Metformin: The Diabetes Wonder Drug Hiding in Plain Sight

Metformin: The Diabetes Wonder Drug Hiding in Plain Sight

By Gary M. Pepper, M.D

Diabetes Treatment

Introduction

Metformin has been used throughout the world for treating type 2 diabetes for over 50 years. It remains one of the most potent oral medications for reducing elevated blood sugar in type 2 diabetes, is among the least expensive anti-diabetes medication and continues to be the most prescribed pill for diabetes management .Add to all of these impressive facts about metformin, is a growing list of potential benefits that are truly mind blowing, including reducing the risk of dementia and certain cancers and even possibly slowing the aging process itself. So why is metformin the Cinderella of the medical world, with a growing undercurrent in the media that there is something not quite right with this drug?  Let’s take a closer look and see what is going on here.

Metformin regulates blood glucose levels by three mechanisms:

● Decreased hepatic glucose output.

● Reduced absorption of glucose via the gut

● Increased insulin sensitivity

Despite years of extensive study the exact mechanism of how this unique medication works is only partially understood.

Metformin’s Unique Effectiveness

An extensive review of multiple studies compared metformin to other anti-diabetic treatments was published in the British Medical Journal in 2007. This analysis found that when compared to other anti-diabetic medications including insulin, metformin was associated with considerably lower all-cause mortality.

The therapeutic efficacy of metformin was also clearly demonstrated in 2011 by a Korean-based study. Newly diagnosed type 2 diabetics receiving this medication were observed to have their HgA1c levels decrease from 7.9% to 7.0% coupled with a decrease in body weight while developing very few side-effects, in this one year study.

A wonder drug not only an anti-diabetic

Metformin-related harm, if any, is generally thought to be minimal. It does not contribute to weight gain, and it has the advantage of being the most reasonably priced diabetic care available. Non-glucose related benefits on the brain, heart, inflammation, ovarian function are becoming increasingly observed. Despite all this, due to the narrow profit margin in today’s market, metformin is fighting a public relations crisis. When it comes to metformin’s cost, safety, availability, and additional health benefits, our belief is that patients are receiving the utmost benefit.

Development and approval history

As mentioned, the voyage of metformin to its current position began in medieval Europe in the 1800s when it was first discovered in the light of herbal medicine ‘Galega officinais, a guanidine-rich plant commonly known as French lilac which was used to treat increased urination.

Previously considered an injurious weed in numerous states of the U.S., this plant was officially reported to decrease blood glucose levels in animals in the 1920’s leading to its use for diabetes. However, the side effects of the naturally occurring herb hampered its transition into clinical use.

Ultimately, Jean Sterne pioneered metformin’s ability to treat hyperglycemia into a therapeutic reality. Through a series of trials and research programs with Lipha pharmaceuticals metformin found its role as a unique medicine in the diabetic world. Ultimately, the FDA-approved metformin in December of 1994.

Soon after its launch, Bristol Myers acquired its marketing rights and initiated the safe introduction of the drug in the U.S. market beginning after the failure of  phenformin, a similar biguanide medication with lethal side effects related to lactic acidosis.

Why metformin remains superior to other anti-diabetic medicines

Many clinical trials have demonstrated the superiority of metformin in terms of its ability to lower elevated glucose levels. One such study comparing the clinical effects of metformin versus sulfonylurea mono-therapy in diabetic individuals appeared in the Diabetes Journal of the American Diabetes Association. The results showed that patients receiving sulfonylurea medication had a death rate of 24.7%, while those receiving solely metformin therapy had a mortality rate of 13.8%.

Another analysis compared several anti-diabetic treatments, published in The British Medical Journal. This study found that when compared to other anti-diabetic medications including insulin, metformin was associated with considerably lower all-cause mortality. The therapeutic efficacy of metformin was demonstrated by a separate 48-week Korean-based study. Throughout the study period, it was observed that Hba1c levels decreased from 7.9% to 7.0% (p< 0.001) coupled with a decrease in body weight.

Most endocrinologists actively support metformin use, and prescriptions have almost doubled within the last two decades for metformin. In 2004, metformin was prescribed for type 2 diabetes more than 40 million times, while in 2020 the number rose to over 90 million times.

