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When 1 + 1 = 3: choosing drug combos in type 2 diabetes.


MUNICH -- Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States--7 of which are considered major--how does anyone make sense of the myriad of possible combinations?

It's not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.

"We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology," said Dr. Ferrannini of the University of Pisa (Italy). "This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?"

The question cannot be answered fully, he said. "If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy --which may eventually arrive--we could be talking about 286 possible combinations. So it's just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action."

The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. "It's rational," because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.

Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter-2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb "huge amounts" of glucose, he said. "Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron," Dr. Ferrannini said. "SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate."

In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. "This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals," Dr. Ferrannini said.

Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced hemoglobin A on the order of almost 1%, regardless of the concomitant medication.

Dapagliflozin works especially well in patients with very high HbAlc levels, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. "If the initial [HbA.sub.1c] was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%," he said (Diabetes Care. 2010 Oct;33[10]:2217-24).

The primary response on [HbA.sub.1c] is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. "Every time you give this pill, you get glycosuria. It just doesn't change," he said.

Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it's given alone or with metformin, insulin, or a sulphonylurea.

But when it comes to shedding calories through urine, the body can't be tricked forever, it seems. "You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake," Dr. Ferrannini said.

In other words, hunger strikes. And strikes hard. That's where the incretins come into play, he said.

"If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in [HbA.sub.1c]. And a very important element of incretin action is that they restore insulin release in patients with diabetes" and moderate appetite, he said.

Incretins like exenatide, a glucagonlike peptide-1 receptor agonist, impose their weight loss effect through an entirely different system. "By delaying gastric emptying and also--more importantly--through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight," Dr. Ferrannini said.

Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve [HbA.sub.1c], and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway--insulin signaling--and has the additional benefit of decreasing inflammation.

The positive results of DURATION-8 support this clinical assumption, he concluded. "I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs," he said.

Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs. On Twitter @alz_gal


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Author:Sullivan, Michele G.
Publication:Internal Medicine News
Date:Oct 15, 2016
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