DPPOS长期结果揭晓：强化生活方式疗效至少可维持15年

旧金山——David M. Nathan博士在美国糖尿病学会（ADA）年会上报告了对糖尿病预防计划结局研究（DPPOS）长期结局的分析结果：参加糖尿病预防计划的患者在被随机分组后，平均可以在15年内保持稳定的血糖控制。意向治疗分析显示，不同干预方式在早期微血管并发症方面没有显著差异，不过强化生活方式干预能有效地减少女性的微血管并发症。

DPPOS是对糖尿病预防计划（DPP）的随访。DPP是一项比较强化生活方式干预、二甲双胍与安慰剂用于预防糖尿病的随机临床试验。该试验于1996年启动，美国27个中心参与了该试验，其目的是确定能够阻止和延缓高危患者发生糖尿病。共有3234例患者被随机分为强化生活方式干预组（通过低脂饮食和增加体力活动使体重降低7%）、标准生活方式干预+二甲双胍组（给予有关饮食和运动的标准建议，并服用二甲双胍），或标准生活方式干预+安慰剂组。

开展3年后，DPP试验比原计划提前1年结束。这种强化生活方式干预在1年时达到了使体重降低7%的目标，并且在剩余的研究期间保持了约5%的体重下降，使得糖尿病发病率降低了58%。标准生活方式干预+二甲双胍组的糖尿病发病率降低了31%。

DPP和DPPOS的主要研究者、哈佛医学院的Nathan博士指出：“安慰剂组每年约有11%的受试者罹患糖尿病，而二甲双胍组和强化生活方式干预组每年分别仅有8%和5%的受试者发展为糖尿病。DPP试验的结果已被广为报道，但该试验仅开展了3年，与糖尿病或高危状态的终身性相比只是很短的一段时间。DPPOS旨在检验，在这3年间被推迟发生的糖尿病，能否被继续推迟甚至或阻止。”

在最初的3234名DPP受试者中，2776名（86%）继续参加了DPPOS。他们首次就诊时的平均年龄为56岁，女性占68%。目前，他们的平均年龄为67岁，31%已在参加DPP后发展为糖尿病。

国立糖尿病、消化病与肾病研究所（NIDDKD）糖尿病流行病学与临床研究室主任William C. Knowler博士指出，来自DPP安慰剂组和二甲双胍组的受试者，其糖尿病年发病率已下降到与强化生活方式干预组受试者相近的水平，“仍然相当稳定，保持在大约5%/年”。糖尿病发病率下降的具体原因尚不清楚，一种可能是研究者向所有受试者提供了有效的生活方式干预。

尽管三组受试者的糖尿病年发病率在长期随访过程中逐渐趋于一致，但在15年随访期间，DPP试验中产生的组间差异仍然导致了总体糖尿病发病率的不同：与安慰剂组相比，二甲双胍组的总体糖尿病发病率降低了18%，而强化生活方式干预组降低了27%。

尽管强化生活方式干预或二甲双胍治疗实质上在15年内阻止或延缓了糖尿病的发生，但所有三个治疗组基本上均保持了良好的血糖控制。随访期间，安慰剂组、二甲双胍组和强化生活方式干预组的糖化血红蛋白平均水平分别为6.1%、6.0%和6.0%。

Knowler博士表示：“虽然这些差异具有统计学意义，但差异的绝对值非常小，未必具有临床意义。好消息是所有三组受试者均基本上保持了良好的血糖控制，这也许不仅是我们干预的结果，还可能与快速诊断和早期治疗糖尿病有关。”

在视网膜病变和神经病变等微血管结局方面，印第安纳大学的Kieren J. Mather博士报告称，DPP随机分组后15年时，安慰剂组的微血管疾病平均患病率为12.4%，二甲双胍组为13 %，强化生活方式干预组为11.3 %。尽管各组间的患病率差异没有达到统计学意义，但男性的微血管疾病平均患病率约比女性高50%。“这一结果令我们有些意外，我们还不清楚其原因。”

他继续指出，强化生活方式干预与女性微血管并发症患病率降低有关（与安慰剂相比降低21%，P=0.03；与二甲双胍相比降低22%，P=0.02），而在男性中未观察到这一现象。DPPOS研究者还发现，随访15年时与未罹患糖尿病的受试者相比，进展为糖尿病的受试者的微血管疾病患病率明显升高（10% vs. 13%），相当于约28%的相对差异。这一现象在所有三组受试者中均存在。

“这实际上是一个悖论。一方面，我们降低了糖尿病发病率，而另一方面，与进展为糖尿病的受试者相比，我们的确使未罹患糖尿病的受者的并发症得以减少，但是未能获得对糖尿病的预防效果。尽管美国人中的糖尿病患病率正在更高，但我们很早就开始随访，而且即使在随访15年时，所有三组受试者的平均血红蛋白水平仍然非常低，在6%左右。”

Nathan博士指出，虽然本项研究目前尚不足以检验干预措施对心血管事件的效果，但所有受试者的心血管疾病危险因素均得到了改善。“这是个好消息。本项研究中没有足够多的心脏事件可供分析，以及总体研究人群的心血管危险因素减少，反映了研究之外医疗水平的提高。”

