The Problem With Insulin

Before folks like Amy Tenderich at her excellent blog Diabetes Mine gets upset with me, insulin is a miracle of modern science. Frederick Banting and J.J.R. Macleod's Nobel Prize wining discovery of insulin has saved millions of lives and helped to prevent countless complications of diabetes such as blindness and kidney failure. While patients with Type 1 diabetes, who produce no insulin on their own, rely on insulin therapy to survive, the use of insulin in Type 2 diabetes is more complicated, since patients with early stage Type 2 diabetes initially have high levels of insulin and some type 2 diabetics with prolonged beta-cell failure eventually stop making useful insulin. Though where and exactly how to use insulin in a Type 2 diabetic is debated, newer recommendations from the American Diabetes Association (ADA) are promoting earlier use of insulin in Type 2 diabetics, which may not be entirely evidence based or in the best interest of the patient. This has caused me great concern.


The Problems With Insulin


Insulin is not just another treatment for Type 2 diabetes. The main complication of insulin use is hypoglycemia, or low blood sugar. Symptoms range to feeling nervous to complete coma. Hypoglycemia from insulin is a frequent cause of ER admissions, hospitalizations, and can even cause death. For both for sugar management and prevention of hypoglycemia, patients who use of insulin require frequent blood sugar monitoring. Though these monitors have become easier to use for patients, this is still a burden as well as an added cost. In addition, for the best blood sugar control, many endocrinologists recommend a basal/bolus approach to insulin therapy which is one injection of a 24 hour long acting insulin (like Lantus) and mealtime injections of short acting inuslins (like Humalog). Thus, the basal/bolus approach requires four injections a day and several sugar checks.


Though insulin is the most effective agent for lowering blood sugar, this may not be the best thing for all type 2 diabetic patients. Three studies presented this summer at 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.

In the January issue of Diabetes Care (the ADA's journal which each year publishes updates to their guidelines), a paper explaining how to interpret these studies come to similar conclusions of my previous posts, mainly that good diabetes control (A1c less than 7%) is still very important. They also mention " it is biologically plausible that severe hypoglycemia could increase the risk of cardiovascular death in participants with high underlying CVD risk. This might be further confounded by the development of hypoglycemia unawareness, particularly in patients with coexisting cardiovascular autonomic neuropathy (a strong risk factor for sudden death). Death from a hypoglycemic event may be mistakenly ascribed to coronary artery disease, since there may not have been a blood glucose measurement and since there are no anatomical features of hypoglycemia detected postmortem."

In other words, it may have been hypoglycemia, which is caused primarily by insulin, that killed the aggressively treated diabetics.

In fact, a recent commentary in JAMA similarly mentions that "the paradox that blood glucose levels are strongly associated with the risk of cardiovascular disease but that glycemic control does not prevent cardiovascular disease may perhaps be explained by insulin resistance or hyperinsulinemia." and "If insulin levels are toxic to the cardiovascular system, then treatments designed to reduce insulin levels rather than glucose levels might be associated with a reduced risk of cardiovascular events in patients with type 2 diabetes."

In other words, glycemic control is important, but other factors such as insulin levels and insulin resistance might be more important, so driving down the sugar with insulin in type 2 diabetics may not have been the way to go.

The Problem With the Older Diabetes Pills


The two most commonly prescribed (and guideline recommended) pills for diabetes are metformin and sufonlyureas. They are generic, inexpensive, have a long track record, and will lower blood sugars in type 2 diabetics. The problem with these medications (beside side effects, particularly hypoglycemia with sulfonylureas), is that they only work for a short period of time.

Analysis have shown that though both metformin and sufonlyurea lower blood sugar; and, compared to usual care, those whose goal A1c was less than 7% had lower microvascular (eye and kidney problems) complications; about half of all patients taking either of these medications lost diabetes control by three years, with the vast majority losing control at 9 years. Though a recent report on the UKPDS showed that just being in the intervention group reduced heart attacks and strokes 10 years after the follow up period, imagine how many heart attacks and strokes might have been prevented had patients maintained glycemic control over a much longer period of time!

It should be no surprise that patients fail on metformin and sufonlyurea because they primarily work by lowering sugar, and don't seem (especially with sufonlyurea) to address the underlying defects of type 2 diabetes which are insulin resistance, beta cell dysfunction and glucose regulation. The good news is that newer agents for diabetes do address this. Published on December 7th, 2006, in one of the largest diabetes studies ever done, the ADOPT trial showed that Avandia, a thiazolidinedione or TZD, substantially reduced loss of diabetes control compared to both metformin (Avandia 32% better) and sufonlyurea(Avandia 63% better). TZD's work by reducing insulin resistance, and also can improve beta cell dysfunction and both effects were seen in ADOPT. After 5 years of treatment, only 15% of patients failed on Avandia monotherapy. This is far better than the failures from UKPDS.

