Veronica Hackenthal, MD

References:1. Whicher CA, Price HC, Holt RIG, et al. Mechanisms in endocrinology: Antipsychotic medication and type 2 diabetes and impaired glucose regulation. Eur J Endocrinol. 2018;178:R245-R258.2. National Institute for Health and Care Excellence. Psychosis and schizophrenia in children and young people: recognition and management. https://www.nice.org.uk/Guidance/CG155. Published January 2013. Accessed July 17, 2018.Â 

Slideshows

Antipsychotic medications may not cause type 2 diabetes but a new review find the drugs may accelerate development of the disease. How can you protect your patients?

Antipsychotics and Cardiometabolic Risk: New Study Sheds Light

The new diabetes tech you'll be tested on here comes from the expanding pool of continuous glucose monitoring systems, eg, the Eversense CGM and the FreeStyleÂ® Libre Flash. How much do you know about the features and benefits of these and their competitors? Find out with our short, 5-question quiz.

The new diabetes tech in question is the expanding pool of continuous glucose monitoring systems. So, what's your CGM IQ?

New Diabetes Technology: A Test 

Taking a small step back in time, the lipid management guidelines issued by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) earlier in 2017 re-affirm the use of LDL-C targets to help minimize cardiovascular risk in all patients, and especially those with type 2 diabetes (T2DM). The guideline includes a first-ever "extreme risk" patient category for whom an LDL-C level of 

The AACE/ACE 2017 recommendations on lipid management renew focus on LDL-C targets, and go far lower than any group has ventured to date.

AACE/ACE Focus on Lipids: 2017 Consensus Guidelines

Beta-blocker use in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) risk factors is associated with an increased risk of CV events and severe hypoglycemia, according to a recent 

“Using the ACCORD trial data, this study demonstrated that the use of Î²-blockers was associated with an increased risk for cardiovascular events and severe hypoglycemia in the modern era. Furthermore, a similar relationship between the use of Î²-blockers and cardiovascular events was found in patients with heart disease. The indication of Î²-blockers may need to be reconsidered when this connection is elucidated through future higher-level evidence,”

 wrote lead author Hiroshi Kajio, MD, PhD, of the National Center for Global Health and Medicine, Tokyo, Japan, and colleagues.

While appropriate glycemic control can decrease the risk of diabetic complications, going too far may be counterproductive. Results from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) 

 suggest that intensive glucose-lowering therapy is associated with increased hypoglycemia and mortality, which led to discontinuation of the trial after 3.5 years.

 One explanation for these results is that intensive glucose lowering can increase hypoglycemic episodes, which in turn are associated with a heightened risk of vascular events and death.

During episodes of severe hypoglycemia, Î²-blockers may serve a protective function by decreasing hypoglycemia-related cardiac arrhythmias, severe hypertension, and CV events. However, Î²-blockers themselves can increase the risk of severe hypoglycemia. They may also dampen early warning signs and contribute to hypoglycemia unawareness. Î²-blockers also may lead to weight gain, which may increase the risk of CV events over time.

How effective are Î²-blockers in patients with T2DM? To find an answer, researchers performed a post-hoc analysis of data from the ACCORD trial. The study took place in 77 clinical centers in the US and Canada and included 10,251 people with T2DM, inadequately controlled hemoglobin A1c, and preexisting CV disease (or at increased risk for it).

Participants were randomized to intensive glucose-lowering therapy or standard therapy. The mean follow-up time was slightly over 4.5 years.

âº Overall, significantly higher risk of CV events and CV death associated with beta blockers:

   âº CV events: 46% increased risk (HR, 1.46; 

   âº CV death: 44% increased risk (HR, 1.44; 

   âº All-cause death slightly increased, but results not significant

âº Presence of coronary heart disease (CHD)/heart failure (HF): 

risk of CV events significantly increased by 27% (HR, 1.27; 

risk of CV events significantly increased by 45% (HR, 1.45; 

risk of CV events increased by 4%, but results not significant (HR, 1.04; 

risk of CV events significantly increased by 69% (HR, 1.69; 

significantly increased risk by 36% (HR, 1.36; 

The authors explained that the elevated risk of CV events associated with Î²-blockers was at least partly related to increased severe hypoglycemia, and that this risk may outweigh the protective effect Î²-blockers may have during severe hypoglycemia. However, they also noted that some subgroups may not have been large enough to reach statistical significance for variables such as CV death and all-cause death. “Newly randomized controlled trials are required to evaluate whether the use of Î²-blockers in patients with diabetes mellitus shows beneficial or adverse effects,” they concluded.

