I have searched the literature and I haven't been able to find any studies comparing the 3 rapid acting analogs against each other. The data on duration of activity generally come from studies carried out by the manufacturers and (perhaps not surprisingly) each compares their analog against recombinant human insulin (aka regular insulin).
Any comparisons on duration of interaction are therefore indirect because the numbers come from separate studies and it is therefore possible that any differences are attributable to differences in the way that the studies were carried out or insulin levels measured.
That having been said, comparing the insulin action graphs, there don't seem to be any significant differences in the time after injection at which activity reaches a peak. However, the DIA (defined as the time at which 95% of the insulin has cleared the blood) of Apidra seems to be slightly shorter at around 4 hours than Humalog and Novorapid (5-6 h).
I switched from Novorapid to Apidra whilst I was still on MDI, and found that the activity had a shorter tail which helped to avoid hypos around 5 hours after injection. As I have said in another post, I recently switched to Humalog because of problems with premature site deterioration using Apidra. I use a Dexcom and with Humalog I can still see action from a bolus at around 5 h whereas with Apidra the activity was pretty much over after 4.5 h.
I have used all three rapid acting analogs in a pump in conjunction with a CGMS for long periods of time and found there was not enough difference to justify any pump program changes. Basal, Bolus timing, I:C ratio, and duration settings all stayed the same. I do prefer Novolog® in my pump but have always liked Humalog® for doing Big corrections with a syringe, the curve and duration seems to be the best fit for this particular purpose as my post correction BG seems to end up closer to my intended target on the first try. I do have some kidney and liver issues so my duration is probably different than the none diabetics that where used as test subjects in the clamp down study's.
Today human insulin can be produced by any company. The protection by patents is long gone. The reaction of pharma companies was to recombine the DNA - to invent something "new". This recombination had the protection of new patents. Here companies in US and Europe have set the standards. Of course there are other benefits as well. For me they act much quicker but this is not true for all patients. Still the companies reduced and in many cases stopped the production of ordinary human insulin. This forced many patients even T2 patients to use analog insulins. This was very good for pharma revenue because they could establish much higher prices. Now these companies see that their analog patents are running out again. Companies in China and India are rapidly adopting pharma technology - especially the use of DNA recombination on bacteria and candida. It seems that the companies owning the current patents have decided to milk their patients as long as they are protected by their patents. This is the real driver behind the rising prices. This strategy works very nice in unregulated markets like the US market. Patients depending on specific drugs have only little choice - they have to accept the high prices. In Europe many states are regulating pharma by limiting the revenue per vial. This is possible because these states have regulations that allow all citizen to benefit from health services. Potential deficits are covered by the state itself. Thus the state has a natural interest to regulate the access of pharma companies to this market (only specific medications are covered, prices are negotiated). If Germany fails to regulate these companies or is too generous other states in Europe will. Since Europe is based on free trade for more than 700 Million people we can cover our demands in states with better prices. This pressure keeps the prices at bay. In some areas we still see obscene climbing rates. So, no Dave - you do not pay for my insulin. Instead you are the victim of a disfunctional pharma market.
The higher concentration will promote the development of hexameric structures of insulin molecules in the vial. Thus U100 insulin will unfold its activity slower than U40 insulin. The U100 concentration is important for pumps due to the limited volume of their reservoir. Parallel production and distribution for U40 and U100 is a cost factor. Thus most companies offer only U100 now. I still wonder how fast the current analogs would be in U40 concentration. VIAject for example uses ordinary human insulin in U20 concentration that acts quicker than analog insulin.
Try Humulin R instead. That will open your eyes to what's fast about current rapid analogs.
There are many long-term T1s here that can speak far more effectively to the miracle long-acting basals and short-acting bolus insulins are compared to the old N/R regimen.
These advances have made a significant difference in improved control, and reduced complications for millions of diabetics. These seem to me to be incredibly valuable advancements. As a diabetic, I'm extremely grateful.
These treatments took enormous investments to discover, and turn into a safe product. Why so many diabetics seem to feel entitled to these innovations just, well... I have a different value system. Like I said, I'm grateful.
I don't look at the price I'm paying to determine if I'm getting ripped off by the manufacturer. I look at their business financials. And that sure looks to me like they need all the revenue they're getting to produce the relatively modest profit they do year to year.
So there must be some other explanation for why we pay $125 a vial in the US, while our fellow diabetics elsewhere pay $25.
The case simply can't be made that it's greed and gross profits on the part of the drug companies. The facts don't support that assertion. I claim it's a regulatory environment that results in US diabetics having to substantially subsidize the cost of these drugs for everyone else. I know this stings if your on the other end of that assertion. However, if there's no basis for the greed claim, and you reject the subsidy claim, then what's the explanation?
