. It found that adding BIAsp 30 to patients with T2D poorly controlled with sitagliptin and metformin was efficacious and well tolerated; however, while BIAsp BID + Sit showed superior glycaemic control, BIAsp QD + Sit had a lower rate of hypoglycaemia and showed no weight gain.


A cost comparison of long-acting insulin analogues versus NPH insulin-based treatment T2D
Iskandar Idris et al. Journal Medical Economics. Doi:10.3111/13696998.2014.991788

This analysis investigated total healthcare costs, HbA1c, and weight changes over a 36-month period in patients with type 2 diabetes initiated on NPH or long-acting insulin analogs. [NPH insulin is intermediate-acting insulin created in 1936 and formulated from porcine insulin by adding neutral protamine to regular insulin. NPH stands for neutral protamine Hagedorn – Hans Christian Hagedorn (1888–1971) obtained the rights from Banting and Best. In 1946, Nordisk was able to form crystals of protamine and insulin and marketed it in 1950 as NPH insulin] The investigators looked at electronic patient data from 479 general practices in the UK. It found that following insulin initiation, the difference in healthcare costs of long-acting analogs compared to NPH insulin was transient. By year 3, the cost differences were not significantly different between the two cohorts, driven by an observed reduction in the cost of self-monitoring of blood glucose (SMBG) in the analog group and an increase in the cost of bolus insulin in the NPH group.


Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes
 Ahmad Haidar et al. The Lancet Diabetes & Endocrinology. Doi: 10.1016/S2213-8587(14)70226-8

The artificial pancreas is an emerging technology for the treatment of type 1 diabetes and two configurations have been proposed: single-hormone (insulin alone) and dual-hormone (insulin and glucagon). This study aimed considered the usefulness of glucagon in the artificial pancreas system. During conventional insulin pump therapy visits, patients received continuous subcutaneous insulin infusion. The primary outcome was the time for which plasma glucose concentrations were in the target range (4·0 to 10·0 mmol/L for 2 h postprandial and 4·0 to 8·0 mmol/L otherwise). Hypoglycaemic events were defined as plasma glucose concentration of less than 3·3 mmol/L with symptoms or less than 3·0 mmol/L irrespective of symptoms. The findings were that single-hormone and dual-hormone artificial pancreas systems both provided better glycaemic control than did conventional insulin pump therapy. The authors suggest that the single-hormone artificial pancreas might be sufficient for hypoglycaemia-free overnight glycaemic control.


Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations
Nicholas W. Carris et al. Drugs. Doi: 10.1007/s40265-014-0325-2

This discussion opens by stating that basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. It asserts that though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. The review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin–GLP-1 receptor agonist regimen. Looked at from both angles it states that basal insulin added to a GLP-1 receptor agonist reduces HbA1c without weight gain or significantly increased hypoglycemia, while a GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. The authors end with the statement that evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.


Offer weight loss surgery to obese people with diabetes
This news item from NICE advises that the NHS should offer weight loss surgery to thousands more people in order to tackle an epidemic of type 2 diabetes. NICE already has an updated guideline that focuses on identifying, assessing and treating people who are already obese – see here:  < >. NICE now recommends that all patients with a BMI of 35 or over who have recent-onset type 2 diabetes should be assessed for surgery. The caveat being that patients must have tried and failed to achieve clinically beneficial weight loss by all other appropriate non-surgical methods and be fit for surgery. They offer the refinement that doctors should consider surgery for people of Asian family origin who have recent-onset type 2 diabetes at a lower BMI than other populations, as the point at which the level of body fat becomes a health risk varies between ethnic groups. Asian people are known to be particularly vulnerable to the complications of diabetes. Financially the initial cost of weight loss surgery is around £6,000 in the short term, but preventing the long-term complications of diabetes is great for the individual and will save the NHS money. Finally, NICE recommends is that for the first 2 years, minimum, patients are followed up within a multidisciplinary team. So they will have access to dieticians, psychology, nurses, exercise therapists, and they will be monitored for nutrition and if they need any vitamins they are supplemented.


Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes
Joseph B. Muhlestein et al. JAMA. Doi:10.1001/jama.2014.15825

Coronary artery disease (CAD) is a major cause of cardiovascular morbidity and mortality in patients with diabetes mellitus, yet CAD often is asymptomatic prior to myocardial infarction (MI) and coronary death. This study assessed if routine screening for CAD by coronary computed tomography angiography (CCTA) in patients with type 1 or type 2 diabetes deemed to be at high cardiac risk followed by CCTA-directed therapy would reduce the risk of death and nonfatal coronary outcomes. The primary outcome used was a composite of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization; the secondary outcome was ischemic major adverse cardiovascular events (composite of CAD death, nonfatal MI, or unstable angina). Counter intuitively it discovered that among asymptomatic patients with type 1 or type 2 diabetes the use of CCTA to screen for CAD did not reduce the composite rate of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization at 4 years. Therefore the authors posit that the findings do not support CCTA screening in this population.