 Post-hoc analysis of the ACCORD trial data suggests that the risk of CV events and severe hypoglycemia is higher in patients with T2DM and established CV risk factors who take Î²-blockers, compared with those who do not.

Î²-blockers are associated with a significantly increased risk of CV events in patients with or without CHD/HF and those receiving standard therapy.

Increased risk of CV events associated with Î²-blockers may outweigh their protective effect on the heart and vasculature during hypoglycemia. 

The indication for Î²-blockers in T2DM may need reconsideration, but randomized controlled trials are needed.

1. Tsujimoto T, Sugiyama T, Shapiro MF, et al. 

Risk of cardiovascular events in patients with diabetes mellitus on Î²-blockers

. 2017;70:103-110. doi: 10.1161/HYPERTENSIONAHA.117.09259.

2. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. 

Effects of intensive glucose lowering in type 2 diabetes

Articles

Post-hoc analysis of ACCORD trial data suggests the indication of beta blocker therapy in T2DM patients be more closely examined. 

Beta Blockers Heighten Risk of CV Events in T2DM

Home use of a closed-loop artificial beta cell system could improve glycemia in patients with type 1 diabetes mellitus (T1DM), according to an article published online in the New England Journal of Medicine.

The article reports on two studies that included 33 adults and 25 children and adolescents who used artificial beta cells for 12 weeks at home. Participants who used the artificial beta cell had better glucose control, less hypoglycemia, and lower HbA1c (adults only) than those who used an insulin pump.

The artificial beta cell uses a control algorithm to independently monitor and increase or decrease insulin delivery based on real-time sensoring of glucose levels.  In contrast, insulin pumps that link insulin delivery to sensors that continuously monitor glucose levels can only temporarily suspend insulin delivery based on preset glucose thresholds. These systems can decrease the risk of hypoglycemia, but cannot respond to hyperglycemia.

“The advantage of a closed-loop system is the responsive, graduated modulation of insulin delivery, both below and above the present pump regimen, which allows for improvements in the proportion of time spent in target glucose range and lowering of the mean glucose level without increasing the risk of hypoglycemia,” wrote lead author Roman Hovorka, MD, of the University of Cambridge and colleagues in the APCam Consortium and AP home Consortium.

Past studies of the artificial beta cell have suggested that it can improve glucose control and decrease the risk of hypoglycemia, but these studies have been limited to 6 weeks at most. 

The results come from two open-label multicenter, crossover randomized controlled trials. In each trial the artificial beta cell was used for 12 weeks, and insulin pumps were used for about the same amount of time. Participants were randomly assigned to use either the artificial beta cell system for 12 weeks, followed by sensor-augmented insulin pumps, or vice versa. The artificial beta cell did calculations every 12 minutes to figure out the insulin infusion rate needed to reach target glucose levels, then automatically sent these results wirelessly to the insulin pump.

The first study included 33 adults from UK, Germany, and Austria. Participants used the artificial beta cell day and night, and administered mealtime insulin using a standard bolus calculator.

The second study included 25 children and adolescents from three sites in the UK. Participants used the artificial beta cell overnight only. 

Participants in both trials received no remote monitoring or supervision, and could perform their usual activities and eat foods of their choice. After the first two weeks, they could travel and use the system while driving. Target glucose levels were 70-180 mg/dL in adults, and 70-145 mg/dl in children.

Key results for the artificial beta cell vs. the pump:

♦ Amount of time spent in the target glucose range: 11% higher (95% CI 8.1-13.8, P<0.001)

♦ Mean glucose level: 11 mg/dL lower (-17to -6, P<0.001)

♦ Mean HbA1c: 0.3% lower (-0.5 to -0.1, P=0.002)

♦ Area under the curve for the period when glucose was <63 mg/dL (estimates the burden of hypoglycemia): 39% lower (24-51, P<0.001)

♦ Amount of time spent in the nighttime glucose target range: 24.7% higher (20.6-28.7, P<0.001)

♦ Mean nighttime glucose: 29 mg/dL lower (-39 to -20, P<0.001)

♦ Area under the curve for the time when day-and-night glucose levels were <63 mg/dL: 42% lower (4-65, P=0.03)

• Three severe episode of hypoglycemia happened with the artificial beta cell, all when the system was not in use because of low battery or the system was not turned on.

 “[W]e found that extended use of a closed-loop system at home over a period of 12 weeks during free daily living without close supervision is feasible in adults, children, and adolescents with type 1 diabetes,” the authors concluded, “Improvements in glucose control and reduction in the burden of hypoglycemia were observed. Among adults, the glycated hemoglobin level was lower with the use of a closed-loop system day and night than with a sensor-augmented insulin pump, even when the insulin pump was adjusted appropriately.”

