Ten years later, UKPDS shows intensive glucose lowering, but not tight BP control, reduces MI, all-cause mortality

Shelley Wood

September 10, 2008

Rome, Italy - Ten-year posttrial monitoring from the landmark United Kingdom Prospective Diabetes Study (UKPDS) indicates that a strategy of early intensive glucose lowering, either with a sulfonylurea or metformin, has lasting, significant effects not only on major diabetes end points but also on risk of MI or all-cause mortality. By contrast, blood-pressure benefits seen with "tighter" blood-pressure lowering in 1997, when the trial first concluded, were not maintained over time.

Drs Rury R Holman and David R Matthews (Oxford Centre for Diabetes, Endocrinology, and Metabolism, UK) presented the 10-year posttrial monitoring results for UKPDS here at the European Association for the Study of Diabetes (EASD) 2008 Meeting, exactly 10 years to the day after the primary trial results were presented at the EASD 1998 meeting in Barcelona, Spain.

"UKPDS has definitively shown today that early glucose-lowering in the longer term really does impact on cardiovascular disease in people with type 2 diabetes," Holman told heartwire . "We're talking about a 13% reduction in all-cause mortality and a 15% reduction in MI. Now, that may not be as big as what we see with a statin or something, but given the millions of people with diabetes, this is a very substantial change, and it is over and above the other treatments that patients are getting."

The 10-year posttrial monitoring results for UKPDS have been published simultaneously online September 10, 2008 in the New England Journal of Medicine[1,2].

Intensive glucose control: "Legacy effects"

Dr Rury R Holman

The original UKPDS was launched in 1977, enrolling patients until 1991 and completed by 1997, with final results published in 1998 showing a reduced risk of microvascular complications, a nonsignificant reduction in MI, and no improvement in all-cause mortality with intensive glucose lowering using a sulfonylurea or insulin, instead of conventional glucose control through diet. In a subset of obese patients treated with metformin instead of conventional diet therapy, metformin was associated with significant reductions in risk of MI and death by 1997. According to Dr Ian Campbell (Victoria Hospital Kirkcaldy, Fife, UK) who introduced the two UKPDS investigators before their presentation, the original UKPDS results have formed the "cornerstone" for diabetes management: "They taught us about the need for intensive glucose control."

Holman explained during his presentation that over the ensuing 10 years since UKPDS wrapped up, surviving patients from the original trial were seen annually until 2002 in UKPDS clinics, but no attempt was made to maintain their previously randomized therapies. From 2002 to 2005, follow-up was conducted via questionnaires to patients and their physicians. In all, 44% of patients randomized to one of the glucose-lowering arms within UKPDS had died by 2007.

As Holman showed today, differences in HbA1c levels disappeared within one year of the trial's completion, partly in response to the trial findings and their impact on diabetes guidelines. But despite the lack of an enduring difference in glucose control between the intensive- and standard-therapy groups, intensive-therapy patients treated either in the sulfonylurea/insulin group or in the metformin arm of the trial had experienced significant reductions in any diabetes end point, microvascular disease, MI, and all-cause mortality, as compared with the conventional-therapy controls, after the additional 10 years of follow-up.

Original and late-follow-up relative risk reduction with sulfonylurea/insulin

End point 1997: Relative risk reduction (%) 1997: p 2007: Relative risk reduction (%) 2007: p
Any diabetes-related end point 12 0.029 9 0.040
Microvascular disease 25 0.0099 24 0.001
MI 16 0.052 15 0.014
All-cause mortality 6 0.44 13 0.007

Original and late-follow-up relative risk reduction with metformin

End point 1997: Relative risk reduction (%) 1997: p 2007: Relative risk reduction (%) 2007: p
Any diabetes-related end point 32 0.0023 21 0.013
Microvascular disease 29 0.19 16 0.31
MI 39 0.010 33 0.005
All-cause mortality 36 0.011 27 0.002
Intensive blood-pressure control: No "legacy effects"

Dr David R Matthews

In the blood-pressure arm of UKPDS, trial participants with hypertension were randomized to standard blood-pressure control or "tighter" control, permitting the addition of ACE inhibitors and beta blockers. In the 1997 results, patients in the more intensive BP-control arm had experienced significant reductions in microvascular disease, but no significant benefits in terms of MI risk or all-cause mortality.

