Sodium-glucose cotransporter 2 (SGLT2) inhibitors THE NEWEST CLASS of medications, called sodium-glucose cotransporter 2 (SGLT2) inhibitors, block glucose reabsorption in the kidney, allowing glucose to escape in the urine, which replicates the protective mechanism used by the body during severe hyperglycemia.
What happens if you don’t block this protective mechanism, but enhance it?
Where the classic diabetes drugs increase insulin, the SGLT2 inhibitors lower it21 by forcing the excretion of glucose outside the body.
The result is lower blood glucose, but also lower body weight, blood pressure, and markers of arterial stiffness.22 As the root cause of diabesity is hyperinsulinemia, here, at long last, was a drug that effectively lowered insulin.
Would this finally translate into proven cardiovascular benefits?
It wasn’t just a home run; it was a grand slam.
A 2015 study called the EMPA-REG study (Empagliflozin: Cardiovascular (CV) Outcomes and Mortality in Patients with Type 2 Diabetes Mellitus)23 revealed that the SLGT2s reduced the risk of death by an incredible 38 percent.
The good news did not stop there.
It reduced the risk of progression of kidney disease by almost 40 percent and the need for dialysis by a stunning 55 percent.24 The elusive cardiovascular and renal benefits that virtually every previous study had failed to deliver were finally found.
Tellingly, the blood glucose, lowering effect was very modest.
The A1C only dropped by 0.47 percent, far less than almost every other medication currently in use, but the benefits were far greater.
This result once again underscored that glucotoxicity is a minor-league player.
The SGLT2 inhibitors simultaneously lowered both insulin toxicity and glucotoxicity, and the results were nothing short of amazing.
Weight loss is one of the most noticeable side benefits of this class of medication.
Not only did patients lose weight, unlike virtually every other dietary trial, they kept the weight off even after the two years.
Canagliflozin, for example, helped patients lose an extra 2.9 kg of body weight and keep it off.25 The main side effect of this class of medications is the increased risk of urinary tract infections and yeast infections due to increased urinary
glucose concentration. However, these infections were generally mild and treatable. The most serious side effect was an increased risk of ketoacidosis. The combination of proven organ protection, lowered blood glucose, lowered insulin, and weight loss is a powerful incentive for physicians to prescribe these new drugs. Sales have been rising sharply as of 2017, with some analysts predicting that sales could hit $6 billion by 2020.26
Alpha-glucosidase inhibitors DESPITE THE HOOPLA, the SGLT2 was not actually the first oral hypoglycemic agent to show proven cardiovascular benefits.
Another now largely forgotten drug was previously shown to have similar benefits.
Acarbose is an oral diabetes medication first introduced in the United States in 1996.
It blocks the enzymes alpha-glucosidase and alpha-amylase, both of which are required for proper digestion of carbohydrates.
Blocking these enzymes prevents complex carbohydrates, which are chains of glucose, from breaking into smaller glucose molecules, thus reducing absorption.
Acarbose is essentially the drug equivalent of a low-carbohydrate diet.
The 2003 Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM)27 trial showed that acarbose, despite relatively unimpressive lowering of blood glucose, reduced the risk of cardiovascular events by a remarkable 49 percent and hypertension by 34 percent.
In addition to these unprecedented benefits, acarbose also reduced body weight by 1.41 kilograms and waist circumference by 0.79 cm.
These results could have been predicted, since blocking absorption of dietary carbohydrates would be expected to lower insulin levels.
At the time of publication, the benefits were ascribed to the blood glucose, lowering effect, and it was expected that more powerful blood glucose, lowering medications would deliver even more impressive benefits.
Yet by 2008, the ACCORD, ADVANCE, VADT, and ORIGIN trials had conclusively demonstrated no benefits to blood glucose lowering.
Acarbose succeeded precisely where other medications failed because it reduces both glucotoxicity and insulin toxicity rather than trading one for the other.
It is still widely used in China and parts of Asia due to its low cost but is now far less popular in North America because its blood glucose, lowering effect is less powerful and bloating is a
bothersome side effect.
Glucagon-like peptide 1 (GLP-1) analogs GLUCAGON-LIKE PEPTIDE 1 (GLP-1) analogs are diabetic medications that mimic the effect of the incretin hormones.
Normally, the incretins secreted by the stomach have several physiological roles when you eat food.
They increase the release of insulin but also slow down the motility of the stomach and increase satiety.
The DPP-4 inhibitors also enhance incretin levels, but the GLP-1 analogs reach levels that are many times higher than normal.
Incretins increase the insulin response to food, so blood glucose decreases after meals.