与此同时，糖尿病的发生伴随着心血管疾病危险因素特征的恶化和冠状动脉钙化严重程度的增加。

血压、血脂等传统心血管危险因素和C反应蛋白、其他炎症指标等新的心血管危险因素的减少，“基本上在强化生活方式干预组中比在安慰剂组中更明显，而二甲双胍组的减少幅度基本上介于两组之间”。

“值得注意的是，并不能用降压或降脂药物使用的增加来解释各组之间的差异。事实上，在DPP和DPPOS的绝大多数时间内，强化生活方式干预组均较少使用他汀类药物和降压药物。在DPPOS期间，糖尿病的发生、较高的血糖水平与较高的心血管疾病危险因素相关。”Nathan博士补充道，各组在冠状动脉钙化水平方面无显著差异。不过，二甲双胍可减轻男性的冠状动脉钙化，提示二甲双胍具有心脏保护作用。

艾伯特爱因斯坦医学院糖尿病临床试验单元主任Jill P. Crandall博士讨论了长期二甲双胍治疗的副作用和其他后果，以及预防糖尿病对健康的影响。

经过大约10,000患者-年的二甲双胍使用随访后，未报告任何乳酸性酸中毒或需要住院的严重低血糖病例。在原先参加DPP试验二甲双胍组的受试者中，维生素B12缺乏症的患病率约为9%。“我们的数据还表明，二甲双胍相关性维生素B12缺乏症常在没有贫血的情况下发生，因此我们建议对服用二甲双胍的患者考虑进行B12检查。

研究者还在二甲双胍组受试者中观察到了“轻度但令人吃惊的持久体重减轻”。“二甲双胍组中依从性最高的患者减轻了大约5%的体重，并且维持了超过10年时间。据我们所知，DPP/DPPOS是迄今为止显示出最长时间的药物性体重减轻的研究。”

如果考虑DPP/ DPPOS干预措施的费用和受试者在研究之外接受医疗服务的总费用，二甲双胍治疗实际上可以节省费用，而强化生活方式干预和二甲双胍治疗均具有成本效益。“在10年随访期间，生活方式干预的净成本比安慰剂多出约1700美元。由于糖尿病相关费用必然与其并发症有关，所以如果并发症被阻止或推迟，干预措施就可以在更久以后带来额外的成本获益。”

这项研究是由国立卫生研究院/国立糖尿病、消化病与肾病研究所资助的。研究者声明称无相关利益冲突。

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By: DOUG BRUNK, Cardiology News Digital Network

SAN FRANCISCO – Glycemic control has remained stable for an average of 15 years after initial randomization for patients in the Diabetes Prevention Program.

No significant differences in early microvascular complications were seen among interventions on intention to treat analysis, although intensive lifestyle intervention was effective in reducing microvascular complications in women.

Those are two key findings from an analysis of long-term outcomes from the Diabetes Prevention Program Outcomes Study (DPPOS), which were presented at the annual scientific sessions of the American Diabetes Association.

DPPOS is a follow-up to the Diabetes Prevention Program (DPP), a randomized clinical trial of intensive lifestyle and metformin, compared with placebo for the prevention of diabetes. Launched in 1996, the trial took place at 27 centers in the United States and was designed to determine whether the development of diabetes could be prevented or delayed in high-risk patients.

A total of 3,234 patients were randomized to either an intensive lifestyle intervention to reduce their weight by 7% through a low-fat diet and increased physical activity, or standard advice on diet and exercise plus metformin, or standard advice on diet and exercise plus placebo.

The DPP ended 1 year ahead of schedule after an average of 3 years of study. The lifestyle intervention program, which had accomplished its goal of 7% weight loss at 1 year, and then maintained about a 5% weight loss over the remaining time of the study, resulted in a 58% reduction in diabetes. The metformin group reduced diabetes development by 31%.

"To put these reductions in perspective, approximately 11% per year of participants in the placebo group developed diabetes," Dr. David M. Nathan, chair of the DPP and DPPOS and professor of medicine at Harvard Medical School, Boston, said during a press briefing. "That was reduced to about 8%/year in the metformin group, and less than 5%/year in the lifestyle group."

The DPP results were "widely heralded and reported," Dr. Nathan continued, "but they only covered a very brief period: Three years in what is in fact a life-long disease or risk state." DPPOS was designed to examine "whether the diabetes development that we demonstrated was delayed over a brief period of time, would continue to be delayed or prevented over a longer period of time."

Of the original 3,234 DPP participants, 2,776 (86%) continued in DPPOS. Their average age at the first visit was 56 years and 68% were women. Their average age is now 67 years and 31% have developed diabetes since enrollment in DPP.

The annual diabetes incidence rates among the original DPP placebo and metformin groups have declined to approximately equal the rate in the lifestyle group, "which have remained remarkably stable, at approximately 5% per year over time," said Dr. William C. Knowler, chief of diabetes epidemiology and clinical research at the National Institute of Diabetes and Digestive and Kidney Diseases. While the reasons for this decline were not clear, one possibility is that an effective lifestyle intervention was offered to all study participants, he said.