Number of prescriptions per year of Metformin

 

 

Figure 1: Graph showing the number of prescriptions in millions from 2004 to 2020.

Source: Statista

The off-label use of metformin

Doctors also prescribe metformin for prediabetes, polycystic ovarian syndrome, and metabolic syndrome due to its ability to reduce insulin resistance.  Oluwaranti Akiyode, PharmD, RPh, BCPS, CDE  a professor and clinical pharmacist at Howard University states, “‘no one exactly knows the full extent of how metformin works” while acknowledging the potential benefits of metformin’s off-label use. One particular potential off-label benefit she points out is for the treatment of ‘HIV-related muscle wasting Also mentioned in this interview are potential benefits of metformin in the treatment of dementia and non-alcoholic fatty liver disease.

Metformin and cancer

A review of the literature conducted in 2019, found that metformin has anti-cancer properties via its interaction with enzymes in the liver. 12 studies were included in the review, all reporting indications of metformin’s anti-cancer properties due to its anti-proliferative nature.

Andrew Chan MD, MPH and a Harvard professor also appreciated the anti-cancer role of metformin. He stated that ‘”individuals taking metformin have a low risk of cancer, as metformin stops the growth of tumor through reducing cell growth, invasion, motility and spread’.

Anti-aging properties of metformin

One of the most major risks of diabetes is accelerated aging, which is almost a thousand fold more than normal. Hence, when targeting diabetes, preventing rapid aging always goes hand in hand. Among the first, a  2014 study published in the Journal of Alzheimer’s Disease found that metformin use delayed the decline in cognition. Biological aging markers, some only recently identified, are thought to be influenced by metformin mechanisms. Its effect on gene expression has also been established in the Metformin in Longevity Study (MILES).

Work in this area is accelerating. A collaborative nation wide effort is actively studying the anti-ageing effect of metformin to treat aging as a disease. Almost 3,000 people between the ages of 65 and 79 are expected to be part in the Targeting Aging with Metformin (TAME) Study, This collaboration involves a set of six-year clinical trials being conducted at 14 top research institutes across the United States.

Metformin and arthritis

Metformin has shown benefit in the fight against arthritis. The primary incapacitating elements of arthritis including inflammation, oxidative stress, and pain, are all counteracted by metformin. Thus, it may be used to treat osteoarthritis in the future since it slows down the structural worsening of the syndrome.

A randomized controlled trial conducted in 2021, established metformin as an effective treatment for rheumatoid arthritis. Sixty patients were started on metformin for 6 months, in comparison to a control, and showed decreased levels of CRP and DAS-28-CRP which are both strongly linked with the inflammation and progression of rheumatoid arthritis.

Does metformin come with side effects?

Metformin has been used as the first-line drug for diabetes worldwide for more than 2 decades, and is generally regarded as among the safest diabetic drug available. Intolerance due to gastrointestinal side effects are relatively minor but it is fair to acknowledge that the incidence is high. A major 2021 review of this issue indicated that 20-30% of metformin users develop some gastrointestinal side effects and that 5% stopped metformin use because of this. Almost all patients can tolerate it long-term through dose adjustment or a switch to the extended release version of the drug which is better tolerated, generally.  However, whenever low compliance is seen it is always due to diarrhea or similar gastrointestinal disturbances.

What is Extended-release formulation?

To simplify the daily routine of taking metformin, in 2020 a once daily version of the drug known as Glucophage XR was FDA approved. This version subsequently was found to have a lesser tendency to cause gastrointestinal side-effects such as diarrhea. This provides users the double benefit of convenience and less risk of gastrointestinal issues, although the price is slightly higher than a similar dose of the original twice daily version.

After being diagnosed with diabetes and taking metformin for 20 years, Gretchen Becker the author of The First Year: Type 2 Diabetes: An Essential Guide for the Newly Diagnosed, started developing diarrhea when the doctor accidentally switched her to the immediate release version from the extended release version of metformin. Becher reported, ‘I had very loose bowels for several months until I figured out what the problem was.’

What are some serious complications and contraindications for metformin?