This transitory rise in insulin is not enough to cause weight gain, but incretins slow the movement of food through the stomach, causing satiety, decreased food intake, and weight loss.
It also accounts for the main side effect of nausea and vomiting.
The 2016 LEADER trial of the GLP-1 analog Liraglutide showed that nausea occurred four times more often in the drug group than the placebo group.28 Patients on the medication averaged 2.3 kg weight loss compared to placebo and lowered their A1C by 0.4 percent.
The blood glucose, lowering effect was fairly modest but the cardiovascular benefits were not.
Liraglutide could reduce cardiovascular disease and death by approximately 15 percent.
While less powerful than the SGLT2 inhibitor class or acarbose, it was still highly significant and promised clinical benefits.
Yet again, the glucotoxicity paradigm was proved inadequate to explain what was happening.
Clinical benefits only accrue when both glucotoxicity and insulin toxicity are reduced.
A TRADE-OFF, NOT A SOLUTION
STANDARD MEDICATIONS FOR type 2 diabetes represent a trade-off between glucotoxicity and insulin toxicity.
Insulin, TZDs, and SUs all increase insulin or its effect to reduce hyperglycemia.
The effect of the increased insulin becomes clinically obvious as weight gain.
The price of better glucose control has been higher insulin dosage, so there is no net benefit.
These medications simply trade lower glucotoxicity for higher insulin toxicity.
Metformin and DPP-4 medications use mechanisms other than raising
insulin to lower blood glucose.
But they do not lower insulin either, so the result is neither weight gain nor weight loss.
Reducing glucotoxicity while keeping insulin neutral produces minimal benefits.
Clinically, these medications are weight neutral, but also neutral with regard to cardiovascular risk or benefits.
Acarbose, SGLT2 inhibitors, and GLP-1 analogs all lower glucose but also lower insulin and cause weight loss.
Since type 2 diabetes is a disease characterized by elevations in both blood glucose and blood insulin, these medications would be predicted to have the best outcome.
And sure enough, that is the case.
In a disease of too much insulin, lowering it creates benefits.
These three categories of medications could easily be called the good (lowers insulin, body weight, and complications), the bad (neutral), and the ugly (increases insulin, body weight, and complications).
Table 11.1.
Oral hypoglycemics in type 2 diabetes: A comparison
Weight loss Weight Weight gain neutral Acarbose SGLT2 Metformin Insulin Drugs inhibitors DPP-4 Sulfonylureas GLP-1 inhibitors TZDs analogues Insulin levels Lowers Neutral Raises insulin insulin Cardiovascular Decreases Increases outcomes hearts Neutral heart attacks compared to attacks and and death metformin death Verdict? GOOD BAD UGLY
The classic oral hypoglycemic agents were exclusively those that were insulin neutral or raised insulin levels. This explains how meta-
analyses reviewing all the available literature up to 2016, including twenty randomized controlled trials, could only conclude that “there is no significant evidence of long term efficacy of insulin on any clinical outcome in T2D (type 2 diabetes).
However, there is a trend to clinically harmful adverse effects such as hypoglycaemia and weight gain.”29 In other words, insulin treatment, including medications that simulate only the blood glucose, lowering properties of insulin, carries no perceptible benefits and significant risks.
Insulin is “significantly more harmful than other active treatments.” A similar review in the Journal of the American Medical Association that included all relevant trials up to March 2016 found that none of the drug classes considered, including metformin, SUs, TZDs, and DPP-4 inhibitors, reduced cardiovascular disease or other complications.30 Importantly, these older medications did not reduce the hyperinsulinemia that is the root problem, or indeed, made it worse.
Again, diabetes will continue unless we treat the root cause.
While the scientific evidence is crystal clear, diabetes guidelines are slow to reflect this new reality.
Dr.
Victor Montori of the Mayo Clinic discovered that 95 percent of published guidelines endorsed the use of diabetes drugs despite their nonexistent benefits.31 Why would you take medications that have no benefits?
Worse, why would you take medications that have no benefits and make you fat?
The classic medical treatment, which relies almost exclusively on pharmaceuticals to reduce blood glucose, can therefore best be described as how not to treat type 2 diabetes.
By contrast, newer agents, which can reduce both blood glucose and insulin levels, show proven benefits to reduce heart and kidney complications of type 2 diabetes.
Nevertheless, these medications, while an important step forward, are clearly not the answer; they do not reverse the root cause of type 2 diabetes, our diet.
Following a low-fat, calorie-restricted diet and increasing exercise have long been the recommended lifestyle treatment for type 2 diabetes.
There is only one problem with this seemingly common sense advice.
It doesn’t work at all.