The Drug Debate Intensifies
Yesterday the Annals of Internal Medicine published online a systematic review comparing newer vs. older drugs treatments of type 2 diabetes. The authors concluded “Compared with newer, more expensive agents (thiazolidinediones, a-glycosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control and other cardiovascular risk factors (blood pressure, lipid levels and body weight). Each oral diabetes agent is associated with adverse events that counterbalance its benefits. Overall, metformin seemed to have the best profile of benefit to risk. Large, long-term comparative studies on major clinical end points, such as myocardial infarction, chronic kidney disease, and cardiovascular mortality, are needed to determine definitively the comparative effects of the oral diabetes agents, especially in light of recent controversy regarding rosiglitazone.”
Here are some highlights from the review:
“Compared with sulfonylureas, most oral agents (thiazolidinediones, metformin, and repaglinide) improved glycemic control to the same degree, with an absolute decrease in hemoglobin A1c level of about 1 percentage point. Based on indirect comparisons of placebo-controlled trials, nateglinide and α-glucosidase inhibitors appeared to have slightly weaker effects on glycemic control.
Compared with other oral agents, the thiazolidinediones were the only class with a salutary effect on high-density lipoprotein cholesterol levels, with a mean relative increase of 0.8 to 0.13 mmol/L (3 – 5 mg/dL), but a harmful effect on low-density lipoprotein (LDL) cholesterol levels, with a mean relative increase of 0.26 mmol/L (10 mg/dL).
Although metformin treatment was associated with a decrease in LDL cholesterol levels by approximately 0.26 mmol/L (10 mg/dL), other oral agents had no apparent effects on LDL cholesterol levels.
Body weight increased by 1 to 5 kg during treatment with most agents other than metformin. Compared with other oral agents, sulfonylureas and repaglinide were associated with increased risk for hypoglycemia, thiazolidinediones with increased risk for heart failure, and metformin with increased risk for gastrointestinal disturbances.
Patients without comorbid conditions who were treated with metformin were no more likely to develop lactic acidosis than were those treated with other oral diabetes agents.
Limitations of this review include few data on major clinical endpoints, inconsistent reporting of adverse events other than hypoglycemia, varying definitions of adverse events in different studies, and the possibility that some adverse events not evaluated in trials or observational studies were overlooked.”
This study comes on the heels of “Efficacy and Safety of Incretin Therapy in Type 2 Diabetes; Systematic Review and Meta-analysis” which was published in the July 11th issue of JAMA. In this study the authors concluded “Incretin therapy offers an alternative option to currently available hypoglycemic agents for nonpregnant adults with type 2 diabetes, with modest efficacy and a favorable weight-change profile. Careful postmarketing surveillance for adverse effects, especially among the DPP4 inhibitors, and continued evaluation in longer-term studies and in clinical practice are required to determine the role of this new class among current pharmacotherapies for type 2 diabetes.”
As part of this meta-analysis the authors listed a 52 week study on Januvia, which Diabetic Investor believes is the longest study done on the drug. Published in the March issue of Diabetes, Obesity and Metabolism “Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial”. The authors concluded “In this study, the addition of sitagliptin compared with glipizide provided similar HbA1c lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycemia relative to glipizide and with weight loss compared to weight gain with glipizide.”
Diabetic Investor took a deeper look at this particular study as it was the only 52 week study we could find on Januvia, the other studies listed in the meta-analysis were 12 or 24 weeks. According to this study “Of the 379 patients excluded from the PP analysis, 96% were excluded because of missing treatment data at Week 52. More patients in the sitagliptin group discontinued treatment with those in the glipizide group; this difference was mainly because of a higher number of sitagliptin-treated patients discontinued for lack of efficacy” Looking even closer of the 588 patients who started in the sitagliptin group 202 discounted, a 34.3% dropout rate. Of the 202 who discontinued 86 cited lack of efficacy as the reason for dropping out.
