Lifestyle, Metformin, Can Delay Diabetes, 15-Year DPP Data Show

June 16, 2014

SAN FRANCISCO — New data from the ongoing US Diabetes Prevention Program (DPP) show that randomizing overweight or obese people at high risk for type 2 diabetes to intensive lifestyle change or giving them the oral agent metformin can reduce or delay the development of the disease for as long as 15 years, in some cases.

Although 50% of the approximately 3000 participants did become diabetic over the time course, "the results show that diabetes is not inevitable in people at high risk; we established that it can be prevented or delayed," Marinella G. Temposa, PhD, of the George Washington University told the American Diabetes Association (ADA) 2014 Scientific Sessions today.

And Judy Fradkin, MD, director of the division of diabetes at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), one of the sponsors of the trial, said the study had already had "major public-health implications for the US."

Both interventions "were effective in delaying the onset of diabetes," she said, and the fact that 85% of the original cohort chose to continue on in the extension program, the DPP Outcomes Study (DPPOS), illustrates the benefits of participation in clinical research, she added. Plus, the fact that 45% of participants were from minority ethnic backgrounds speaks to the broad applicability of the results.

One audience member warned, however, that the research team should be cautious in claiming that these findings are applicable to all people with prediabetes, since the latter is a very loose definition and in some nations affects large swathes of the population. Study investigators said they had never claimed this and noted that they had strict inclusion criteria for their study.

Encouraging Signs for Diabetes Complications in DPP/DPPOS

Drs. Judy Fradkin, William C. Knowler, Jill Crandall, and Kieran Mather

In the DPP study, the original 3234 participants, who had to be at high risk for diabetes by virtue of impaired glucose tolerance and their weight and, for the most part, also a family history of diabetes, were randomized to 1 of 3 treatment groups: intensive lifestyle modification, metformin at a dose of 850 mg twice daily, or placebo. In 2002, the results of the DPP were reported in the New England Journal of Medicine and showed a dramatic 58% reduction in new type 2 diabetes with the intensive lifestyle intervention and a 31% reduction with metformin compared with controls, in both men and women, across a broad spectrum of races, and across age groups, including the elderly.

At this point, the DPPOS was instituted, and all patients previously in the placebo arm transferred to a lifestyle-intervention group. Those originally taking metformin also received group lifestyle training, while the original lifestyle arm received a lifestyle "boost."

The aim of DPPOS was to continue to examine the effect of the original DPP intervention on further development of diabetes, on cardiovascular disease and its risk factors, and on microvascular complications such as retinopathy, nephropathy, and neuropathy, as well as look at the economic implications, principal investigator William C. Knowler, MD, DrPH, of Southwest American Indian Centers and NIDDK, Phoenix, Arizona, explained at the meeting.

Now, 15 years on, all 3 groups have a similar annual incidence of diabetes, he noted, likely the result of effective lifestyle interventions being offered to everyone on DPPOS and the fact that all "susceptible" persons have been exhausted (ie, developed diabetes), among other things, he explained.

But differences in cumulative incidence remain, although these have diminished over time, as would be expected, he said: there is still a 27% reduction in prevalence of diabetes among the original intensive-lifestyle group compared with the original placebo group and an 18% reduction in the original metformin group compared with placebo.

And while it appears to be too soon to show any significant benefit of either original arm, lifestyle or metformin, on the prevention of cardiovascular disease or on diabetic retinopathy, nephropathy, and neuropathy, there are some encouraging early signs, Dr. Knowler added.

Results "Credible" Due to ITT Analysis

Asked to discuss the 15-year DPP/DPPOS findings, Hertzel Gerstein, MD, from McMaster University, Hamilton, Ontario, who was not involved with the study, told the ADA meeting that trying to prevent diabetes "is a good investment. It is far more extensive than just thinking about macro- and microvascular complications."

He listed a myriad of other conditions that occur more frequently in diabetes, such as cirrhosis, cancer, cognitive decline, depression, sleep apnea, gut problems, fractures, and sexual dysfunction, and noted that diabetes is really "accelerated aging."

Dr. Gerstein said one of the reasons the DPP/DPPOS results "are credible" is "that first and foremost it used a proper design, a randomized controlled trial."

He outlined the results as detailed using an intention-to-treat analysis, for both the original intensive-lifestyle therapy arm vs placebo and for metformin vs placebo arm.

For the former, as well as the 27% less diabetes mellitus over the 16 years of the trial, there has been a 1.1-year shorter duration of diabetes over the same time course, as well as a 3% to 4% weight loss, and a 0.1% lower mean HbA1c.