Although rare, one serious side effect of metformin is lactic acidosis, in which the blood acidity is reduced due to increased levels of the metabolite, lactate. This side effect is mostly seen in patients with significant kidney problems dehydration or alcoholic liver disease, hence one of the contraindications of metformin is markedly impaired kidney or liver function. Recent studies have confirmed that this drug, with proper monitoring, exhibits low risk of lactic acidosis even in the face of mild to moderate reduction in kidney function. However, patients on metformin, as are most of those with diabetes, are advised to undergo regular kidney monitoring.

Comparison of metformin with other anti-diabetic medicines

Numerous studies have demonstrated that most of the widely prescribed oral anti-diabetic drugs were essentially similarly effective at suppressing and regulating blood sugar levels. Yet metformin stood out since it provided the same or superior degree of effectiveness at a lower cost without decreasing glucose readings to dangerous levels. Additionally, scientific study points to metformin as a potential inhibitor of atherosclerosis thereby limiting cardiovascular mortality. The estimate of expenditure on insulin and newer anti-diabetic drugs is far more as compared to metformin as noted by the American Diabetes Association. Shari Bolen, a lead study author for diabetic drugs at John Hopkins, said ‘Sometimes newer is not necessarily better.’

Price comparison of metformin to other drugs

As mentioned, metformin is among the least expensive of the anti-diabetic medications as demonstrated in this graphic. Spending hundreds of dollars per month less on medication can influence standards of living. Crucially, spending significantly less on medications enables purchase of healthier and often more expensive foods, gives people access to health sustaining activities and hobbies and generally improves quality of life potentially extending lifespan.

Comparison of the Cost of Diabetes Medications

Figure 2: Price comparison for a month’s supply of diabetic medicines (prices are averages)


Conclusion

Metformin has been called the aspirin of the 21st century and remains undefeated in being the first-line drug for type 2 diabetes. It is cheap, effective, essentially safe and multi-beneficial which makes it stand out. Due to its low profit potential, metformin remains invisible in the mass marketing blitz of newer anti-diabetes medications. Despite its low public profile it is still considered by most experts to be the best first line choice for treating type 2 diabetes with many other non-diabetic related benefits still waiting to be clarified.

Are you or a loved one navigating the complexities of Type 2 diabetes? Dive deeper into the world of metformin and discover how this time-tested medication can be a game-changer in diabetes management. Stay informed, stay healthy.

Disclaimer; This publication/article, as well as all publications originating at www.metabolism.com is/are for the sole purpose of information and education and not intended as medical treatment or advice or in anyway to substitute for the care rendered by a personal healthcare provider. We acknowledge that in the rapidly evolving field of medical science and treatment, our publication may contain unintentional informational gaps and inaccuracies. If so, we appreciate feedback on these deficiencies so we may correct them. Only your personal health care provider can supply treatment and advice suitable for your needs. Users of www.metabolism.com understand that their use of the website is governed by the disclaimer and terms of use found at www.metabolism.com.

 

Stopping Prediabetes in Its Tracks: Simple Interventions that Work

Stopping Prediabetes in Its Tracks: Simple Interventions that Work

By Gary Pepper, M.D. and Sam Jeans MSc

In our previous article The Prediabetes Puzzle: What the Blood Tests Mean, we investigated controversies surrounding diabetes diagnosis.

There’s a clear lack of consensus surrounding thresholds for diagnosis of prediabetes, the tests used to measure blood sugar, and the way forward for those at risk of transitioning from prediabetes to diabetes.

If left untreated, at least 37% of individuals with prediabetes typically develop type 2 diabetes in 4 years. But, with appropriate and early intervention, this can be dramatically reduced to 17% or less.

Here, we’ll investigate what diabetes interventions are effective, including lifestyle changes and medication.

Early Interventions For Prediabetes

Diagnosis of prediabetes is a useful wake-up call for many.

A sedentary lifestyle, a poor diet…these are significant contributors to prediabetes, and fighting back to take back control of one’s health vastly decreases the likelihood of transitioning to diabetes. The earlier prediabetes is caught, the easier it is to tackle.

