A dual-hormone bionic pancreas

Year in Review: Top Diabetes Stories of 2014

A dual-hormone bionic pancreas, turning stem cells into beta cells, and new insulin options top the list.

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• by Kristina Fiore 
  Staff Writer, MedPage Today

 
• This article is a collaboration between MedPage Today® and:
   

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MedPage Today surveyed several diabetes experts for their thoughts on the top milestones in the condition for 2014. From novel insulins to advances in the artificial pancreas, the majority said it was an exciting year for the field.

1. Dual-Hormone Artificial Pancreas

The device, developed by Edward Damiano, PhD, of Boston University, and Steven Russell, MD, PhD, of Massachusetts General Hospital, delivers both insulin and glucagon. A five-day outpatient trial -- presented at the American Diabetes Association meeting in June -- showed significant declines in plasma glucose levels without hypoglycemia concerns. The researchers have future trials planned, and hope to have the device on the market by 2017.

2. Turning Stem Cells into Beta Cells

In September, two papers reported successful transformation of human stem cells into insulin-producing beta cells. One team was led by Douglas Melton, PhD, of Harvard, and the other by Timothy Kieffer, PhD, of the University of British Columbia. Although many questions remain unanswered, experts say these papers are a significant step forward in engineering beta cells.

3. New Insulins on the Block

In August, the FDA granted tentative approval to Eli Lilly's "biosimilar" insulin glargine. The Lantus copycat will be marketed in the U.S. as Basaglar -- as soon as the company resolves ongoing patent litigation with Lantus drugmaker Sanofi. Lantus comes off patent in February 2015. Lilly's biosimilar version is already approved in Europe. "Generics and biosimilars are welcomed as the cost of these medications is exuberant in the U.S.," said Joel Zonszein, MD, of Albert Einstein College of Medicine in New York.

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Meanwhile, the third time was the charm for MannKind's inhaled insulin, Afrezza. The FDA finally approved the drug in Juneafter two earlier denials.

4. Does CV Risk Guidance Apply?

Experts have expressed concerns that recent national guidelines on blood pressure and lipid management may not apply to the diabetic population. Criticisms include a lack of specific LDL cholesterol targets (along with little direction for management with drugs beyond statins), and the possibility that a blood pressure target of 130/80 may be too strict.

5. No Legacy Effects in ADVANCE-ON

Tight glycemic control didn't reduce mortality or major cardiovascular events during the 10-year follow-up period of the ADVANCE study. "ADVANCE was a negative trial and, no surprise, remains negative," saidDavid Nathan, MD, of Massachusetts General Hospital. On the other hand, strict blood pressure control did diminish overall and cardiovascular death during that time.

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6. USPSTF Recommends Diabetes Screening

The U.S. Preventive Services Task Force recommends that adults at risk for type 2 diabetes should be screened for elevated blood sugar levels and should be treated with lifestyle interventions if they have hyperglycemia. Patients at risk include those age 45 and older, those who are overweight or obese, and those who have a first-degree relative with the disease. Previous guidance from 2008 said there was insufficient evidence to recommend diabetes screening.

7. Diabetes Complication Rates Down

Complications of diabetes, particularly amputation and cardiovascular disease, have plummeted since the 1990s, according to an April report by the CDC. An analysis of national data found that MI rates in diabetic patients dropped 68% and amputation rates were halved over the last 20 years. But experts note that rates are still high and additional reductions are needed.

8. SGLT2s Advancing in Practice

There are now three options from the newest diabetes drug class on the market: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance). A review and meta-analysis reported at the European Association for the Study of Diabetes meeting showed that the drugs are good at controlling HbA1c while simultaneously helping patients lose weight and lower their blood pressure.

"The hope is that they will catch on as we are all trying to figure out where that class fits," said George Grunberger, MD, of the Grunberger Diabetes Institute in Michigan. "Theoretically, they can be used in anyone who has functioning kidneys. In addition to fixed-dose combinations with metformin, the race is on for a fixed-dose combination with DPP-4 inhibitors."

The FDA cleared a blood test for lipoprotein-associated phospholipase A2

CARDIOVASCULAR 12.15.20140 COMMENTS

FDA Clears CAD Screening Test

Test works particularly well for black women.

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• by Crystal Phend 
  Senior Staff Writer, MedPage Today

 
• This article is a collaboration between MedPage Today® and:
   

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The FDA cleared a blood test for lipoprotein-associated phospholipase A2 (Lp-PLA2) to screen for heart disease risk.

The PLAC Test for Lp-PLA2 Activity -- a marker of vascular inflammation produced within atherosclerotic plaques -- was cleared for use in all adults with no history of heart disease.

But the test is best at discerning risk in women, particularly black women, the FDA announcement noted, citing its review of subgroups within the validation study.