Note the facts once again: Lilly is not making obscene profits, by any measure. As such, I expect that if they charge $25/vial for humalog in the US, the financials very well may not support development an manufacture of the drug at all.
Just 4-5 years ago, "full retail" for Humalog and Lantus was circa $60. Today it's $125+. I do not understand the doubling in price. You would think that if they were amortizing research costs, that the cost would not be going up.
In any event, those are "full retail" and it's very likely that reimbursement from insurance companies is at a very different (presumably lower) rate. That's just wrong too - if insurance companies want us to make wise and informed decisions as consumers about health care costs, hiding the back-room "preferred formulary" deals from consumers is not going to do it.
I'm not opposed in principle to the sort of Marshall-Plan-for-insulin that you suggest is happening, but I don't feel that is what's happening here. If we wanted to have a formal policy like the Marshall Plan, where the US shoulders the burden for research costs and gets the street cred for helping third world countries get the drugs at reduced costs, I would definitely support that.
Some more information about the patent situation can be found here. Interesting to read that the patent for Lantus already ended in 2013. In contrast to the author I do not fear that biosimilar insulins from other manufacturers might contain impurities. These manufacturers will have a learning curve but this is similar to the curve of the current market leaders.
I agree that it is highly unlikely that biosimilar insulins will contain impurities. As I have posted elsewhere, the technology is now pretty standard
Here is a key quote from the link posted by Holger.
“Proteins like insulin are different. They are built from a small number of identical small molecules (amino acids), the same ones often being used many times over, but in a critically important order. The molecule then folds in complex ways which are necessary to its biological action. Showing that a protein molecule like insulin has the right number of amino acid components is easy, but showing that they are all in the right order, and that the molecule is folded correctly, is very difficult.”
In fact, the last sentence (which I have highlighted) is not correct. Showing that the amino acids are in the correct order and that they have folded correctly is straightforward and requires technology/equipment that is in use in tens of thousands of labs worldwide.
It is worth adding that in any case, proteins produced in microorganisms using recombinant DNA techniques will not contain amino acid sequence errors and ensuring correct folding is again straightforward. A major attraction of using recombinant DNA technology is in fact its simplicity.
I'm not opposed in principle to the sort of Marshall-Plan-for-insulin that you suggest is happening, but I don't feel that is what's happening here.
Then what do you think is happening here?
The price differential between what US diabetics pay and what everyone else in the world pays is huge -- regardless of whether we're talking about the "list price", or the US insurer "contract price".
Pharmaceuticals are not making extraordinary profits.
So, what do you think is happening? Given the drug industry financials, if we all paid $25/vial for insulin analogs, out of the gate, do you think the drug companies would be profitable?
Do you think these drugs would be developed?
Again, the context of this question is simple: US diabetics pay the same low price for these drugs as the rest of the world.
Please, no one misunderstand me here: I too would -- very much -- like to see the cost of insulin in the US as inexpensive as in Canada, the UK, Germany, Italy, Spain, and on and on.
However, in my list of priorities, having it available AT ALL ranks higher than frustration over the cost.
Why doesn't Lilly charge the same price outside the US? Simple: Because if they do, the rest of the world -- including the First World -- will not play fair. They'll ignore patent law, justified by ethical arguments about people's lives. While at the same time ignoring ethical arguments about sharing in the cost to developing these drugs.
Interesting... A pack of 5 pens then contains 52 mg pure insulin.
My TDD is 40 units so in a year it will amount to only 0.5 gram insulin.
It will be diluted in 0.15 liters of water and other additives.
In my country, the price per KG pure insulin is more than 2 million US$. A quick google for expensive materials, insulin is not mentioned but would be high up on the list - over gold and illegal drugs, but less than diamonds and very specialized materials made in nuclear reactors.
While insulin (like all health care items) are "free" to the patient in the UK, they aren't really free as we pay for them though general taxation which means no matter who you are, be a millionaire or the homeless, you will always get your insulin, test strips or even a pump if your doctor decides you need one. We all pay just in a different way.
I know when Lantus first appeared it cost a fortune, and got muttered at every time I picked some up due to the cost (£62 per 3ml vile at the time). It's come down now and no one cares. But with the US system where it's insurance based, a patient might get a pump for example where in the UK it's deemed not necessary. If a patient has a good A1c without any excess hypo's than they won't ever be offered one. Medical need judged by the doctor is the deciding factor here, along with available funds in an area to fund you which can be the problematic part causing you to change hospitals to get what you want.
