This blog entry reviews five very-recent clinical trials related to diabetes treatments, three that have failed and two that have succeeded. I conclude by commenting on what I think are some underlying messages.
FAILED DIABETES-RELATED CLINICAL TRIALS
I picked these items up from a March 14 New York Times story pointing to studies just published on March 14 in the New England Journal of Medicine, studies that have invalidated three favorite strategies for treating diabetics. As the article points out “An estimated 21 million Americans have Type 2 diabetes, the kind once known as adult-onset, and they are at enormous risk for heart disease. The only measures proved to reduce their chances — avoiding cigarettes and taking medication to lower bad cholesterol and blood pressure — still leave diabetics with a heart attack risk equivalent to that of a nondiabetic who has already had a heart attack. — So doctors began trying other strategies they hoped would help: getting blood pressure to a normal range; raising levels of good cholesterol and lowering levels of dangerous triglycerides; or modulating sharp upswings in blood sugar after a meal.” In large-scale clinical trials, all three strategies failed.
Strategy 1: Reducing high blood pressure in diabetics will reduce incidence of heart attacks and heart attack deaths.
“Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg(ref).1,2,3”
According to the March 14 2010 NEJM report Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus Background There is no evidence from randomized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus. We investigated whether therapy targeting normal systolic pressure (i.e., <120 mm Hg) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events. — Methods A total of 4733 participants with type 2 diabetes were randomly assigned to intensive therapy, targeting a systolic pressure of less than 120 mm Hg, or standard therapy, targeting a systolic pressure of less than 140 mm Hg. The primary composite outcome was nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years. — Results After 1 year, the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% confidence interval [CI], 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (hazard ratio, 1.07; 95% CI 0.85 to 1.35; P=0.55). The annual rates of stroke, a prespecified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (hazard ratio, 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).
Conclusions In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events. (ClinicalTrials.gov number, NCT00000620 [ClinicalTrials.gov] .)
Strategy 1 is shot down. In fact, the Times article points out that many of those taking the blood pressure reducing medication were worse off because of side effects and that “A second, less rigorous study, involving 6,400 patients with Type 2 diabetes and heart disease, asked whether getting systolic blood pressure lower than 130 was any better than getting it to 130 to 140. It found that patients actually were worse off: those with the lower blood pressure ended up with a 50 percent greater risk of strokes, heart attacks or deaths.”
Strategy 2: Raising levels of good cholesterol and lowering levels of dangerous triglyceride in patients with diabetes will reduce incidence of heart attacks and heart attack deaths.
Another March 14 NEJM report is Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. “Background: We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease. — Methods We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
“The hypothesis that we tested in ACCORD Lipid was that in high-risk patients with type 2 diabetes, combination treatment with a fibrate (both to raise HDL cholesterol levels and to lower triglyceride levels) and a statin (to reduce LDL cholesterol levels) would reduce the rate of cardiovascular events, as compared with treatment with a statin alone.”
“By the end of the study, the mean LDL cholesterol level fell from 100.0 to 81.1 mg per deciliter (2.59 to 2.10 mmol per liter) in the fenofibrate group and from 101.1 to 80.0 mg per deciliter (2.61 to 2.07 mmol per liter) in the placebo group (Figure 1, and Section 16 in Supplementary Appendix 1). Mean HDL cholesterol levels increased from 38.0 to 41.2 mg per deciliter (0.98 to 1.07 mmol per liter) in the fenofibrate group and from 38.2 to 40.5 mg per deciliter (0.99 to 1.05 mmol per liter) in the placebo group. Median plasma triglyceride levels decreased from 189.0 to 147.0 mg per deciliter (2.13 to 1.66 mmol per liter) in the fenofibrate group and from 186.2 to 170.0 mg per deciliter (2.10 to 1.92 mmol per liter) in the placebo group.”
“Conclusions The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620 [ClinicalTrials.gov] .)”
Strategy 2 is shot down.
Strategy 3: Modulating sharp upswings in blood sugar after a meal will reduce incidence of diabetes, heart attacks and heart attack deaths among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors.“
A final study investigated the popular hypothesis that rapid rises in blood glucose after a meal were dangerous and could lead to heart disease. Many doctors were giving drugs assuming the hypothesis was correct, Dr. Nathan said(ref).”A third March 14 2010 NEJM publication Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events reports “Background The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. — Methods In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. — Results After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. —Conclusions Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786 [ClinicalTrials.gov] .)