That study in a subset of 4,598 people ages 45 to 92 without any heart disease history in the NIH Reasons for Geographic and Racial Differences in Stroke study showed that individuals above the threshold level for Lp-PLA2 were more than twice as likely to have an event (rate 7.0% versus 3.3%).

Lp-PLA2 activity greater than the threshold of 225 nmol/min/mL is considered elevated risk for a heart attack or other coronary heart disease event.

The label will show separate performance data for black women, black men, white women, and white men.

A prior meta-analysis supported that activity as distinct from the inflammatory marker C-reactive protein.

The test is manufactured by diaDexus, based in South San Francisco, Calif.

Antibodies Predict Scleroderma Renal Crisis

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Antibody test aids assessing risk for this potentially lethal complication.

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• by Nancy Walsh 
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The presence of a specific group of autoantibodies in patients with scleroderma was associated with a high risk of renal crisis, Japanese researchers reported.

The scleroderma renal crisis occurred in 24% of patients who had anti-RNA polymerase III (RNAP III) antibodies but in only 1% of those without these autoantibodies, for an odds ratio of 21.6 (95% CI 7.8-60.3, P<0.00001), according to Manabu Fujimoto, MD, of theUniversity of Tsukuba in Ibaraki, and colleagues.

And in a multivariate analysis that adjusted for relevant factors such as steroid use and modified Rodnan skin scores, positivity for all three subclasses of RNAP was independently associated with the development of renal crisis (OR 11, 95% CI 1.6-222.8, P=0.0118), the researchers reported online in Arthritis and Rheumatology.

Scleroderma renal crisis, characterized by acute progressive loss of kidney function and accelerated hypertension, is a particularly dangerous development associated with high mortality.

More than 90% of patients with scleroderma, also known as systemic sclerosis (SSc), have detectable antinuclear antibodies. Several types of these antibodies are SSc-specific, including antibodies against centromeres, topoisomerase I, and RNAP III.

"Importantly, antinuclear antibodies are closely associated with distinct clinical subsets, and thus detection of SSc-related antibodies is useful not only in the diagnosis, but also for predicting forthcoming organ involvement and prognosis," Fujimoto and colleagues wrote.

Some previous research has identified anti-RNAP III antibodies as being present in about one-third of patients with scleroderma who experienced renal crises, but more specific immunologic and clinical predictors within this group of patients have not previously been identified.

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Therefore, Fujimoto and colleagues conducted an analysis of 583 patients seen between 1995 and 2012 at two Japanese centers.

Clinical assessments included modified Rodnan skin thickness scores and progression rates, organ system involvement, and ELISA and immunoprecipitation assays for anti-RNAP.

Among the cohort, 60% had the limited cutaneous form of scleroderma, while the remainder had diffuse cutaneous disease. A total of 37 (6%) had positive ELISA assays for anti-RNAP III, and most of these had the diffuse cutaneous type.

On the immunoprecipitation assays for RNAP, 17 of the 37 patients were positive for all three classes of anti-RNAP (I/II/III), 19 were positive for the I and III forms, and one was positive only for anti-RNAP III. For the purposes of the analysis, the patient who was positive for only the III class was included with the I/II/III group.

Scleroderma renal crisis occurred in 17 patients (2.9%), nine of whom were anti-RNAP positive. Renal crisis also occurred in eight patients out of 546 who were anti-RNAP negative but had other autoantibodies such as anti-topoisomerase I.

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Eight of the anti-RNAP-positive patients received corticosteroids, most often in dosages higher than 15 mg per day.

The researchers then compared clinical characteristics of the nine anti-RNAP-positive patients who developed scleroderma renal crisis with 28 antibody-positive patients who had no renal crisis, and found only nonsignificantly higher Rodnan skin scores in the renal crisis group (21 versus 17, P=0.2778).

There also was no difference in steroid doses, but significantly higher ELISA indexes, which were determined by the receiver operating characteristic curves for anti-RNAP III, were identified in the renal crisis group (250.4 versus 141.6, P=0.0013). In addition, the ELISA index showed a positive correlation with skin scores (R2=0.11365, P=0.0413).

In a univariate analysis, factors that were significantly associated with the occurrence of scleroderma renal crisis were positivity for anti-RNAP I/II/III, with an odds ratio of 16.9 (95% CI 1.8-156.3, P=0.0055) and the ELISA index for anti-RNAP III being above 157, with an odds ratio of 33.5 (95% CI 4.2-268.2, P<0.0001).

The ELISA index also remained significant, along with anti-RNAP I/II/III positivity, in the multivariate analysis.

The authors noted that ethnicity is an important factor in anti-RNAP-III positivity. In a U.S. cohort, 25% of patients were antibody positive, as were 15.3% of Australian patients and 4% of French patients. In a previous study of Japanese patients, the prevalence was 10.7%, similar to the 6% seen in this study, "confirming our previous finding that anti-RNAP III is more prevalent in North American than in Japanese SSc patients," the authors noted.