When prediabetes is diagnosed, people face a series of choices. Should you tackle it with lifestyle changes alone?

Will you stick to the plan for long enough to see the benefits?

Or is early intervention with medication a good idea? And if so, what medication?

The Impact of Diet And Exercise

Unsurprisingly, a healthy diet and exercise are essential for weight management and glycemic control. Sustained lifestyle improvements improve insulin sensitivity, decreasing blood sugar levels and stunting the development of full-blown diabetes.

But how effective are lifestyle interventions?

An influential study of lifestyle interventions, The Diabetes Prevention Program (DPP), demonstrated that a low-fat, low-calorie diet reduced the incidence of diabetes by 58% in individuals with prediabetes.

The study recommended a daily intake of less than 25% of total calories from fat, increased fiber intake, and reduced daily calorie intake to achieve 7% weight loss. It’s worth highlighting that the study involved 1,079 participants and was highly structured with a relatively strict regime of 16 taught sessions. Non-adherent participants were introduced to a “toolbox” of extra interventions.

Another major systematic review found that, after one and three years of lifestyle intervention, the risk of diabetes decreased by 36% to 54% compared to treatment as usual.

Several studies also found a reduced incidence of cardiovascular and microvascular illnesses (e.g., neuropathies). Even when blood sugar levels don’t drop to normal, lifestyle changes were shown to improve overall health and lower the risk of mortality.

Further, multiple studies show that lifestyle exercises are considerably more effective than medication alone:

“Lifestyle intervention decreased the incidence of type 2 diabetes by 58% compared with 31% in the metformin-treated group” The Diabetes Prevention Program (DPP).

In short, it’s certain that lifestyle changes can change the course of diabetes.

However, not everyone has access to targeted diabetes interventions like that provided by the DPP.

Self-led and clinician-supported lifestyle interventions are still effective – here’s what people can do.

What To Do

(Reminder: Any recommendations made here are for educational purposes only. Only your health care provider can prescribe lifestyle modifications or medications appropriate for you as an individual)

Firstly, it’s time to get moving. The American Diabetes Association (ADA) recommends at least 150 minutes of moderate-intensity aerobic exercise per week, with no more than two consecutive days without activity. Resistance training is also recommended at least twice a week if possible.,

In terms of diet, all the usual recommendations apply. Decrease saturated fat, sugar, refined carbs, and calories and swap for protein, fiber, and wholegrains.

Add plenty of fruit, veg, grains, legumes, nuts, and good fats like olive oils. Ditch processed food.

While any lower-fat, lower-calorie diet with plenty of fruit and veg is better than a heavily processed diet, the Mediterranean diet is shown to be particularly effective.

Characterized by high consumption of fruits, vegetables, whole grains, legumes, nuts, and olive oil, the Mediterranean diet performs better than other diets.

5-Step Plan for Reducing Diabetes Risk

Here is a 5-step plan to reduce the risk of diabetes through lifestyle changes:

  • 1. Weight management: Achieving and maintaining a healthy weight is crucial for diabetes prevention. The Diabetes Prevention Program (DPP) found that a modest weight loss of 5-7% of initial body weight significantly reduced the risk of developing type 2 diabetes in individuals with prediabetes. 5 to 7% is achievable for most people.
  • 2. Dietary modifications: Consuming a balanced and healthy diet is essential for diabetes prevention. The DPP recommended a low-fat, low-calorie diet with high consumption of fruits, vegetables, whole grains, legumes, and nuts.
  • 3. Physical activity: Regular exercise helps improve insulin sensitivity and aids in weight management. The American Diabetes Association (ADA) recommends at least 150 minutes of moderate-intensity aerobic exercise per week, with no more than two consecutive days without activity.
  • 4. Quit smoking: Smoking has been associated with an increased risk of developing type 2 diabetes. Quitting smoking can help reduce the risk of diabetes and various other health issues, including cardiovascular diseases and respiratory illnesses.
  • 5. Stress management: Chronic stress has been linked to an increased risk of developing type 2 diabetes. Adopting stress reduction techniques, such as mindfulness meditation, yoga, or engaging in hobbies and relaxation activities, can help manage stress and contribute to overall well-being, potentially reducing the risk of diabetes.