Ten-year posttrial monitoring for the blood-pressure arm of the UKPDS was conducted in much the same way as the glucose portion of the trial, with clinic-based follow-up for the first five years, followed by questionnaire-based follow-up from 2002 to 2007. As Matthews told a packed conference room today, differences in blood-pressure levels seen in the original trial disappeared within two years postcompletion. As anticipated in 1997, 51% of the trial participants had died by the time the 10-year posttrial monitoring ended in 2007.

But unlike the enduring benefits seen in survivors randomized to intensive glucose control, tighter control in the blood-pressure arm of the study produced no lasting improvements in microvascular disease, MI, all-cause mortality, or any diabetes-related end point. Indeed, differences in microvascular disease seen at the end of the trial had disappeared over the subsequent 10 years.

Original and late-follow-up relative risk reduction with intensive BP lowering

End point 1997: Relative risk reduction (%) 1997: p 2007: Relative risk reduction (%) 2007: p
Any diabetes-related end point 24 0.0046 7 0.35
Microvascular disease 37 0.0092 16 0.20
MI 21 0.13 10 0.35
All-cause mortality 18 0.17 11 0.18

"Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained," the authors conclude.

In a press statement, Matthews offered one hypothesis behind the disappointing blood-pressure results. '"With glucose control it matters how well you are treated now and how well you were treated in the past; with blood pressure, it seems to be related just to current therapy, confirming how essential it is to maintain good blood-pressure levels over time if the risk of complications is to be minimized."

Holman, likewise, speculated that the findings speak to different pathophysiological mechanisms. "It does seem that the metabolism for glucose and its way of causing complications is very different from that of blood pressure," he told heartwire . "That's not really surprising—blood pressure is a mechanical issue, but for glucose, with its effects on the endothelium, encouraging atherosclerosis, it's a longer-term process."

Much-needed optimism?

Commenting on the results for heartwire , Dr Darren McGuire (University of Texas Southwestern Medical Center, Dallas, TX) observed: "These analyses are very interesting and inject some much-needed optimism into the potential for glucose modulation to favorably affect atherosclerotic vascular risk."

He pointed out that one of the "most plausible" theories as to why the recent ACCORD, ADVANCE, and VADT trials showed no benefit of glucose control on cardiovascular outcomes was that the glucose control was too late and could not "stop the moving train."

"In UKPDS follow-up, after 66 000 person-years of observation and accumulating almost 1500 primary atherosclerotic disease events, not counting CV deaths, the end points go consistently in the right direction," McGuire observed. "This is quite reassuring, compared with the UKPDS primary report, where MI was improved with intensive glucose control, although it just missed statistical significance, but the point estimate for stroke was in the opposite direction. That trend has been reversed in this longer-term follow-up, with more events and therefore more statistical accuracy."

Holman believes the late UKPDS data reinforce the need to start glucose control at the "earliest possible time" in the progression of disease, which means diagnosing diabetes earlier, rather than later.

"With other interventions like blood pressure drugs and statins, cardiologists have been successful in reducing risk in people with established cardiovascular disease," Holman said. "You can't play catch-up with glucose control. . . . I think this will change the paradigm. It will mean that we can't afford to wait until people have problems; we'll have to treat glucose from day one and treat it properly.

Holman disclosed receiving research support from Ashai Kasei Pharma, Bayer Healthcare, Bayer Schering Pharma, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Merck Serono, Novartis, N ovo Nordisk, Pfizer, and Sanofi- Aventis; and receiving honoraria from Amylin, Astella, Bayer, Eli Lilly, GlaxoSmithKline, King, Merck, Merck Serono, Novartis, N ovo Nordisk, Takeda, and Sanofi- Aventis. Matthews disclosed receiving lecture and advisory fees from Novo Nordisk, GlaxoSmithKline , Servier, Merck, Novartis, Eli Lilly, Takeda, and Roche; and owning shares in OSI Pharmaceuticals and Particle Therapeutics.

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