The Problem With the Diabetes "Experts"

You would think that with all the problems with insulin and the older diabetes pills that diabetes experts and researchers would welcome newer therapies for Type 2 diabetes, but the trend is just the opposite.

In the editorial to the ADOPT study, Dr. David Nathan, author of the current American Diabetes guidelines stated that "given the modest glycemic benefit of rosiglitazone and higher cost metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes." Yet, at this point in time, even he seemed convinced that Avandia was a better second choice then sulfonylurea, stating "the benefits of rosiglitazone over glyburide, which is often not recommended for older patients because of its increased risk of hypoglycemia, are more convincing. "

However, only a few months later (2/1/2007), in response to the recent approval of Januvia, Dr. Nathan published this Perspective piece in the New England Journal of medicine , in which he railed against new diabetes medicines stating that newer diabetes drugs like Avandia and Januvia , "are generally no more potent, and often less effective in lowering glycemia, than the three oldest classes (insulin, the sulfonylureas, and the biguanides), all of which are more than 50 years old. Moreover, the newer classes are uniformly more expensive and are associated with adverse effects — some that are shared by the older drugs, but others that are new." In essence, Dr. Nathan is suggesting (despite the problems with insulin and the failure of the older drugs that I mentioned above), that we just stick with the status quo, and use caution before approving newer diabetes medicine. See my Letter to the Editor in the NEJM criticising this position.

The current guidelines for the medical management of diabetes (which are taken directly from Dr. Nathan's previous consensus statement) state the patients with Type 2 diabetes should be started on metformin, and when that fails, add either sulfonlyurea, insulin or TZD. The language of that paper states that TZD's are an option, but are expensive and cause side effects. In the more recently published consensus statement (also authored by Dr. Nathan) that will likely be adopted in the 2009 guidelines, Avandia and Januvia are not recommended. The recommended choices of treatment for type 2 diabetes are metformin, sulfonylurea and insulin. Less preferred are Actos and Byetta. Thus, given that we know the older medications fail, the newer guidelines will likely push more and more type 2 patients to use insulin. I have previously commented that this trend is already happening.

I recently blogged about conflicts of interest that go beyond the drug companies, and used the example of differing prostate cancer screening guidelines. The government's guideline (which wants to save money) does not recommend this practice, where as the urologist's guidelines (who benefit from aggressive screening) do recommend prostate cancer screening. Both guidelines use the same studies, and neither guideline is right or wrong, but must be interpreted from the perspective of the authors.

So, given the problems with insulin and the older diabetes pills as elicited above, why would the "experts" of the new guidelines recommend these therapies over newer therapies with potential benefits (and leave out some newer therapies altogether)?



One answer (in my opinion) is that endocrinologists make recommendations that will lead more patients toward insulin is because they have an incentive to do so. Most patients with type 2 diabetes are cared for not by specialists but by primary care physicians. Though many primary care physicians are quite comfortable using insulin, many referrals to endocrinologist come from primary care because a patient has failed pills and now needs to be started on insulin. Insulin therapy requires substantial time, education and close patient follow up. This is time that many PCP's simply don't have, whereas most endocrinologists work with a certified diabetes educator who is specifically trained just for this purpose.



One can look at the failure of Exubera, Pfizer's inhaled insulin, as evidence of how many endocrinologists cling to injections. Pfizer did not pull Exubera because it didn't work (worked great) or that patients didn't like it (my patients and I were extremely upset when this was pulled), but because endocrinologists didn't prescribe it. Whereas endocrinologist see starting insulin therapy as common and easy, my perspective as a PCP is that patients do not want to take insulin and see it as an absolute last resort. (Based on the evidence above, I would tend to agree).



The Problem With the New ADA Guidelines

To be fair, not all endocrinologists agree with the ADA or Dr. Nathan, similar to the way not all Republicans agree with George Bush. However, guidelines, especially ones from such as prestigious group as the ADA, have a tremendous influence on the way that primary care physicians practice medicine. Thus, these guidelines will likely have a tremendous impact on the way future diabetic care is delivered.

The problem with the new guidelines is that they been extremely affected by two factors: one poorly done, controversial study on Avandia (see here ) and one (or a few) highly influential endocrinologist, like Dr. Nathan, who sees no need for new diabetes meds, and would prefer that once patients lose control on the two older medicines most commonly used (which most will based on the data), that they be started on insulin. Furthermore, these recommendations which will encourage more insulin use are coming from specialist who might have an incentive to make such recommendations. Thus, these recommendations are not entirely evidence based and seem not to be in the best interest of patients to whom insulin is a burden and potential danger.