Figure 10.1. Intensive insulin therapy leads to major weight gain4
Some patients, however, paid a price.
Hypoglycemic episodes during the DCCT study were three times more common in the intensive insulin group compared to those receiving standard treatment.
Other patients experienced major weight gain.
Over nine years, almost 30 percent of the subjects in that group gained a significant amount of weight, defined as an increase in body mass index of more than 5.
This far exceeded the impact on those receiving conventional insulin therapy.
One-quarter of that intensive treatment group had increased their body mass index from 24 (normal weight) to 31 (obese).
Given the health consequences of obesity, this was no small concern.
Other disquieting danger signs appeared, too.
The weight gain was concentrated in the abdominal area, the central obesity known to be far more predictive of future cardiovascular disease.
Other key risk factors, blood pressure and blood cholesterol, also increased.
Over time, weight, waist circumference, and insulin dosage continued to grow inexorably.
Intensive insulin treatment had led to metabolic syndrome.
Type 1 diabetic patients with the most weight gain also developed the highest coronary artery calcification (CAC) and carotid intimal medial thickness (CIMT) scores;5 their high insulin dosage reliably predicted these measures of advanced atherosclerosis.6 Heavy-handed dosing of insulin to reduce blood glucose had produced all the problems
of excessive insulin: obesity, metabolic syndrome, and atherosclerosis.
Despite these side effects, intensive insulin dosing was worth the risk for the proven cardiovascular benefits, but only for type 1 diabetes.
However, this glucotoxicity paradigm, the idea that elevated blood glucose was the primary cause of end-organ damage, was accepted for both type 1 and type 2 diabetes.
The paradigm had not yet been proven for type 2 diabetes, but it seemed only a matter of time.
The logical treatment was to give enough insulin or other medication to keep blood glucose normal.
Even today, most doctors cling to this unproven treatment for type 2 diabetes like chewing gum clings to a boot sole.
Does it work?
GLUCOTOXICITY AND TYPE 2 DIABETES
THE LANDMARK DCCT trial had established the paradigm of glucotoxicity in type 1 diabetes.
The United Kingdom Prospective Diabetes Study (UKPDS), started in the 1970s, was expected to prove the benefits of intensive blood glucose control in type 2 diabetes.7 Researchers set out to determine two things about treatment: first, whether intensive glucose control could reduce complications, and second, whether there were differences among the different medications.
The study randomly assigned almost 4000 newly diagnosed type 2 diabetic patients to either conventional or intensive treatments, using the available medications of the time: insulin, sulfonylureas (SUs), and metformin.
Published in 1998, the UKPDS results were stunning, stunningly bad, that is.
Intensive treatment produced almost no measurable benefits.
Sure, it successfully lowered the average blood glucose, but the higher dosages of medication resulted in more weight gain, by an average of 2.9 kg (6.4 pounds).
In particular, those in the insulin group gained an average of 4 kg (8.8 pounds).
Hypoglycemic reactions significantly increased, too, but these side effects were expected.
Instead of mirroring the significant benefits of the DCCT trial, there was only some minor benefit in reducing eye disease.
Ten years of tight blood glucose control produced no cardiovascular benefits: there were no fewer heart attacks or strokes.
That discrepancy was shocking, but the story would get stranger still.
Metformin was considered separately in UKPDS sub-study 34,8 which
focused on overweight type 2 diabetic patients.
Metformin lowered the hemoglobin A1C blood glucose level from 8.0 percent to 7.4 percent.
This was good, but not as good as the results seen with the more powerful insulin and SU medications.
Despite the mediocre blood glucose reductions, however, the cardiovascular results were spectacular.
Metformin reduced diabetes-related death by a jaw-dropping 42 percent and the risk of heart attack by a whopping 39 percent, greatly outperforming the more powerful blood glucose, lowering agents.
In other words, which specific type of diabetic medication you took made a huge difference.
Metformin could save lives where the others could not, but its benefit had little or nothing to do with its blood glucose, lowering effect.
