Tuesday, March 24, 2009

The Problem with Insulin- Part 2

In my previous post- The Problem With Insulin - I mention concerns about a recently published consensus statement from the ADA (essentially the new ADA 2009 guidelines) which no longer recommends the new drugs Avandia and Januvia, suggest that other newer drugs (Actos and Byetta) are less preferred, and essentially leaves the recommended options to treat type 2 diabetes as metformin, sulfonylurea and insulin. I have also previously mentioned that though the older, generic medications do work, most patients will eventually fail the pills. This means that the "new" guidelines essentially recommend using old pills until they fail, and then everyone goes on insulin. The problem is that insulin is not benign, and it may not be the best way to go.

Three studies presented June 2008 the ADA (VADT, ACCORD and ADVANCE which I have blogged about before-here and here) not only failed to show cardiovascular benefit with aggressive diabetes control, but there was substantial hypoglycemia in the intervention arms (which used more insulin) and in ACCORD, the study was stopped early because of increased deaths. Regarding ACCORD, some the experts stated that " it is biologically plausible that severe hypoglycemia could increase the risk of cardiovascular death in participants with high underlying CVD risk.

Two new studies give further evidence to this hypothesis. The first is from the New England Journal of Medicine and has been mentioned in multiple news reports. The NICE-SUGAR trial randomly assigned 6100 medical-surgical ICU patients to intensive control (sugars between 81 to 108 mg/dL) or to conventional control ( sugars 180 mg/dL or less) and achieved these targets with the use of intravenous insulin. Patients who were in the intensive group had about a 14% increase in death. Not surprisingly, severe hypoglycemia (sugars less than 40) occurred in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001).

Another study, not given the same degree of media attention, was also published in today's Archives of Internal Medicine. This study looked at close to 400 outpatient diabetics on insulin, and gave half metformin in addition to insulin (the other half got placebo). Doctors could increase the insulin in both groups and both groups tried to achieve the same targets for sugar control. After 4.3 years' follow-up, there was no difference between groups in the composite outcome of microvascular disease (e.g., progression of retinopathy, nephropathy, or neuropathy) and macrovascular disease (e.g., MI, heart failure, stroke, or diabetic foot). However, macrovascular disease by itself showed a nearly 40% reduction for the patients taking metformin. By treating just 16 patients with metformin on top of insulin, as opposed to insulin alone, you could prevent one heart attack, stroke, etc. Though you can read this study as "metformin is good," I read the study as "insulin may be bad." The patients on metformin, not only achieved better sugar control, but did so using LESS INSULIN, and heart attacks were prevented.

Don't get me wrong. Insulin is a wonder drug, particularly for Type 1 diabetics who would die without it. However, for Type 2 diabetics there are other choices. Besides the fact that insulin seems to be linked with heart attack and deaths, patients can suffer even from mild hypoglycemia, they have to check their sugars much more regularly, and they have to inject themselves, which can't be too much fun.

My concern is that despite having other options, despite the burden on patients, and despite more and more evidence showing that insulin (in type 2 diabetics) can be harmful; the new ADA guidelines continue to promote insulin use even more than a few years ago. Why would they do this? Instead of pushing type 2 diabetics to insulin earlier and earlier, shouldn't we be saving this as a last resort (like surgery or dialysis) once all other options have failed? As I have speculated before, it is the endocrinologists that make the guidelines, and they may have a bias toward keeping patients on injectable agents.

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