The positive effects of lifestyle changes start quite quickly – within days to weeks.

But, blood sugar levels can take months to years to come down. So, regular check-ups are essential, and don’t become disheartened if the impact isn’t immediate.

Diabetes Medication

Medications remain extremely important in treating diabetes.

Not everyone can commit to the lifestyle changes required to reduce blood sugar levels naturally.

For example, some with prediabetes may be unable to partake in intense exercise due to musculoskeletal issues, disabilities and complications from other diseases. But, of course, that isn’t to say that diet and healthy eating alone won’t have an impact.

The critical issue is, lifestyle interventions often aren’t adhered to for long enough to have an impact. Or in other words, people give up.

Studies place adherence to lifestyle interventions at around 50 to 60%. So over half of people give up in many cases. Those that give up are very likely to develop diabetes without other interventions.

This has led many health authorities to encourage medication almost immediately.

Diabetes Drugs are Changing

Diabetes medications remained fairly consistent for almost 50 years.

Metformin and thiazolidinediones (formerly known by the brand name Actos), in particular, have been considered highly reliable in treating diabetes.

There’s been an explosion in new diabetes drugs in recent years, with the 50-year-old metformin, although remaining the first choice, this dominance has been challenged in the last few years.

Newer peptide-1 (GLP-1) agonists (e.g., semaglutide/liraglutide with brand names like Victoza and Ozempic) and SGLT-2 inhibitors such as Jardiance and Invokana have grown in interest for their ability to lower blood sugar levels and reduce weight. While their performance for reducing blood sugar are very similar to older drugs, they may have a better combined impact on blood glucose and weight loss.

There’s an all-too-familiar issue at play, though. Liraglutide and semaglutide drugs are expensive.

An article published in the Wall Street Journal sums this up well, “The newer drugs cost more than metformin, however, and some patients might not be able to afford the out-of-pocket costs and need to go with metformin. Ozempic, for example, lists for nearly $900 a month, and Jardiance comes in at about $590 a month.”

So, what does this all mean for metformin and other diabetes drugs? Will they merely fade into the background?

Metformin: Still a Wonder Drug?

Metformin is still the world’s most widely used medication for treating type 2 diabetes and has demonstrated efficacy in preventing the progression from prediabetes to diabetes.

Metformin primarily reduces glucose production by the liver and increases insulin sensitivity in peripheral tissue.

The DPP revealed a 31% reduction in the incidence of diabetes in individuals with prediabetes treated with metformin compared to the control group. While combined metformin and lifestyle change was significantly more effective at 58%, metformin’s impact is still impressive.

The drug is generally well tolerated, with gastrointestinal side effects being the most common adverse events. Some patients do experience lower exercise tolerance after taking metformin, which may impede exercise interventions, but evidence suggests this is minimal in most cases. Metformin has been around for a long time, and there’s not much we don’t know about it – no nasty surprises means a lot. Furthermore, metformin costs pennies per month making the overall appeal of this drug for diabetes management almost unchallengeable.

However, despite its excellent safety and tolerability profile, we can see early indications that pharma is falling out of love with the drug.

Some 80% of those with diabetes are eligible for new drugs, according to this publication by WebMD. The report emphasizes Ozempic, which currently costs $814 to $1040 per month.

Indeed, higher profit margins on new drugs are hardly discouraging pharma from thrusting semaglutide/liraglutide into the limelight.

Another Contender: Pioglitazone

Another veteran diabetes drug, pioglitazone, originally marketed as Actos, has also demonstrated efficacy in preventing the progression from prediabetes to diabetes.

It works by increasing insulin sensitivity in peripheral tissues and reducing hepatic glucose production.

The ACT NOW study showed that pioglitazone reduced the risk of developing diabetes by 72% in individuals with impaired glucose tolerance – better than metformin and newer semaglutide/liraglutide drugs.

However, concerns that pioglitazone raised the risk of heart failure and carried a small risk of bladder cancer impacted its reputation in the early-2000s.

Pioglitazone: Dangerous or Disregarded?

A few studies have drawn attention to pioglitazone’s controversial status in diabetes treatment.

