Where is the Management of Type 2 Diabetes Heading?

By Michael Jorrin, "Doc Gumshoe", June 26, 2014

[ed note: Michael Jorrin, a medical writer who we have dubbed “Doc Gumshoe” (he’s not a doctor), shares his thoughts with us once or twice a month — what follows is his latest missive, the words and opinions below are his alone.]

I didn’t plan it this way, but the timing of this Doc Gumshoe post couldn’t have been much better. As I was gathering material, news items from the American Diabetes Association’s 74th scientific meeting, which ran from the 13th to the 17th of June, kept popping up.

“Popping up” isn’t a bad way to describe what these news releases were doing. They were mostly modest pops, like back yard Fourth of July fireworks. Some of the news media covering this event did throw around the B word, but if any of the agents discussed at the meeting attain Blockbuster status, it will be because of the magnitude of the problem (and the opportunity!) posed by diabetes, and not because any of the drugs appear to have the capacity to work genuine miracles.

So, what’s the magnitude of the problem?

In Doc Gumshoe’s previous piece about diabetes (“The Why and the What of Diabetes Management”) there was a Tiny Addendum that noted that the Centers for Disease Control had upped their estimate of the number of persons in the US from about 26 million in 2011 to about 29 million today. That’s an increase of a million per year. Note that those figures include both Type 1 and Type 2 diabetes, and that somewhere between 25% and 30% of all diabetes is undiagnosed. Previously the ADA had stated that there were about 1.9 million newly diagnosed cases of diabetes in adults per year. Yes, those numbers are estimates, albeit careful estimates based on the best data.

And here’s another estimate from the CDC: 86 million people in the US have what is labelled “prediabetes,” i.e., insulin resistance or impaired glucose tolerance. The CDC projects that without intervention, about 30% of those persons would have Type 2 diabetes within 5 years.

That would up the total diabetic population of our fair land to somewhere in the neighborhood of 55 million individuals.

My bet is that we won’t reach that figure – that’s a worst-case scenario, and a lot of effort is being lavished on diabetes awareness, screening, healthy living, etc. Just because Mayor Michael Bloomberg’s proposed ban on half-gallon sugary drinks (or whatever size) didn’t go through doesn’t mean that Attention Isn’t Being Paid.

All the same, Doc Gumshoe wouldn’t be a bit surprised if we got to 35 – 40 million cases of frank diabetes by the year 2020.

Here’s something else: United Healthcare projects that the costs of diabetes treatment could reach $500 billion by 2020. I don’t know whether that’s meant to strike terror into the hearts of the citizenry, who would have to fork over that moolah, or to provide an incentive to the pharmaceutical industry to come up with drugs that could snaffle a chunk of that loot. However, as I write these words, the ghost of Miss Truesdell is looking over my shoulder and shaking her head. She doesn’t think that $500 billion number makes sense. The 2012 medical costs totaled $176 billion, and the $69 billion in lost productivity brings the total to $245 billion. I am skeptical about adding lost productivity to the costs of diabetes treatment, but even if we include lost productivity, I wonder whether the cost will really double to $500 billion in 8 years. Anyway, however we figure it, the whole pie is immense and Pharma wants its slice.

Big Pharma steps up to the plate

Despite the recommendation by McKinsey & Company a couple of years ago that big pharmaceutical outfits should ease back on R & D and concentrate their efforts on their “core competency,” that being sales and marketing, Big Pharma is lavishing lots of resources on R & D in the diabetes area. Here’s a quick list (by no means exhaustive) of the clinical trial activity of some of those outfits:
bigpharmatrials

No surprise that Novo Nordisk (NVO) tops the list, since they are the long-established leader in diabetes treatment products, specifically a range of insulins, but also the incretin mimetic Victoza (liraglutide). Further down, we’ll be discussing the benefits vs potential risks of the entire class of drugs that relate to incretins and the rapid insulin response, as well as the duel between Victoza and Eli Lilly’s (LLY) dulaglutide.

