That’s the main, plain message I want to put forth at the beginning of this post before I dismantle the New York Times distortion of the study. The Times article not only over hypes the results but fails to mention the primary source anywhere in the article. That would at least have pointed readers to reliable information.
The opening sentence, patently absurd to anyone who understands epidemiologic issues related to type 2 diabetes, might be a bit confusing to the lay public:
For decades, researchers believed that if people with diabetes lowered their blood sugar to normal levels, they would no longer be at high risk of dying from heart disease.
That might have been the popular hype but it is absolutely not what researchers believed for decades (or at any time, for that matter). Although a decade or so ago we learned that intensive glycemic control reduces microvascular complications in DM-1 (DCCT) and in DM-2 (UKPDS) there’s been nary a shred of evidence that it helps macrovascular disease (heart attacks and strokes) at least in DM-2. (A very long follow up of DCCT suggested late macrovascular benefit in DM-1 but that’s a different disease entirely from DM-2, and not the focus of this discussion).
Although evidence of macrovascular benefit in DM-2 with intensive control was lacking, as early as 1998 an analysis of UKPDS hinted at macrovascular benefits (stroke only) attributable to a unique drug (metformin) though not to intensive control, and only in a very narrowly defined population (patients with DM-2 who were obese and on metformin as initial monotherapy, not as add on). Hardly clean and convincing evidence, but it was a hint.
A stronger hint that any drug treatment might improve macrovascular outcomes in DM-2 did not come until quite recently with the release of the PROACTIVE study. So, not until late 2005 did we begin to see evidence that treatment might offer macrovascular benefits. That was unprecedented, and I blogged about it at the time as something of a breakthrough. But it was not evidence, nor in my opinion was it even hypothesis generating, that the benefits were a result of glycemic control. Far more plausible was a unique effect of pioglitazone via non-glycemic mechanisms such as favorable lipid effects, improvement in insulin resistance and improvement in endothelial function. (For a more detailed analysis on the non-evidence for the glycemic control-macrovascular notion see my posts here, here and here).
The New York Times article quoted several medical experts who expressed concern and disappointment in the results, over characterizing their reaction (in a one sentence paragraph, as if to add to the dramatic effect) as “stunned.”
There was nothing stunning or even surprising about it. So what was going on? Ironically, the clue might be found in a quote from the NYT article itself, although the article missed the significance of the clue entirely:
Dr. John Buse, the vice-chairman of the study’s steering committee and the president of medicine and science at the American Diabetes Association, described what was required to get blood sugar levels low, as measured by a protein, hemoglobin A1C, which was supposed to be at 6 percent or less.
“Many were taking four or five shots of insulin a day,” he said. “Some were using insulin pumps. Some were monitoring their blood sugar seven or eight times a day.”
Therein may lie the answer. Patients with type 2 diabetes, many of whom were no doubt obese, were given intensive insulin treatment. Some of then were even pumping! I suspect most of the patients were on insulin, given the aggressive glycemic targets that were achieved. Insulin resistant to start with, the patients treated intensively with insulin likely required high doses which promoted weight gain, sure to beget worsened resistance followed by up-ramping of the dose as they drifted out of control, and on the vicious cycle went.
Anyone who treats obese type-2 diabetics with insulin has seen the cycle. The patient is out of control, so up goes the insulin dose. After transient improvement the inevitable weight gain leads to worsened insulin resistance and worsened hyperglycemia. Up goes the dose again and the cycle repeats. That can’t be good for one’s macrovascular health because insulin resistance is in and of itself a potent macrovascular risk factor. Moreover, it fuels the metabolic syndrome, the principal dyslipidemia of type 2 diabetes.
The suggestion that intensive insulin treatment drove macrovascular disease should surprise no one. It adds to our understanding of the treatment of DM-2 by confirming what we already suspected: 1) that intensive glycemic control does not prevent macrovascular disease and 2) pharmacologic agents for DM-2, including insulin, with the possible exception of those with unique vascular protective actions, have the potential for macrovascular harm.
Other blog reactions to the study came from Med Rants and Health Care Renewal, which I may comment on in future posts as time permits. Their posts cover issues relating to the appropriateness of current guidelines and whether guideline concordant glycemic control for DM-2 really produces meaningful microvascular ourcomes.