Jay H. Shubrook, DO; James LaSalle, DO

Disclosures

March 09, 2017

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Insulin: Helpful or Harmful?

Jay H. Shubrook, DO: Hi. I am Jay Shubrook, DO, a family physician and diabetologist. I am a professor at Touro University, in California. I'm joined today by Jim LaSalle, DO, family physician and diabetes expert. We are going to talk about the safety of insulin as it relates to systemic disease.

Insulin is a hormone, and it has many effects beyond glucose. Could you tell us about the effects of insulin and what I should be thinking about when I treat diabetes?

James LaSalle, DO: Reavens[1] told us about insulin's other effects in 1988 when he talked about insulin resistance. Steve Haffner of the San Antonio Heart Study[2] told us that insulin resistance has other effects that may include cardiovascular issues.

Insulin resistance has consequences. Insulin resistance is defined by the failure of insulin to function biologically at usual concentrations. Those may be the key words—"at usual concentrations."

The metabolic effect of insulin resistance is hyperinsulinemia. Hyperinsulinemia is associated with elevations of systolic blood pressure and heart rate, and changes in lipids, including elevated triglycerides, low high-density lipoproteins, and small dense low-density lipoproteins. These are very atherogenic particles. Furthermore, hyperinsulinemia changes smooth-muscle proliferation and causes weight gain, central obesity, inflammation, visceral adiposity, and everything that goes along with these changes.

So as a result, the question at hand was this: If you give exogenous insulin to people who already have hyperinsulinemia, are you really doing anything to help them, or are you actually worsening their disease process?

Insulin and Cardiovascular Disease

Dr Shubrook: When I am talking with my patients, I get the question, "Is it safe to take insulin? Am I going to have problems with my heart if I take insulin?" How do you address the cardiovascular effects of insulin? Is it safe to take? What do you tell your patients?

Dr LaSalle: The safety of insulin was controversial a number of years ago. Then along came the ORIGIN trial,[3] which looked at giving insulin to patients with prediabetes, those with early diabetes, and those with diabetes and cardiovascular disease. The question was whether insulin was going to harm them. This trial was designed to answer that question that we get from patients.

The trial lasted about 6 years, and a follow-up study (the ORIGINALE trial[4]) went on for another 2.2 years. After about 8 or 9 years of insulin therapy, the good news was that exogenous insulin in patients with insulin resistance had no negative effects. It did not increase cardiovascular disease, nor did it decrease cardiovascular disease.

Dr Shubrook: We know that improved glucose control reduces microvascular complications, and at least in long-term epidemiologic studies, it appears to decrease macrovascular complications. It's important to remember that we need to treat diabetes.

Dr LaSalle: Absolutely. Diabetes is still the thing that we are treating. The other benefits from insulin are just the icing on the cake.

Cancer, Diabetes, and Insulin

Dr LaSalle: As we achieve success in treating cardiovascular issues and diabetes, the death rates are decreasing. Everything is getting better. The untold consequence is that patients with diabetes die of both cardiovascular disease and cancer. The better we are in treating cardiovascular disease, the worse the outcomes look for cancer down the road, because people live longer and then they are exposed to the things that cause cancer in diabetes.

Dr Shubrook: Cancer is a hot topic as it relates to diabetes. Type 2 diabetes increases the risk for many types of cancer. What about insulin? There was a discussion for a while that insulin might affect growth factors, thereby raising cancer risk. What do you tell your patients?

Dr LaSalle: In the evolution of insulins, when we started to modulate the human insulin molecule, we began to add side chains to the B chain of the insulin molecule. Scientists were worried that this modification, although it had positive effects on glucose lowering, might increase the molecule's affinity for the insulin-like growth factor (IGF) sites, causing cellular proliferation and potentially, mitogenesis. They were also worried about decreasing apoptosis. Unlike causing de novo carcinogenesis, if you already had tumor cells, these insulin analogues might make those tumor cells grow. There was concern about that.

Kurtzhals and colleagues[3] found that insulin glargine has a sixfold increase in affinity for the IGF-1 receptor, and this caused a lot of concern. People started getting very worried about giving this type of insulin to patients over a long period, wondering whether and would it cause cancers.

The ORIGIN study, which randomly assigned more than 12,500 patients over a period of 6-9 years, showed no evidence of increase in cancer.[5] This was significant, as there were reports from Europe about glargine causing cancer. It made us all feel more comfortable in prescribing these new insulins.

Dr Shubrook: In summary, we can certainly use insulin effectively in diabetes, and there is good evidence that we can get improvement in diabetes-related complications. People with diabetes are at higher risk for cardiovascular disease and cancer. As we do better at managing the disease, patients will be more susceptible to the problems that we all face.

Dr LaSalle: It's important to note that observational studies of patients taking high-dose insulin for 15 years or longer found that their risk for cancers of the breast, uterus, bladder, and skin increased. Providers who treat patients with high-dose insulin need to be on the lookout for this situation. For low- or moderate-dose insulin, I don't think there is any risk at all.

Dr Shubrook: How do you define "high-dose insulin"?

Dr LaSalle: It is 1 U/kg/day. If a patient is exceeding that level of insulin, then there should be some due diligence in screening for cancers, particularly if the therapy is long term. For short-term therapy (eg, the patient is having surgery and needs high-dose insulin for a short period), it's not an issue. But this is a big problem in patients who are on 100-150 U daily long-term.

Dr Shubrook: Insulin is a powerful medication. It has no ceiling effect, but there is a point of diminishing returns with very high doses of insulin, particularly in people who are very insulin-resistant. With so many classes of medicine today, hopefully we would be looking at multiple strategies, other than insulin alone, to achieve glycemic control, at least in type 2 diabetes.

Dr LaSalle: Correct. We need a multimodal effect with diabetes in 2017 and beyond. We know the mechanisms of action. We need to treat core defects beyond pure beta-cell failure.

We also want to reduce cardiovascular disease. We now have a couple of drugs that have been shown to decrease cardiovascular disease in diabetes. This important topic will be much talked about this year and beyond, because this is the first time that, with certain medications, we have been able to change the course of human events in diabetes.

Dr Shubrook: Thank you for sharing some very important insights on a difficult topic.

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