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by
Jason Fung
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March 30 - April 4, 2024
EACH ADDITIONAL COMPONENT of metabolic syndrome—high triglycerides, low HDL, central obesity, high blood glucose, and high blood pressure—significantly increases the risk of all the modern metabolic diseases, such as heart attacks, strokes, peripheral vascular disease, type 2 diabetes, Alzheimer’s disease, and cancer. These symptoms cluster together, but not every disease manifests in every person: one person may have low triglycerides, another person will have high blood sugars from insulin resistance, and yet another will have high blood pressure. But having one of these factors
In a typical patient, gaining as little as 2 kilograms (4.4 pounds) of weight is the first detectable abnormality related to hyperinsulinemia/insulin resistance, followed by low HDL cholesterol levels. High blood pressure, fatty liver, and high triglycerides emerge next, at roughly the same time. The very last symptom to appear is usually high blood glucose, which clinches the diagnosis of type 2 diabetes.
Metabolic syndrome, of which obesity and type 2 diabetes are a key part, are ultimately caused by—you guessed it—too much sugar.
Obesity is the first line of defense against the root problem of hyperinsulinemia/insulin resistance. Similarly, insulin resistance is the body’s attempt to prevent fat from amassing in the internal organs by preventing it from entering. The liver refuses to allow more glucose to enter because it is already overfilled, and the result is visible as insulin resistance, which represents a second protective mechanism. The final line of defense lies in shutting down pancreatic production of insulin.
All the conditions we thought were problems—obesity, insulin resistance, and beta cell dysfunction—are actually the body’s solutions to a single root cause—too much sugar. And when we understand the root cause, the answer to all of these problems—and to type 2 diabetes—becomes immediately obvious. We need to get rid of the sugar and lower insulin. If we fail to remove the problems of too much sugar, too much insulin, and ectopic fat, then the problem is chronic and progressive. When we treat the root cause, then type 2 diabetes, and indeed the entire metabolic syndrome, is a completely
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THE CONVENTIONAL TREATMENT for both type 1 and type 2 diabetes has long been injection of exogenous (external) insulin. Human insulin, one of the great triumphs of modern pharmaceutical science, can be produced in a laboratory and packaged for convenient injection.
Extremely high blood glucose can cause diabetic ketoacidosis in type 1 diabetes and non-ketotic hyperosmolar coma in type 2 diabetes, but these complications are relatively uncommon.
THE DIABETES CONTROL and Complications Trial (DCCT)2—a large, randomized, controlled trial of patients with type 1 diabetes carried out between 1983 and 1993—proved that intensive insulin therapy, including tight management of blood glucose levels, could have dramatic beneficial results.
Despite several setbacks, by 2015 sales of diabetes drugs had reached $23 billion, which is more than the combined revenue of the National Football League, Major League Baseball, and the National Basketball Association.5
Every 1 percent increase in the hemoglobin A1C is associated with an 18 percent increase in risk of cardiovascular events, 12 to 14 percent increase in the risk of death, and 37 percent increase in risk of eye disease or kidney disease.7
But correlation is not causation. Lowering blood glucose with medications, as opposed to diet and lifestyle, is not necessarily beneficial.
Despite their popularity among doctors, these blood glucose–lowering pills—oral hypoglycemics in medicalspeak—are not long-term solutions to diabetes, either. I divide these medications into three categories based upon their effect on insulin and thus body weight. In general, the more they raise insulin levels, the more they cause weight gain and many of the complications associated with diabetes.
MEDICATIONS THAT CAUSE WEIGHT GAIN
Sulfonylureas (SUs) SULFONYLUREAS STIMULATE THE pancreas to produce more insulin, thereby effectively reducing blood sugars.
Thiazolidinediones (TZDs) DURING THE 1980s and 1990s, drug companies did not develop a single new oral hypoglycemic agent because the number of patients
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.
By 2007, the influential New England Journal of Medicine reported that rosiglitazone unexpectedly increased the risk of heart attacks.
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.
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.
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.
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.
MEDICATIONS THAT CAUSE WEIGHT LOSS
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.
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
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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 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.
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.
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.
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).
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.
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
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IN 2015, WHEN Dr. Sarah Hallberg stepped onto the stage at Purdue University to deliver a TEDx talk1 about reversing diabetes, few in the audience expected to hear what she was about to say: reversing type 2 diabetes starts with ignoring the guidelines.
And where did that advice come from? In the U.S., the Senate Select Committee on Nutrition and Human Needs first released its Dietary Guidelines for Americans in 1977. Since 1980, the United States Department of Agriculture (USDA) and the Department of Health and Human Services have published a set of dietary guidelines every five years.
Type 2 diabetes is characterized by high blood glucose. 2.Refined carbohydrates raise blood glucose levels more than any other foods.
THE 2012 TREATMENT Options for Type 2 Diabetes in Adolescents and Youths (TODAY) randomized study5 reduced caloric intake to a miniscule 1200 to 1500 calories per day of a low-fat diet, combined with increased exercise.
Massive effort by both patients and study staff failed to improve blood glucose—and the failure rate was astronomically high. Almost 50 percent of patients required increased doses and numbers of medications.
What was certainly behind the recommendation of a low-fat diet was the belief that lowering dietary fat could protect against heart disease and stroke. The most common cause of death in type 2 diabetes is cardiovascular disease, which had been falsely attributed to dietary fat.
Despite forty years of research trying to link dietary fat, dietary cholesterol, and heart disease, not a single shred of evidence could be found.10
All the scientific evidence has consistently refuted the dearly held belief that reducing dietary fat would lead to weight loss and reduce heart disease.12
THE EXERCISE APPROACH LIFESTYLE INTERVENTIONS, TYPICALLY a combination of diet and exercise, are a universally acknowledged mainstay of type 2 diabetes treatments.
Exercise improves weight-loss efforts, although its effects are much more modest than most assume. Nevertheless, physical inactivity is an independent risk factor for more than twenty-five chronic diseases, including type 2 diabetes and cardiovascular disease.13 Low levels of physical activity in obese subjects are a better predictor of death than cholesterol levels, smoking status, or blood pressure.14
And the benefits of exercise extend far beyond simple weight loss. Exercise programs improve strength and balance, blood pressure, cholesterol, blood glucose, and insulin sensitivity, without involving medications and their potential side effects.
Meta-analyses show that exercise may significantly reduce A1C, without a change in body mass. This finding suggests that exercise does not need to reduce body weight to have benefits, which echoes clinical experience with patients.
The main problem has always been noncompliance. Many real issues may deter someone from embarking on an exercise program: obesity itself, joint pain, neuropathy, peripheral vascular disease, back pain, and heart disease may all combine to make exercise difficult or even unsafe. Overall, however, I suspect the biggest issue is lack of visible results. The benefits are greatly overhyped and exercise doesn’t work nearly as well as advertised. Weight loss is often minimal. This lack of results despite great effort is demoralizing.