Strategy 3 is shot down.
SUCCESSFUL DIABETES-RELATED CLINICAL TRIALS
Not all the diabetes-related clinical trial results have been negative. A Feb 11 2010 News Highlights report from Gen describes how “Roche Reports Positive Data from Five Phase III Trials of Type 2 Diabetes Therapy — Roche says data from the first five Phase III trials with its once-weekly type 2 diabetes candidate taspoglutide showed that the GLP-1 analogue met its primary endpoints of reducing blood glucose levels. — “These Phase III studies have shown that treatment with once weekly taspoglutide leads to significantly improved blood glucose control, consistent weight loss, a minimal risk of hypoglycemia, and a manageable safety profile,” comments Hal Barron, Roche’s global head of product development. — The Phase III development program for taspoglutide includes eight studies that will enroll some 6,000 patients. Four of the studies have active comparators including exenatide, sitagliptin, insulin glargine, and pioglitazone.”
A January 26 report in Gen indicates “Novo Nordisk’s Type 2 Diabetes Drug Green-Lighted by FDA — FDA sanctioned Novo Nordisk’s type 2 diabetes drug Victoza® (liraglutide) as a monotherapy in second-line treatment and in combination with other commonly prescribed oral diabetes therapeutics. U.S. approval comes less than a week after Japanese regulatory authorities gave Victoza the go-ahead. — U.S. approval of Victoza came with a Risk Evaluation and Mitigation Strategy consisting of a medication guide and a communication plan. Novo Nordisk aims to introduce the drug in the U.S. within weeks. — Victoza is a once-daily human GLP-1 (glucagon-like peptide-1) analogue and is given as an injection. “This is the first direct competition to the Byetta franchise,” according to Canaccord Adams life sciences analyst Adam Cutler. Amylin Pharmaceuticals’ Byetta and Victoza belong to the same family of drugs. “Byetta sales and prescription trends have remained flat, and we expect this news to further weaken them.” Byetta brought in $503.9 million through U.S. sales during the first three quarters of last year. ==Victoza is intended to help lower blood sugar levels along with diet, exercise, and other selected diabetes medicines. It is not recommended as initial therapy in patients who have not achieved adequate diabetes control on diet and exercise alone. –In five clinical trials involving more than 3,900 people, pancreatitis occurred more often in patients who took Victoza than in patients taking other antidiabetics, the FDA points out. The agency also advices that the therapy should be used with caution in people with a history of pancreatitis.”
First, I acknowledge that these clinical trials have contributed to our incremental knowledge about what diabetes is and treatments that do and do not work. Taspoglutide which has to be taken only once a week has the potential of becoming a blockbuster drug. Exenatide, an existing drug in the same class, has to be taken twice daily.
Second, the clinical trial failures indicate how much we still are in an extremely expensive trial-and-error approach to treating diabetes, as I believe we are in for multiple other diseases. Enormous amounts of money, effort and time have been poured into these clinical trials, each involving thousands of participants. Taspoglutide alone has been scheduled for eight Phase III trials. Ultimately these costs of hundreds of millions of dollars are reflected in the prices of approved drugs and contribute to the cost of health care. Further, time required for the tests can keep needed drugs off the market for years.
Third, all the treatments mentioned relate to management of diabetic conditions or cardiovascular risk factors. Such management is extremely important but lifestyle and dietary factors can be equally or even more important in preventing onset of diabetes as well as its management. I wonder whether spending the amount of money required for these clinical trials instead on anti-obesity education might have resulted in a much greater overall positive impact.
Fourth, as time progresses, basic scientific approaches may obviate the necessity for such large-scale trial-and-error clinical trial approaches and allow smaller, faster and more focused clinical trials. As more individual genomes are decoded and more and more diabetes whole-genome association studies are performed(ref)(ref), “one size fits all” therapies will give way to personalized ones. (See the recent blog entry on Genome-wide association studies.) Emphasis will hopefully shift from management of diabetes to its prevention(ref). Genomic knowledge may allow determining susceptibility of an individual to diabetes early in life and establishing a lifestyle program to assure that diabetes does not emerge in that person(ref)(ref)(ref).
Once upon a time, an emphasis in medical treatment of people with polio was to have them live their lives in iron lung machines. Then, basic scientific research allowed us virtually to wipe polio out. It is time for us to do the same with Type 2 diabetes, and perhaps to let up on looking for better iron-lung type disease-management approaches.