The NHS also has a set of rules for buying things, sometimes companies won't jump to them and as such items won't become available here. A good example is Dexcom refusing to deal with the NHS and solely selling their CGM online. Sometimes the NHS will judge it simply can't afford something which would be available in the US.
There's good in bad in all systems. But I am incredibly glad I've never had to pay for anything to support being D when I read many of the horror stories online.
Thank you both for your comments; however, neither addressed the issue that is in question here: If greed/excess profits doesn't explain the pricing differential (simple fact, based on available financials), and unfair subsidy of non-US consumers by US consumers also is not the case (the explanation I claim), then what explains the price difference?
To take my favorite example, if Lilly is making a decent profit on non-US sales of Humalog -- in line with their overall, quite reasonable overall company earnings performance -- then where is all that extra, excess profit being sucked out of abused americans going? Secret accounts?
Probably still is, don't have any figures really on it. We more consider it as a good thing since everyone pays, every one has the same right to health as everyone else. I might come out about even with D costs, although many others probably won't use much at all. And others cost more. But it's good anyone and everyone can have what's necessary. It might not be perfect but seeing people on here etc. have so many issues with test strips, and even some who can't get insulin, or are doing kickstarter campaigns to try and fund a pump etc. really makes me appreciate it so much more.
Oh I would blame profits. Looking at some companies info posted for the last year of 15% profit increase over the year due to insulins, and a profit of $4.8bn on sales of $14.9bn (worldwide) I think it's a pretty healthy margin they have.
As for devices the going rate is considerably higher. A pump doesn't cost thousands, it can be made with parts bought off the internet with change from $50 buying the bits retail and not in bulk like they are doing. A sensor for a CGM costs next to nothing to make, well less than $1 per unit.
Every time medical companies get questioned on pricing they pull out the "we spend it on research" card, which is a joke. They don't finance much. Ok they do some, but the vast majority is done by universities and charities funding the research. Medical companies will see promising lines and then usually license it off the university and then develop it into a product. This isn't blindly researching, this is taking what's been shown and getting a product from it. Ok it still costs but it takes the risk out of it for them. After that it's testing and certification. This costs, but is a drop in the ocean for what these companies are making.
and a profit of $4.8bn on sales of $14.9bn (worldwide) I think it's a pretty healthy margin they have
Were that net profit, I'd agree. However, that's gross margins.
Net profit margins are more like 8-12%.
A pump doesn't cost thousands, it can be made with parts bought off the internet with change from $50 buying the bits retail and not in bulk like they are doing. A sensor for a CGM costs next to nothing to make, well less than $1 per unit.
I have no more patience to explain amortizing R&D costs for products here on TuD for a while.
It does depress me, to some degree, how misinformed so many people are about such things, render judgement based on that ignorance, and then push public policy and law on that basis. It depresses me because I see a future where innovation and miracle treatments diminish steadily in discovery -- because most people see things the way you describe above.
There is a very good reason the US far outpaces the EU in development of new and advanced medical treatments -- drugs, devices, techniques, etc.
It's not because Americans are smarter. Or more motivated. Or a host of other things. It is a regulatory regime that stifles innovation, and the main obstacle is return on investment.
I don't think that extra profits are being sucked out of americans. The actual average prices actually paid in the US are significantly less for most people. I was surprised reading Novo Nordisk financial statements explanation of rebates and chargebacks in the US. The price of insulin varies dramatically, depending on the customer. 42.3% of the selling price is given back in the form of rebates and chargebacks. The biggest recipient is Medicare/Medicaid who received 1.73 billion. Healthcare providers and wholesalers received 2.71 billion. Others? and returns was 0.517 billion. So the actual price paid to the manufacturer is discounted quite a bit. This price rebate/chargeback system looks to be happening mainly in the US. $4.95 billion was returned out of 11.7 billion in sales. In the rest of the world, only $650 thousand was for rebates and returns.
I conclude from this that if you do not have a third-payer, that's when you get shafted.
I'm not ready to throw in the towel yet, though :-) Judging by your figures, looks like on average the "real" price is about half the list price, or about $70. Still almost 3x what the rest of the world pays.
In light of the rather ordinary profit margins for these companies, it still looks pretty damning that US diabetics are subsidizing the rest of the world's diabetics.
It sure would be nice if we could simply have a single price that allows for reasonable profit (with amortized development costs factored in) that everyone pays.
Problem is, all the data suggests that is about double what non-americans pay, and they're not willing to pay it.
Novo Nordisk's profits are anything but ordinary. 2013 financial statements show 30.1% net profit on sales. They have about 59% of their sales in insulin, so are a pretty good indication of profit margins. It's harder to tell with Sanofi or Eli Lilly as they only have about 17-18% of their sales as insulin but even they had 20.3% net profit on sales.