The glucotoxicity paradigm, proven in type 1 diabetes, failed miserably in type 2.
The Cochrane group, a well-respected independent group of physicians and researchers, later estimated that glucose control was only responsible for a miniscule 5, 15 percent of the risk of cardiovascular disease.9 Yet that still wasn’t the end of the story.
Tired of all the controversy, and still confident of the glucotoxicity paradigm in type 2 diabetes, the National Institutes for Health in the United States funded the massive Action to Control Cardiac Risk in Diabetes (ACCORD) randomized study,10 which began in 1999.
The ACCORD study recruited more than 10,000 type 2 adult diabetics across North America who were considered at high risk for heart attack and stroke.
The trial was designed, in part, to test whether taking medications for intensive blood glucose control would reduce the risk of heart attack, stroke, death from cardiovascular disease, and other cardiovascular events.
One group of patients received standard treatment.
The other group received high doses of medications and insulin to reduce blood glucose to as close to normal as possible.
The first results from the ACCORD study were published in 2008 and proved that intensive medical therapy could reduce the A1C.
Great.
Did this make any difference to health?
It sure did.
Intensive treatment was killing people.
Completely contrary to expectations, intensively treated patients were dying 22 percent faster than the standard treatment group, in spite of, or perhaps because of, the intervention.
This equaled one extra death for every ninety-five patients treated.
The study could not ethically be allowed to continue.
Many similar studies finished around the same time.
The results of the randomized Action in Diabetes and Vascular Disease Controlled Evaluation (ADVANCE) trial, which looked at intensive blood glucose control and vascular disease in patients with type 2 diabetes, were published simultaneously with the ACCORD results.11 Once again, this blood glucose, reducing strategy failed to deliver cardiovascular benefits; thankfully, it also failed to increase mortality.
In contrast, blood pressure, lowering medications reduced cardiovascular disease, as expected.
So certain medications did truly benefit type 2 diabetic patients, but those that reduced blood glucose did not.
Two further randomized controlled trials quickly followed to confirm these disappointing results.
The Veterans Affairs’ Diabetes Trial (VADT) found that intensive medical therapy produced no significant benefits to heart, kidney, or eye disease.12 The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial treated prediabetics with early initiation of insulin.13 There was no reduction in heart disease, stroke, eye disease, peripheral vascular disease, or any measurable health benefits.
The classic medications for type 2 diabetes, including insulin, metformin, TZDs, and SUs, had utterly failed to improve health.
The ACCORD, ADVANCE, and VADT trials all followed up with patients in the longer term and published extended results,14 but these yielded little new information.
All the trials agreed that intensive glucose control with medications did not save lives and had marginal, if any, benefits.
Furthermore, there were serious side effects, including an increased risk of hypoglycemic reactions.
The most obvious concern was the well- known propensity of SUs, TZDs, and insulin to cause weight gain in patients who were already obese, which could lead to cardiovascular problems down the line.
Metformin, which does not raise insulin, does not cause obesity and this was the crucial difference.
Peer-reviewed commentary from 1999 reveals that concerns were already percolating about the real issue: exacerbating hyperinsulinemia in a patient who already had too much insulin.
Dr.
Richard Donnelly from the University of Nottingham, U.K., wrote, “The findings could also be interpreted as indicating that insulin and sulphonylureas are equally harmful in the obese, possibly as a consequence of hyperinsulinaemia.”15 In type 1 diabetes, blood insulin is low, so replacing insulin is logical.
In type 2, blood insulin is high, so giving more insulin seems problematic.
After all, giving more alcohol to an alcoholic is not a winning strategy. Using heating blankets on a heat stroke victim is not a winning strategy. Treating sunburn by getting more sun is not a winning strategy. And giving more insulin to somebody with too much insulin is not a winning strategy. Logically, effectively treating type 2 diabetes requires an approach to lower both glucose and insulin, thereby minimizing both glucotoxicity and insulin toxicity.