Hypoglycemia

Glucagon receptor antagonist: a diabetes drug development

Glucagon and insulin work in concert to achieve and maintain proper blood glucose levels. Glucagon, released by pancreatic alpha cells, prevents hypoglycemia, while insulin released by beta cells prevents hyperglycemia. Together they preserve a tight blood glucose concentration between 70-100 mg/dL fasting and 70-140 mg/dL after meals. In type 2 diabetes, glucagon production, release, and action are malfunctioning. Overproduction of glucagon leads to over-stimulation of gluconeogenesis and glycolysis, in turn exacerbating hyperglycemia of diabetes mellitus.

It is only natural to look for ways of lowering the synthesis, secretion, or effects of glucagon. In this phase-2 clinical trial, the researchers tested the ability of a glucagon receptor antagonist in lowering A1c in 166 patients with metformin-uncontrolled type 2 diabetes over 12 weeks. The glucagon receptor antagonist RVT-1502, at the high dose 15 mg per day, lowered A1c by 1.0% without severe hypoglycemia. Slight and mild elevation of aminotransferases and blood pressure were documented respectively.

Since study results are meaningfully positive, a follow-up phase-3 randomized clinical trial would be expected.

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New FDA approval: glucagon nasal powder for severe hypoglycemia

Although uncommon, severe hypoglycemia can be devastating. It can occur in patients with type 1 diabetes or those with type 2 diabetes receiving insulin or sulfonylurea. If a patient experiences loss of consciousness or seizure from profound low sugars, glucagon needs to be administered immediately by a friend, family member, or caregiver.

The FDA has now approved a glucagon nasal powder as the second form of glucagon delivery for patients with severe hypoglycemia. In clinical trials, glucagon nasal spray has demonstrated similar efficacy as the injectable counterpart in increasing blood glucose concentrations.

The glucagon nasal powder is an excellent additional tool to combat severely low sugars in individuals with type 1 or type 2 diabetes. It has been approved for patients age four or older.

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Hypoglycemia due to gastric bypass surgery

Obesity and its complications are common, yet on the rise. Subsequently, gastric bypass surgery is on the rise too. Severe hypoglycemia can be a long-term complication of bariatric surgery. The most common method to negate or reduce hypoglycemia is dietary modifications. Patients need to consume small meals of a low glycemic index frequently. Medical therapies with acarbose, diazoxide, and octreotide are often not useful.

Here authors describe the utility of calcium channel blockers (CCBs) in two patients. Difficult to treat hypoglycemia developed in 8 and 13 years after the bypass procedure. Standard approach did not work. Only the use of nifedipine and verapamil improved patient’s resistant hypoglycemia. The proposed rationale is that CCBs reduce or delay insulin secretion by pancreatic beta cells.

Although more clinical studies are needed, it is essential to be aware of the potential benefits of CCBs. For some patients with refractory and devastating hypoglycemia, they could be the last resort. Additionally, physicians are already familiar with CCBs as they have been on the market for decades.

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The semi-automated insulin pump performs well

The study reveals that the hybrid closed loop device, MiniMed 670g, helps in reducing A1c by 0.75% compared to standard insulin pumps. For those transitioning to it, carbohydrate to insulin ratio needs to be adjusted immediately. This semi-automated system, differently called semi-artificial pancreas, is a significant advancement in the field of type 1 diabetes. The device was approved by FDA in September 2016.

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β-blockers in diabetes: not a good idea

Analyses from ACCORD trial show that β-blockade increases cardiovascular events, deaths, all-cause mortality and severe hypoglycemia in adults with diabetes. Similar trends were seen in patients with established coronary heart disease and heart failure.

A possible mechanism is the reduced sympathetic tone from β-blockade, which in turn lowers the body’s ability to sense and negate hypoglycemia. Evidence is mounting that prolonged hypoglycemia can lead to arrhythmias and cardiovascular events. 

Findings imply that strong indications are needed to prescribe b-blockers in patients with diabetes.

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EKG helps predict CVD in type 1 diabetes

A group of 1300 patients, from DCCT/EDIC study, with type 1 diabetes were followed for 19 years. Authors found that presence of major EKG anomalies worsened cardiovascular outcomes by 200%. Future ADA guidelines could include EKG criteria to identify DM1 individuals at high risk for CVD.

Examples of major EKG derangement are left ventricular hypertrophy with strain pattern, atrial fibrillation/flutter, complete left or right BBB, bifascicular block, ventricular tachycardia, Wolf-Parkinson-White syndrome/pre-excitation, and major QT prolongation.

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Low sugars (hypoglycemia) can cause heart conduction anomaly

This original study gives us a possible new mechanism of how hypoglycemia can lead to cardiac conduction anomalies. Increased QT dynamicity and QTc prolongation was seen in 50% of patients with glucose levels < 70 mg/dL. QT dynamicity is well known to carry poor cardiac prognosis.

Of a concern, sulfonyluria caused hypoglycemia in one third of individuals with “well controlled” diabetes, most of whom were asymptomatic. Although further research is needed, these findings suggest avoidance of insulin injections or secretagogues, if feasible, to minimize hypoglycemic events.

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