• The closed-loop artificial beta cell uses a control algorithm to independently monitor and increase or decrease insulin delivery based on real-time sensoring of glucose levels.

• Insulin pumps that use continuous blood glucose monitoring can decrease the risk of hypoglycemia, but do not respond to hyperglycemia.

• Two open-label multicenter, crossover randomized controlled trials in 33 adults and 25 children and adolescents found that using the artificial beta cell for 12 weeks resulted in better glucose control, less hypoglycemia, and lower HbA1c (adults only) than the insulin pump.

The study was sponsored by Abbott Diabetes Care, and DIasend. Two of the authors hold patents for closed-loop insulin delivery systems and a system for insulin delivery that uses various measurements-error models.

Home use of an artificial beta cell in type 1 diabetes

Artificial beta cell systems and insulin pumps went head-to-head in two trials with type 1 diabetes patients.

Home Use of Artificial Beta Cells

A new study has turned conventional wisdom about metformin on its head, and suggested that the drug’s main glucose-lowering effect lies in the gut, not the blood. The results could be a boon to millions of people who cannot take metformin because of kidney disease.

The study compared metformin delayed release (Met DR) to metformin immediate release (Met IR) and metformin extended release (Met XR). Results showed that, even though Met DR was found at much lower levels in the blood than Met IR and Met XR, Met DR was about 40% more potent than Met XR.

“The observation that low doses of Met DR appear to be more effective than similar doses of the more bioavailable Met XR suggests that the gut contribution to glucose lowering may be more important than systemic mechanisms,” wrote first author John Buse, of the University of North Carolina School of Medicine in Chapel Hill, North Carolina, and colleagues.

Metformin has been used for treating type 2 diabetes (T2DM) for over fifty years, yet its mechanism of action has remained elusive. For long, metformin was thought to exert its effects systemically, with major sites of action being the liver and skeletal muscle.

Met IR and Met XR are mostly absorbed in the duodenum and jejunum. Met DR undergoes pH-dependent dissolution in the ileum, delivering active drug to the lower intestine where there is low absorption of metformin, resulting in lower plasma levels of the drug.

The results stem from two studies. The first was a phase 1, randomized, crossover study in 20 healthy participants that looked at the bioavailability of various formulations of metformin. Healthy participants were randomized to Met DR (500 mg twice daily, or 1000 mg twice daily), Met IR (1000 mg twice daily) and Met XR (2000 mg once daily). Participants were mostly male (70%), and white (65%), with a mean age of 32.2 years and mean BMI of 29.6 kg/m

• Bioavailability was about 50% lower for Met DR compared to Met IR and Met XR.

The second study was a phase 2, multicenter, placebo-controlled study in 240 patients with T2DM. Participants were randomized to 12 weeks of Met DR 600, 800, or 1000 mg once daily; blinded placebo; or unblinded Met XR 1000 or 2000 mg once daily.

• 50% lower median fasting glucose levels for 1000 mg Met DR compared to the same dose of Met XR (1000 mg).

• 40% increased potency for Met DR compared to Met XR.

• Increased plasma lactate concentrations with Met XR but not with Met DR, compared to placebo.

• Treatments were well tolerated, with adverse effects similar to known side effects.

Because high plasma concentrations of metformin can increase plasma lactate levels and the risk for metformin-associated lactic acidosis, Met DR may be better tolerated in patients with renal impairment, the authors suggested. 

“[T]he delivery of metformin to the lower bowel with Met DR resulted in a glucose-lowering efficacy comparable to that with Met XR, but with lower doses and significantly lower systemic exposure. These data provide substantial evidence that currently prescribed metformin doses work predominantly in the gut and that the contribution of systemic metformin is small,” the authors concluded. “Based on its gut-restricted properties, Met DR may allow for the metformin treatment of patients with renal impairment without the risk of lactic acidosis associated with metformin accumulation.”

• Met DR has about 50% lower bioavailability than Met IR and Met XR.

• Met DR 1000 mg lowers fasting glucose levels by about 50% more than the same dose of Met XR.

• Met DR has about 40% increased potency compared to Met XR.

• Metformin’s main site of action lies in the gut.

• Patients with renal impairment may tolerate Met DR better than other formulations of metformin.

The primary glucose-lowering effect of metformin resides in the gut, not the circulation. Results from short-term pharmacokinetic and 12-week dose-ranging studies

. Diabetes Care. 2015 Aug 18. [Epub ahead of print]

A new study turns conventional beliefs about metformin’s main site of action upside down.