Sulfonylureas (SUs) SULFONYLUREAS STIMULATE THE pancreas to produce more insulin, thereby effectively reducing blood sugars. The sulfonylurea (SU) drug class was discovered in 1942 and has been widely prescribed since then. By 1984, more powerful second-generation SUs had been introduced in the United States. The most commonly used drugs in this class include glyburide,
glipizide, and glicizide.
In its research on type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS; see chapter 10) demonstrated that intensive treatment with the SU class of drugs produced almost no benefits in controlling the long-term complications of diabetes.
Of particular concern was that exacerbating weight gain in already obese patients could lead to cardiovascular problems down the line.
Extended follow-up of the original UKPDS study showed only mild cardiovascular benefits: the death rate was reduced by 13 percent.9 The paradigm of glucotoxicity was established for type 2 diabetes, but only barely.
Blood glucose, lowering medications had marginal benefits that took twenty years to become apparent.
The risk associated with increasing insulin, with its accompanying weight gain, could barely offset the benefit of lowering glucose.
Further studies have borne out these concerns.
A 2012 review of more than 250,000 newly diagnosed type 2 diabetics in the Veterans Affairs database across the United States showed that starting treatment with SUs instead of metformin carries a 21 percent higher risk of cardiovascular disease.10 Studies from the U.K. and elsewhere estimate the use of SUs increases the risk of heart attack or death by 40 to 60 percent.11 Furthermore, these risks increase in a dose-dependent manner.12 That is, the higher the dose of SU, the greater the cardiovascular risk.
A 2012 randomized, controlled trial, the gold standard of evidence- based medicine, confirmed that initial therapy with SUs compared to metformin increases the risk of vascular disease by 40 percent13 despite equal blood glucose control.
The importance of this study cannot be underestimated.
Two drugs that control blood glucose equally could have widely divergent effects on cardiovascular health.
The main difference?
One stimulates insulin and causes weight gain whereas the other does not.
Glucotoxicity is equal, so the difference is the insulin toxicity of SUs.
Thiazolidinediones (TZDs) DURING THE 1980s and 1990s, drug companies did not develop a single new oral hypoglycemic agent because the number of patients using them was too small and the benefit was dubious. But the growing number of diabetics and prediabetics changed the economics of diabetic
medications completely.
In 1999, the Federal Drug Administration (FDA) approved the first new diabetes drug class in more than a decade, the thiazolidinediones (TZDs).
These drugs bind to receptors in the fat cells, making them more sensitive to insulin and thereby amplifying insulin’s effects.
So TZDs such as rosiglitazone, sold under the brand name Avandia, and pioglitazone, sold as Actos, lower blood glucose but do not raise insulin levels; instead, they help the body use the available insulin more effectively.
Predictably, research showed TZDs’ magnifying effect was both positive and negative.
Blood glucose was lowered, but patients could reliably expect to gain 3 to 4 kilograms (6.6 to 8.8 pounds) of fat, as insulin is a key driver of weight gain.
They also retained fluid, typically around the ankles but sometimes in the lungs, which caused shortness of breath and congestive heart failure.
These setbacks were mild, but worse was still to come.
By 2007, the influential New England Journal of Medicine reported that rosiglitazone unexpectedly increased the risk of heart attacks.14 The FDA hastily convened an advisory board of independent experts that same year;15 similar deliberations took place in Europe.
The FDA investigated concerns of data tampering in the Residential Environment and Coronary Heart Disease (RECORD) study, one of the largest trials that had “proved” the safety of rosiglitazone, and eventually concluded that the concerns about heart disease were well placed.16 Rosiglitazone was associated with a 25 percent higher risk of heart attack.
By 2011, Europe, the U.K., India, New Zealand, and South Africa had all banned the use of rosiglitazone, though the FDA continued to allow its sale in the United States with a warning label for patients.
These concerns devastated sales.
Doctors stopped prescribing the medication, patients refused to take it, and by 2012, sales had fallen to a paltry $9.5 million.
The debacle left some beneficial policy changes in its wake.
All diabetes medications henceforth were required to conduct large-scale safety trials to safeguard the public interest.
