Older Human Insulins May Work As Well As Newer Insulins for Type 2 Diabetes

What are older insulins?

In the 80’s, researchers found a way to create “human” insulin, improving on previous versions extracted from cows and pigs, to mimic natural human insulin. Humulin was the first such human insulin to go to market.

Some human insulin comes in regular (or short-acting) form, which is best administered 30-60 minutes before a meal and takes about 2-4 hours to reach its peak. (The “peak” refers to when insulin is most effectively lowering glucose, or blood sugar, in the body, and is ideally timed to match when your body is absorbing sugar from a meal at the highest rate.)

Human insulin is also available as NPH (or intermediate-acting) insulin, which is as close to basal insulin as human insulin can get. NPH insulins are regular insulins mixed with microcrystals, so it is absorbed more slowly in the body. The onset time for NPH insulins is 2-4 hours, and they take about 4-8 hours to peak.

Human insulin brands available today include Humulin and Novolin. A combination of regular and NPH insulins, or a pre-mixed version (like Humulin 70/30), is typically used to maintain daily insulin profiles.

What are newer insulins?

Newer insulins refer to insulin analogs—essentially, human insulins whose proteins have been tweaked to change how quickly the insulin gets absorbed. Insulin analogs were introduced in the late 90’s.

Bolus insulin analogs, or rapid-acting insulins, are absorbed into the bloodstream more quickly than human, short-acting insulins. Taken only 15 minutes before a meal, they peak in 1-2 hours, half the time it takes for human insulins. Because of this sharper peak, they offer more flexibility in routine: You can have an earlier or later meal and adjust injection times accordingly.

On the flip side, long-acting insulin analogs more closely mimic natural basal or background insulin profiles than intermediate-acting insulins as they have a short onset, no real peak, and stay at a steady level for a very long time. They are generally more stable and more predictable than intermediate-acting insulins, and require fewer injections throughout the day.

Rapid-acting insulin brands include Humalog and Novolog, and long-acting insulin brands include Lantus and Levemir. Then there’s Tresiba, an ultra long-acting insulin, and Toujeo, which is the same insulin as Lantus, only three times more concentrated. They are both designed to last much longer than other basal insulins, so in theory, you’ll need a smaller dose each day.

Is newer always better?

Newer insulin analogs were developed so patients could worry less about mealtime planning without sacrificing glucose control. Such innovations deserve a higher price tag, but are they absolutely necessary? The JAMA study says maybe not.

Though a more flexible schedule may mean a higher quality of life for some patients, the reality is that many Americans cannot afford these insulins. As the study suggests, older, more cost-efficient insulins may lead to better treatment adherence and overall better health outcomes because people are actually filling and taking their medications as prescribed. After all, you can’t take a medication if you don’t have the money to purchase it.

There are a couple of other financial considerations. For one, fewer senior participants in the study reached the Medicare coverage gap, or donut hole, since they paid less for the older insulin. However, the relatively unpredictable nature of older insulins should be managed with more frequent testing, which translates to more money spent on test strips.

What does the science say?

The JAMA study determined that switching patients from insulin analogs to human insulin resulted in a small but clinically irrelevant increase of average HbA1c levels (+0.14%). There was also no change in emergency room or hospital visits from hypo- or hyperglycemic episodes.

This is not the first study to compare the efficacy of newer insulin and older insulin for type 2 diabetes patients. Another recent paper, also published in JAMA, showed that in non-clinical settings, using long-acting insulin analogs (newer insulin) over NPH human insulins (older insulin) didn’t lead to reduced hypoglycemia-related hospital visits or better control of blood sugar. There was also a 2007 meta-analysis of six studies that concluded though type 2 patients using long-acting insulin analogs did show lower rates of overall and overnight hypoglycemia, there was no difference in rates for severe hypoglycemia, compared to those being treated with NPH human insulin.