"Our findings should be confirmed in a large-scale study of patients of different ethnicities in future studies," they concluded.

The authors disclosed no financial conflicts of interest.

• Primary Source

  Arthritis and Rheumatology

  Source Reference: Hamaguchi Y, et al "Clinical and immunological predictors of scleroderma renal crisis for Japanese systemic sclerosis patients with anti-RNA polymerase III autoantibodies" Arthritis Rheum 2014; DOI: 10.1002/art.38994.

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Thrombectomy and other intra-arterial treatments shone in MR CLEAN trial.

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Stroke Rounds: Clot Removal Proves Mettle in Large-Vessel Strokes

 
 
 
 
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• by Crystal Phend 
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• This article is a collaboration between MedPage Today® and:
   

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Thrombectomy improved functional outcomes in severe stroke with proximal large-vessel occlusion treated up to 6 hours after stroke onset, the MR CLEAN trial showed.

Good functional outcome at 3 months was 67% more likely in the intra-arterial treatment group after adjustment for other factors than with usual care alone (95% CI 1.21-2.30), Diederik W. Dippel, MD, PhD, of Erasmus MC University Medical Center in Rotterdam, the Netherlands, and colleagues found.

Survival with little or no disability as measured by a modified Rankin score of no more than 2 occurred in 32.6% of patients who got intra-arterial treatment compared with 19.1% who got medical treatment alone, they reported online in the New England Journal of Medicine.

The intra-arterial treatments used were predominantly retrievable stents (82%) atop IV thrombolytics (87%), with the rest largely accounted for by additional thrombolytics given directly into the affected artery.

Mortality came out similar between groups, and there was no excess risk of symptomatic intracranial hemorrhage with the interventional strategy in the trial.

A Society of NeuroInterventional Surgery release called it the "most significant stroke treatment clinical trial since NINDS-2," which led to approval of IV tissue plasminogen activator (tPA).

"While IV-tPA revolutionized stroke care, it must be administered within 4.5 hours," the statement pointed out. "Neurointerventional surgery can be performed up to 6 hours from the onset of stroke, significantly expanding the treatment window."

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It's too soon to call this strategy the standard, though, cautionedWerner Hacke, MD, PhD, of Germany's University Hospital Heidelberg, in an editorial accompanying the NEJM paper.

"Several similar trials are ongoing," he wrote. "We need and will get results from other well-designed trials, not only to confirm or refute the results of MR CLEAN but also to look at effects in subgroups (according to stroke severity, occlusion site, or time to treatment initiation), for which most single trials are underpowered.

MR CLEAN is the first step in the right direction."

A Change in Direction

That direction hasn't been supported by prior thrombectomy trials.

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The SYNTHESIS Expansion andInterventional Management of Stroke (IMS) III trials both showed no impact of endovascular therapy on survival without disability compared with conventional treatment with IV tPA alone.

The MR RESCUE trial showed no benefit of endovascular mechanical clot removal for large-vessel, anterior-circulation strokes selected by MR or CT imaging.

The reason for the different results in MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands) could have been several, Hacke suggested.

"These trials were criticized for their use of older recanalization devices," he wrote, "which were associated with lower recanalization rates than those found with newer devices such as retrievable stents; for the long interval between the onset of stroke and intervention; and for disappointingly low recruitment rates, which suggested that many suitable patients had been treated outside the trials.

Perhaps most important, two of the trials did not require evidence of an occluded vessel before randomization, thereby making intracerebral treatment futile from the start."

Addressing Quality Issues

MR CLEAN addressed those concerns by using modern thrombectomy devices -- almost all used were retrievable-stent types, which Hacke said have a track record of successful recanalization -- and by quick enrollment because the Dutch government would only pay for thrombectomy in the context of a randomized trial.

The trial required all patients to be able to initiate intra-arterial treatment within 6 hours of onset of a stroke with occlusion of the distal intracranial carotid artery, middle cerebral artery, or anterior cerebral artery proven by CT, MRI, or digital-subtraction angiography.

Of the 500 patients at 16 medical centers in the Netherlands randomized to treatment with intra-arterial treatment plus usual care or usual care alone, almost 90% received intravenous thrombolysis first.

All secondary clinical and imaging outcomes favored the interventional strategy, although Hacke noted that the recanalization rate came in a bit below expected (59% with good reperfusion score compared with 80% or higher in recent case series).

Serious adverse events were no different between groups, although the new ischemic stroke rate at 90 days was higher with intra-arterial treatment (5.6% versus 0.4% among controls).

Procedure-related complications included embolization into new territories in 8.6%, procedure-related vessel dissection in 1.7%, and vessel perforation in 0.9%.

From the American Heart Association:

• Science News from ISC 2014
• New Guidelines for the Early Management of Patients with Acute Ischemic Stroke