And here’s a list of the top 10 diabetes drugs in terms of sales:

diabetesdrugs

As you see, seven of the ten are insulin products in one of several forms, and five are Novo Nordisk products. This may come as a surprise, since the great majority of persons with diabetes have Type 2 diabetes (T2DM), which is, at least initially, usually treated with non-insulin agents. Several factors contribute to the global dominance of insulin:

  • One, eventually almost all persons with T2DM wind up needing supplementary insulin, as their pancreatic beta cells quit functioning after long years of battling against systemic insulin resistance. (We discussed this at greater length in the previous blog.)
  • Two, many persons with T2DM, particularly in less-developed regions of the world, have advanced disease at the time of diagnosis, likely beyond the stage where merely increasing the sensitivity of insulin receptors does much good. Exogenous insulin is the quick answer, and mostly does the trick.

Metformin, which is a usual first-line drug for treating T2DM, is also huge seller globally, but it’s relatively cheap. If the sales of generic metformin plus branded formulations such as Glucophage (Bristol Myers Squibb (BMY)) are added, the total dollar amount only hits somewhere between $1.5 billion and $2.0 billion.

However, another trend worthy of our notice: all three of the top sellers that are not insulin products are drugs that target first-phase insulin release through the incretin response. And many of the drugs discussed at the ADA meeting, particularly the ones that attracted the most attention, also address the first-phase insulin response. Why is this?

A bit more about incretins and the first-phase insulin response

In a non-diabetic person, the pancreatic beta cells are secreting insulin all the time, because every cell in our bodies requires insulin to enable the process of converting glucose into energy. Even when we’re sound asleep, our hearts pump, our lungs suck in air, and our brains have dreams or nightmares, as the case may be. We don’t turn off.

This constant insulin release is called the basal insulin response. It accounts for about half the total. The other half, called the first-phase, or sometimes prandial insulin response, is in direct response to food intake. When nutrients of any kind get into the digestive system, a couple of different peptides are released from the gut, mostly from the small intestine, although some are also released from the colon. These peptides are designated GLP-1 and GIP and are generally termed incretins.

What they do is send a message to the beta cells that it’s time to step up insulin secretion, because a load of glucose is being dumped into the bloodstream. In addition, they send a message to the liver that it’s time to stop breaking down glycogen into glucose and releasing that glucose into the bloodstream – it’s okay for the liver to do that when there’s no food in the digestive system, but we don’t need that extra glucose right after a meal.

Incretin release starts quite soon – about 15 minutes after any nutrients pass into the small intestine – and continues for up to 2 hours. The response of the beta cells to this signal is actually more rapid than their response to the presence of glucose in the blood. This has been demonstrated by studies timing insulin response to intravenous glucose injections compared with insulin response to food in the gut. Food in the gut triggers a quicker response.

However, the half-lives of these two peptides are very short – GLP-1 about 2 minutes, and GIP about 5 to 7 minutes. That’s because incretins are broken down by an enzyme labelled DPP-4. The release of incretins and their breakdown by DPP-4 is clearly a homeostatic process – the organism only requires a robust first-phase insulin release during digestion (while glucose is being sent to the bloodstream) but not after.
But in persons with diabetes, the incretin response is not sufficient to trigger the release of enough insulin to bring the blood glucose to normal levels. This may result in that adverse feedback loop, in which high blood glucose brings about increased insulin release, which in turn leads to resistance at the insulin receptors and continued high blood glucose.

Two classes of drugs attempt to remedy this defect. One class consists of the inhibitors of DPP-4 (the breakdown enzyme), thus prolonging the life of the incretins. DPP-4 inhibitors are called “gliptins.” Merck’s (MRK) Januvia (sitagliptin), second on the list of best-selling diabetes drugs, is one of these.

Strong competition for Januvia

One current challenger is Galvus (vildagliptin). Novartis (NVS) is putting the pedal to the metal on this one. Currently 139 clinical trials with vildagliptin are at various stages. Galvus has not received FDA approval, even though Novartis has been knocking at the door since 2007, the reason being that there were hints that, along with other incretin-based drugs, there might be an association with pancreatic cancer. Note, there was no evidence that vildagliptin itself ever led to pancreatic cancer in a patient, and the FDA and the European Medicines Association (EMA) have reviewed huge amounts of evidence regarding sitagliptin (Januvia) and exenatide (Byetta), an incretin mimetic, and found no evidence of increased incidence of pancreatic cancer. The FDA/EMA statement and a summary of the evide