What does this all mean? There is good reason to believe that patients with type 2 diabetes can safely use older versions of insulin, such as Humulin R (short-acting) and Novolin N (intermediate-acting).

Great, how do I switch insulins?

If you have type 2 diabetes and are having trouble affording the insulin analog(s) you were prescribed, the first thing you need to do is to see your doctor or endocrinologist. Switching insulin brands is not as simple as “one in, one out”. For example, long-acting insulin analogs and NPH human insulin, both used to keep glucose levels stable between meals, have very different peak and duration of action times, and cannot be used interchangeably. Because each insulin has its own glucose-lowering behavior, you will have to work with your physician and relearn what dosage and frequency to inject at, especially when working to strike a balance between bolus and basal insulins.

Here are your insulin options:

Bolus (mealtime) insulin

Basal (background) insulin

Pre-mixed basal insulin

Pre-mixed bolus + basal insulin

What about “Walmart insulin”?

Walmart retail stores across the country carry Novolin insulins under the brand “ReliOn”. They typically cost the same as their Novolin counterparts—about $25 for a 10ml vial of 100 units/ml.

It’s important to keep in mind that ReliOn, like all other human insulins, is less predictable than insulin analogs, with more variability in glucose-lowering effects from one person to another. If you’ve read this far, you’ll know that this blog post and the studies it cites are only relevant to those with type 2 diabetes. Human insulins are less effective for those with type 1 diabetes, and type 1 advocacy group T1International has even issued a statement against relying on ReliOn, or “Walmart insulin”, in non-emergency situations.

What about people with type 1 diabetes?

You might be wondering, “Why don’t human insulins work as well for people with type 1 diabetes?”

Think of it this way: Type 1 diabetes and type 2 diabetes are two different diseases with different causes, and therefore should be treated differently. People with type 1 don’t produce insulin at all, while those with type 2 don’t respond to insulin or don’t produce insulin as effectively as the average person. Type 1 is an autoimmune disease, and type 2 is a result of different genetic and lifestyle factors.

Type 1 patients must take insulin so their bodies are able to process glucose from food. For type 2 patients, insulin is just one of several lifestyle and medication changes to help manage (and perhaps even reverse) their condition. Because of this, type 2 patients may be less sensitive to insulin changes.

How do you treat type 2 diabetes?

With the onset of type 2 diabetes and even pre-diabetes, the recommendation is to start with being more active, eating a more balanced diet, and losing weight. Then, the first-line medication treatment is metformin, which reduces how much glucose the liver releases throughout the day, lowers how much glucose is absorbed from food, and improves the body’s sensitivity to insulin. Other commonly prescribed medications like sulfonylureas (e.g., glipizide, glimepiride) and meglitinides (e.g., repaglinide, nateglinide) help the pancreas make more insulin.

Insulin is not always necessary to treat type 2 diabetes, and was traditionally only prescribed in later stages of the condition. But now, some doctors believe that insulin should be used sooner by type 2 patients for better glycemic control earlier on. However, patients should still aim to improve the body’s response to insulin, as large injections of insulin over time can lead to injection site reactions, weight gain, and high blood pressure.

Again, the difference here is that type 2 patients can usually produce some insulin on their own, while type 1 patients don’t produce any at all and thus depend on insulin injections throughout the day. Because insulin is so fundamental to type 1 patients surviving day to day, more advanced insulin analogs are much more beneficial than human insulins due to their predictability and ability to more closely replicate natural insulin production in the body.

Not a single day passes by without a new reminder that insulin prices are too damn high in the US. While it’s true that the Novolin brand of insulins costs only 10%-15% of what the cheapest new alternatives cost, there is no good reason why Americans shouldn’t have access to the most effective treatments available. And perhaps it is this reality that has driven researchers to look back on older, more affordable insulins, and for us to accept that they can work just as well in the meantime.

Note: All insulin timelines based on https://dlife.com/insulin-chart/.

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