Commentary by Mitchell Charap MD, Senior Associate Program Director, NYU Internal Medicine Residency Program
Caveat: What follows below reflects my perspective on new and old pharmacologic approaches to Type 2 Diabetes. It is not intended to be a comprehensive review of this topic.
The ADA did not mount a serious attack on the Nissen NEJM metanalysis of Rosiglitazone. They suggested that patients speak to their physicians regarding the drug. I missed the Nissen/ADA debate that occurred, but gather that the ADA did not have a statistician to counter his suggestion that “it was not ethical to wait for the results of the DREAM trial.”
Nevertheless, I had the opportunity to talk to several leaders in the field of diabetes. The consensus regarding TZDs was that Rosiglitazone will not survive regardless of subsequent analyses and clinical trials. They predicted that both TZDs (Rosiglitazone and Pioglitazone) would have black box labeling for CHF and perhaps acute myocardial infarction after the FDA review later this month, and that other drugs such as Exenatide and Sitalgliptin will likely become second line drugs after metformin. An additional nail in the coffin for TZDs which may be warranted is their potentially detrimental effect on bone formation. I find it hard to imagine the entire class vanishing and think that PIO will stay around and will be used in combination with a DPPIV inhibitor. TZDs will become third line oral agents.
DPPIV inhibitors (much ado about not much?)
There are 23 in various stages of development. The posters for vitagliptin and saxagliptin did not suggest that they were any better than sitagliptin. Issues related to excretion and toxicity may effect their role in future therapeutics. In monotherapy comparisons with metformin, the DPPIV inhibitors have equal reduction in HgA1c at one and two years. Since neither has dramatic reduction in HgA1c, they will probably be used in combination with other oral agents such as metformin, e.g. Januvamet. Very importantly, they will likely be used for patients with impaired glucose tolerance and for the elderly.
Sitagliptin- This drug will be the drug that others are measured against. It has a remarkable safety record. The concern about the effect of DPPIV inhibition on other substrates has not become clinically apparent.
Vitagliptin- Novartis lost six months because of failure to deal with renal issues. There were a few cases of unexplained edema, but the posters/orals suggest it is as good as sitagliptin. There is one caveat. This drug lowers fasting glucose to the same extent as sitagliptin, but it does not have the same effect on postprandial glucose excursions. Whether this difference has any clinical meaning is unclear.
Saxagliptin- Data presented by Defronzo again suggest it is efficacious particularly when used with other orals
Conclusion- The DDPIV inhibitor landscape has changed dramatically in the last year due to several factors:
1. TZD popularity is waning (whether deserved or not).
2. Sitagliptin has been found to be easy to use and well tolerated (although not potent).
3. Primary care providers don’t like hypoglycemia, which does not occur with this class.
4. Pay for performance will make doctors more aggressively treat both diabetic and pre-diabetics and they will therefore be forced to use more drugs
GLP 1 analogs
Exenatide – There is nothing bad to report on exenatide, and good long-term data exists. The problem with the three-year data is the high number of dropouts that have not been characterized except to say that their dropping out was not due to drug side effects. The patients fit into four quartiles with regard to weight loss. At one end are the patients who lose more than 20 lbs and on the other are patients that gain weight. However, even in patients who gain weight there is a reduction in HgA1c suggesting that weight is not the driving force for improved glycemic control. The patients with the highest BMIs tend to have the most significant reductions.
Liriglutide- This drug is given once a day and has less GI toxicity than exenatide. It may cause slightly less weight loss. It is a naturally occurring compound as opposed to one derived from the salivary gland of a Gila Monster (exenatide). I do not find that a compelling reason to use it, but the once daily formulation will drive patient interest.
LAR (long acting release) Exenatide- The once a week formulation of exenatide was presented last year at the ADA yet it was not mentioned this year. However, the previous data suggest it is well tolerated (i.e. fewer GI side effects) and is associated with significant weight loss. The problem is delivery. The drug is difficult to administer with a small needle (it is a viscous compound). Hopefully, Amylin will figure out how to deal with this issue. If the phase three data is as positive as suggested by earlier phase data, this drug will replace both exenatide and liraglutide
Amylin/Leptin Drug- Fourth quarter 2007 data will be available (some of the scientists think this is an optimistic estimate). The animal data is impressive. The company describes a mechanism in which leptin action is enhanced by increased GLP-1.
Symlin and basal insulin for T2DM with or without oral agents
The data was not very impressive. In a study with an endpoint being A1C less than 7, 25% in symlin reached endpoint vs. 7% endpoint in placebo. However, there was a 2.3 kg weight loss and HgA1c dropped .75.
Sodium glucose co-transporter 2 (SGLT2) plays a key role in maintaining glucose equilibrium in the human body. SGLT2 is a kidney transporter that reabsorbs glucose from the renal filtrate and prevents the loss of glucose in the urine. Competitive inhibitors of SGLT2 cause the renal excretion of glucose. This observation has led to the hypothesis that SGLT2 inhibitors could be effective agents in the normalization of high blood glucose levels that are associated with diseases such as Type 1 and Type 2 diabetes.
These drugs increase glucose excretion by inhibiting reabsorption in the kidney. The posters suggest that they do lower glucose, but they do not direct themselves to any cause of diabetes, i.e. insulin, GLP1, glucagon, etc. I wonder what the effect of persistent glycosuria will have on the kidney and the entire urinary tract.
Central Cannabinoid Antagonists
Sanofi is unreasonably optimistic about Rimonabant’s future. However, there is no reason for optimism in view of the vote of the FDA initial review. The potential for increased depression and suicide will make any central Cannabinoid antagonists problematic. This issue has not stopped two other pharmaceutical companies from pursuing similar drugs.
Late breaking posters
Emisphere has developed an oral GLP 1 (they also have an oral insulin at an early stage of development). The levels of GLP 1 achieved were not very high. Veroscience is developing Cycloset, a quick release bromocriptine which at 52 weeks showed improved glycemic control and reduced CV events. OSI is working on GPR119, an oral agent that, in rats, binds to the G protein coupled receptor and increases GLP 1 release.