It was also interesting that the authors found that maximal efficacy was observed at 24 to 30 weeks, “with subsequent increases in mean values of both endpoints in the sitagliptin and glipizide groups.”
What Diabetic Investor finds so interesting with this particular study besides its length is it merely shows Januvia is as good not better than standard treatment, a finding that is consistent with the review published yesterday. The high dropout rate was also interesting as it is two and half times higher than the dropout rates in the shorter term studies. Based on patient and physician interviews it appears the lack of efficacy issue with Januvia identified in this study are consistent with what we are hearing. Mainly because of the Avandia situation Januvia has become the oral agent of choice by default and not because it works any better than what’s available. The fact of the matter Januvia is no wonder drug and really doesn’t work all that well when you look at all the available data. Add in the fact the drug is much more expensive then the many generic drugs on the market that do a fine job Diabetic Investor believes Januvia sales will slow in the future and fail to meet the many optimistic sales estimates put out by the Street.
Given that more than two-thirds of patients using oral medications fail to achieve adequate control these study’s and reviews bring about some interesting questions.
1. 1. Does this mean physicians will move patients towards Byetta or insulin therapy?
2. 2. With the concern over adverse events will the FDA go beyond glycemic control as the primary endpoint before approving new therapies?
3. 3. Already popular with insurers will generics gain an even larger share of the oral market?
As everyone knows at the end of this month the FDA will hold a panel meeting to discuss the Avandia controversy. As Diabetic Investor has previously indicated we are not confident this meeting will produce any clear guidance for patients or physicians. In what surly will be a statistical battle the likely result is patients and physicians will be even more confused. Left with no clear guidance and based on the all available data Diabetic Investor sees physicians taking a more conservative path for their type 2 patients a move that favors generics.
We further see physicians taking an even closer look at Byetta and insulin for their type 2 patient population. The risk reward profile of insulin and Byetta are well established, the major obstacle particularly with primary care physicians has been these drugs must be injected. As physicians look more closely at study data Diabetic Investor sees Byetta as the winner here for several reasons.
1. 1. Byetta has strong efficacy.
2. 2. Simple dosing.
3. 3. Progressive weight loss.
4. 4. It’s not insulin.
The fact that Byetta is not insulin should not be over-looked. Besides being an injectable insulin therapy requires a high level of patient education. Unlike Byetta, patients cannot simply inject a set amount of insulin. Insulin therapy requires that a patient regularly monitor their glucose levels, something the majority of type 2 patients don’t do. Effective insulin therapy also requires that patients understand meal intake and other factors such as stress and exercise. There is also the risk of hypoglycemia with insulin, something that does not happen with Byetta. Add in the psychological aspects as patients see a move to insulin as a personal failure and that physicians have used the threat of insulin therapy as means to keep patients compliant on their oral medications and Byetta becomes even more attractive. Finally, the physician also knows if the patient does not tolerate Byetta therapy, they have fall back position with insulin.
What’s becoming increasingly evident is that no one therapy option is the ultimate for type 2 patients. It’s also clear every drug has side effects and when it comes to making therapy decisions physicians need to be more forthcoming with their patients and educate their patients on what to expect. People with diabetes are no different than other consumer when it comes to deciding upon treatment options. They want to make an informed choice. Knowing a drugs possible side effects is part of this process. Physicians cannot merely point out the good things a drug does.
Diabetic Investor has not held out much hope that the Avandia controversy would benefit the millions of patients with type 2 diabetes or the physicians who treat them. Perhaps there is a silver lining here in that physicians will take a closer look at the various treatment options and provide more education to their patients. Should that happen, and we think it will, Diabetic Investor see Amylin (NASDAQ:AMLN), Novo Nordisk (NYSE:NVO), Sanofi-Aventis (NYSE:SNY), Becton Dickenson (NYSE:BDX) and even Lilly (NYSE:LLY) as the big winners.