Despite the convergence of the annual diabetes rates in long-term follow-up, the differences between groups obtained in the first 3 years of DPP "resulted in continued lower overall long-term incidence of diabetes over the 15 years of follow-up, during which the diabetes incidence rate overall was 18% lower in the metformin group and 27% lower in the original lifestyle group, than in the original placebo group."

Even though diabetes prevention or delay was substantial with lifestyle or metformin over 15 years, all three treatment groups maintained good glycemic control on average. HbA1c averages over follow-up were 6.1%, 6.0%, and 6.0% in the original placebo, metformin, and lifestyle groups, respectively.

"While these differences are statistically significant, they are very small and of questionable clinical importance," Dr. Knowler said. "The good news is that all three groups maintained good glycemic control on average, perhaps as a result not only of our interventions, but [also as] a result of rapid diagnosis and intensive treatment of diabetes once it developed."

As for microvascular outcomes such as retinopathy and neuropathy, Dr. Kieren J. Mather, professor of medicine at Indiana University, Indianapolis, reported that the average prevalence of microvascular disease at year 15 following DPP randomization was 12.4% in the placebo group, 13% in the metformin group, and 11.3% in the lifestyle group. While these differences between groups did not reach statistical significance, the mean prevalence of microvascular outcomes was about 50% higher in men than in women.

"This is not something we expected, and we have not had an opportunity to explain that," Dr. Mather said.

He went on to note that the intensive lifestyle intervention was associated with a lower prevalence of microvascular complications in women (21% vs. placebo; P = .03, and 22% vs. metformin; P = .02), but not in men. The DPPOS researchers also observed a significant difference in microvascular disease prevalence at year 15 in those who progressed to diabetes, compared with those who did not progress to diabetes (13% vs. about 10%, respectively). This equated to about a 28% lower prevalence in those who had not progressed to diabetes, an effect was present in all three treatment groups.

"This equates to a paradox. We have diabetes reduction and we have a reduced prevalence of complications in those who did not develop diabetes, compared to those who did, but we don’t have a treatment effect to prevent diabetes at this point," Dr. Mather said.

"We interpret these findings in the context of the achieved levels of glycemia. Despite the rising prevalence of diabetes in our population, we started following them quite early, and even at year 15, all three treatment groups have very low mean hemoglobin A1cs, in the 6% range."

Dr. Nathan noted that even though the study is currently insufficiently powered to test the effects of interventions on CVD events, CVD risk factors improved in all subjects.

"This is a good news message, the fact that we had too few cardiac events to analyze and that CVD risk factors fell in the entire population speaks to the high level of care they were getting outside of the study."

At the same time, development of diabetes was accompanied by a worsening CVD risk factor profile and increased coronary artery calcification severity, compared with those who did not develop diabetes.

The reduction in conventional CVD risk factors such as blood pressure and lipids, and in the novel CVD risk factors, such as C-reactive protein and other indices of inflammation, "was generally greater in the lifestyle group than the placebo group, and it was generally intermediate (somewhere between lifestyle and placebo) in the metformin group," Dr. Nathan explained.

"Notably, it was not an increase in use of blood pressure– or lipid-lowering drugs that explained the differences among the treatment groups. In fact, during much of DPP and much of DPPOS, the lifestyle group was using fewer statins, using fewer blood pressure lowering medications. During DPPOS the development of diabetes and higher glucose levels was associated with higher levels of CVD risk factors."

Dr. Nathan added that there were no differences in the level of coronary calcification among the treatment groups. However, metformin reduced coronary artery calcification in men, which suggests that metformin has cardioprotective effects.

Dr. Jill P. Crandall, director of the diabetes clinical trials unit at the Albert Einstein College of Medicine, N.Y., discussed side effects and other consequences of long-term metformin therapy as well as the health impact implications of diabetes prevention.

After an estimated 10,000 patient-years of follow-up with metformin use, there have been no reported cases of lactic acidosis or severe hypoglycemia requiring hospitalization. The prevalence of B12 deficiency was about 9% in original DPP participants randomized to the metformin group.

"Our data also show that metformin-associated vitamin B12 deficiency often occurs in the absence of anemia, leading us to recommend that B12 testing be considered for patients taking metformin," Dr. Crandall said.

The researchers also observed a "modest but surprisingly durable weight loss" among participants in the metformin group. "The most highly adherent patients in the metformin group lost or maintained about 5% of their initial body weight over 10 years of follow-up," she said. "To our knowledge, the DPP/DPPOS represents the longest pharmacologic weight-loss study ever conducted."

When considering the measured cost of the DPP/DPPOS interventions and the aggregate cost of medical care received by the participants outside of the study, metformin was actually cost saving, and both the intensive lifestyle intervention and metformin were cost effective.

"The net cost of the lifestyle intervention was approximately $1,700 more than placebo over the 10 years of follow-up," Dr. Crandall said. "Since the nature of the costs associated with diabetes is related to its complications, additional cost benefits of the interventions may accrue over time if these complications are prevented or delayed."

The study was funded by the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

The researchers stated that they had no relevant financial conflicts to disclose.