And although there is not yet any visible effect on microvascular or macrovascular outcomes of intensive lifestyle, there is less dyslipidemia, hypertension, and metabolic syndrome and lower CRP, with a 5% lower use of lipid-lowering medications, he noted. Also, the cost of the intensive lifestyle intervention was reasonable, at $10,760 per quality-adjusted life-year (QALY) gained compared with placebo.

For metformin vs placebo, the 18% less diabetes mellitus since the start of the trial was accompanied by a 0.6-year shorter duration of diabetes, a 1% to 2% weight loss, and a 0.1% lower mean HbA1c. There is again no benefit as yet on micro- or macrovascular outcomes, but there is less metabolic syndrome and lower CRP, plus an intriguing possibility that metformin might reduce coronary artery calcification (CAC) in men. A big plus is that there were annual cost savings for metformin.

There is also a hint of a possible stronger effect of both the lifestyle intervention and metformin compared with placebo in women with prior gestational diabetes, he noted.

And "although we have not yet seen in the DPP that diabetes mellitus prevention stops diabetes-related outcomes," there are hints from other trials that this may occur eventually, he observed.

For example, in the Da Quing study, it took 20 years of intervention to show a reduction in diabetic retinopathy, he noted. And the PREDIMED study is the first to have shown that a dietary intervention, in this case Mediterranean diet, prevents cardiovascular events, although he called these findings "almost too good to be true" and noted that they do require replication.

Nuances for CVD, Microvascular Complications

David Nathan, MD, from Harvard Medical School, Boston, Massachusetts, and chair of DPP/ DPPOS, presented the findings so far with regardto cardiovascular disease, which he called "the most severe consequence of type 2 diabetes."

"This is one of the major outcomes we wanted to study when we began, but the number of events currently is too small to examine [differences in] myocardial infarctions or strokes."

However, he agreed with Dr. Gerstein that there are promising indicators, with lifestyle intervention appearing to have the strongest effect on CVD risk factors, with that of metformin being somewhat less.

And there was a clear-cut difference between those who did and didn't develop diabetes, he added. "Those who remained without diabetes had a lower CVD risk profile; when you made the transition to diabetes, CVD risk factors got worse."

Meanwhile, Kieran Mather, MD, from the Indiana University School of Medicine, Indianapolis, who presented the data on microvascular outcomes, said there was a similar picture emerging here: "Participants who did not develop type 2 diabetes had a 28% lower occurrence of the microvascular complications than those who did." These interventions show that interceding in the phase before diabetes "is important in reducing early-stage complications," he noted.

Largest and Longest Weight-Loss Study and Study of Metformin

Jill Crandall, MD, from Albert Einstein College of Medicine, Bronx, New York, and a DPP/DPPOS investigator, noted that the study is the largest and longest in duration to examine the effects of metformin in people who have not been diagnosed with diabetes — with 10,000 patient years of follow-up.

It therefore yields important information about this inexpensive, well-known, and generally safe diabetes medicine, she noted.

For example, metformin was associated with "a modest but surprisingly durable degree of long-term weight loss," she said, adding that this makes the trial "by far the longest pharmacologic weight-loss study ever."

And there is the possibility that metformin may be cardioprotective — as evidenced by the suggestion that men who received this drug had significantly better CAC scores than those who didn't — although this requires further investigation, Dr. Nathan noted

And despite a small increase in vitamin B12 deficiency, which Dr. Crandall said is a recognized side effect of metformin therapy, which patients should be monitored for, she noted that the drug has otherwise proven safe and has been well-tolerated over the 15 years of the study.

And she also stressed, as did Dr. Gerstein, that metformin therapy is also "cost saving" compared with placebo, she stressed.

Many Questions Remain

Dr. Temposa said the study has also generated many more questions that still remain to be answered.

These include:

  • When is the most advantageous time to introduce prophylaxis for long-term complications?

  • What are the effects of long-term metformin during the phase before diabetes on cardiovascular disease and cancer?

  • What is the effect of the transition from a state prior to diabetes to diabetes on risk for various disease outcomes?

  • Also, what is the clinical course of diabetes from its inception to development of more advanced complications, and what are the effects of established and putative risk factors on the development of diabetes and its complications?

  • Finally, what are the effects of diabetes prevention or delay on longer-term microvascular outcomes and other newly recognized complications, including functional impairment and quality of life, and what are the long-term health economic implications of diabetes prevention?

Dr. Gerstein reports receiving grants and research support from Sanofi, Lilly, Novo Nordisk, Roche, Boehringer Ingelheim, AstraZeneca, and Bristol-Myers Squibb and speaker honoraria from Sanofi and Bayer. He has consulted for Sanofi, Lilly, Novo Nordisk, GlaxoSmithKline, Boehringer Ingelheim, Abbott, AstraZeneca, and Bristol-Myers Squibb.

American Diabetes Association 2014 Scientific Sessions. Presented June 16, 2014

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