Dr.
Clifford Rosen, the chairperson of that FDA committee, clearly identified the key problem.
New drugs were approved based solely on their ability to lower blood glucose, under the unproven assumption that this effect would reduce the cardiovascular burden.
However, the evidence to date, including the
UKPDS, ACCORD, ADVANCE, VADT, and ORIGIN studies, had failed to confirm these theorized benefits.
Lowering blood glucose had little to do with protecting against the organ damage of type 2 diabetes.
A second TZD, pioglitazone, faced its own concerns about bladder cancer.
Compared to other diabetes medications, the use of pioglitazone is associated with a 63 percent increased risk of bladder cancer.17 The risk rises with longer duration of use and higher dosages.
The known side effects of weight gain and fluid retention were enough to give physicians pause, but these new concerns about cardiovascular and cancer risks effectively sealed the fate of the TZD drug class.
In North America, they are very rarely prescribed and usage has effectively ceased.
MEDICATIONS THAT ARE WEIGHT NEUTRAL
Metformin METFORMIN, THE MOST powerful of the biguanide class of medications, was discovered shortly after insulin and described in the scientific literature in 1922.
By 1929, its sugar-lowering effect was noted in animal studies, but it was not until 1957 that it was first used in humans for the treatment of diabetes.
Biguanides work by blocking gluconeogenesis and thereby preventing the liver from producing glucose.
This effect lowers the risk of hypoglycemia and weight gain because it does not increase insulin levels in the body.
Metformin entered the British National Formulary in 1958 and was introduced in Canada in 1972.
The FDA did not approve it in the United States until 1994 due to concerns about an extremely rare side effect called lactic acidosis.
However, given the powerful lifesaving effect demonstrated in the UKPDS compared to other comparable diabetes drugs, the benefits are felt to be well worth the risk and it has become the most widely prescribed diabetes drug in the world.
Since metformin does not raise insulin, it does not cause obesity and therefore does not worsen diabetes.
So metformin sounds pretty good.
The problem is that metformin (and other biguanides) does not take away the root cause of the illness, that is, they do not rid the body of excess sugar.
Remember, hyperinsulinemia causes type 2 diabetes.
While these
drugs target blood glucose, they do little to relieve the underlying hyperinsulinemia.
They take care of the symptom but, since they do not eliminate the cause, insulin resistance continues to rise and diabetes is managed but not eliminated.
Clinically, this is obvious.
Once started on metformin, it is highly unlikely that one will ever be able to stop it without intensive lifestyle changes.
Therefore, metformin may manage the disease for a while, but eventually, the patient will require higher and higher doses.
The underlying disease process continues progressing, solemn as a clergyman.
Dipeptidyl peptidase-4 (DPP-4) inhibitors IN 2006, the FDA approved a new class of medications called the dipeptidyl peptidase-4 (DPP-4) inhibitors.
These drugs are designed to lower blood glucose by blocking the breakdown of incretins, which are hormones released in the stomach that increase insulin secretion in response to food.
High incretin levels stimulate insulin release; however, this insulin response is not sustained and therefore these drugs do not cause weight gain.
The risk of hypoglycemia is also low.
Hopes were high for this new class of medication, but a study completed in 2013, called the SAVOR study18 (Saxagliptin Assessment Of Vascular Outcomes Recorded In Patients With Diabetes Mellitus), along with 2015’s Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study,19 soon dashed these hopes.
The FDA mandated both randomized controlled trials after the rosiglitazone debacle and neither found safety concerns with the long-term use of these medications.
However, neither were there any protective effects against cardiovascular diseases.
These medications effectively lowered blood glucose but did not reduce heart attacks or strokes.
Once again, the glucotoxicity paradigm was proven false.
Yes, you could reduce blood glucose, but, no, you were not any healthier for it.
In spite of that, the fact that these medications were at least not killing people was apparently a good enough reason to prescribe them.
In 2015, the top DPP-4 inhibitor, sitagliptin, raked in $3.86 billion, enough to rank it as the second bestselling diabetes drug in the world, trailing only Lantus, a long-acting form of insulin.20