● One such 2014 article Pioglitazone: An Antidiabetic Drug with Cardiovascular Therapeutic Effects, concluded that pioglitazone has beneficial effects, contrary to some earlier concerns about its safety. In addition, they draw attention to the 2005 PROactive study, which demonstrated that pioglitazone reduced non-fatal myocardial infarction and stroke in patients with type 2 diabetes.

● Studies in 2007 and 2013 both encouraged new insights into the drug, the latter, published in the journal Diabetes Care, suggesting “more commonly used regimens (other than pioglitazone) are both less effective and more likely to result in worse safety outcomes.” The authors also address the concern of an increased risk of bladder cancer associated with pioglitazone use, stating that the evidence is inconclusive and the absolute risk, if any, is low.

● In 2021, another study Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug , further highlighted pioglitazone’s cardiovascular benefits, such as reducing the risk of major adverse cardiovascular events in certain patient populations.

As the pharmaceutical industry slowly shifts the emphasis to newer, more expensive peptide-1 (GLP-1) agonists and SGLT-2 blockers, it’s essential to remain mindful of longstanding, reliable drugs with well-understood safety profiles.

Pioglitazone and metformin are exceptionally well known to medical science. Although some practitioners imply that these older medications have become outdated, their long record of safety and efficacy should be a major plus when considering treatment options.

Summary: Preventing the Progression from Prediabetes to Type 2 Diabetes

Preventing the progression from prediabetes to diabetes is critical. This important window of intervention shouldn’t be ignored.

Evidence-based strategies, including weight management through diet and exercise and the use of medications such as metformin, pioglitazone, and newer agents such as Ozempic , can significantly reduce the risk of developing diabetes in individuals with prediabetes.

Lifestyle changes are extremely effective and can have a transformative effect. People must stick to them – don’t be part of the 50%+ of those who give up.

When it comes to medication, old is still sometimes gold. Newer medications may grab the headlines (and advertising time), the reliability and affordability of older medications like metformin should not be overlooked

Disclaimer; This publication/article, as well as all publications originating at www.metabolism.com,  is/are for the sole purpose of information and education and not intended as medical treatment or advice or in anyway to substitute for the care rendered by a personal healthcare provider. We acknowledge that in the rapidly evolving field of medical science and treatment, our publication may contain unintentional informational gaps and inaccuracies. If so, we appreciate feedback on these deficiencies so we may correct them. Only your personal health care provider can supply treatment and advice suitable for your needs. Users of www.metabolism.com understand that their use of the website is governed by the disclaimer and terms of use found at www.metabolism.com.
The Prediabetes Puzzle: What the Blood Tests Mean

The Prediabetes Puzzle: What the Blood Tests Mean

by Gary M. Pepper, M.D. with Samuel Jeans, MSc

As an endocrinologist, I frequently encounter patients who are confused about whether they have diabetes or prediabetes. Many have been told that their blood sugar levels were above normal on recent blood tests, possibly indicating prediabetes. However, this concern is often unfounded. So why is this scenario so common?

I believe that commercial lab facilities are partially responsible. Their routine procedure is to flag blood sugar levels over 99 mg% as abnormally high, which can result in many false positive diagnoses of abnormal glucose metabolism. But why do medical facilities continue to follow this protocol?

To understand this, let’s take a closer look at how prediabetes and diabetes are diagnosed.

Diabetes type 2 is a metabolic disease in which the body’s insulin production and sensitivity is impaired, resulting in consistently higher-than-normal blood glucose levels.

At current estimates, between 1 in 10 and 1 in 11 of the world’s population have diabetes.

Around 90% of those who have diabetes have type 2 diabetes.  This is a disease in which the body is able to create insulin but either can’t create enough insulin or has become resistant to it. Insulin helps move glucose (sugar) from the blood into the cells that need it for energy. Diabetes complications include nephropathy (kidney), retinopathy (eye), and vascular disease. In the worst cases, this can lead to complete loss of feeling in the feet, kidney failure or blindness.

The complications of diabetes grow worse with age. At age 50, those with diabetes live six years less on average than those without, according to the CDC. However, early intervention and proper treatment have been shown to restore life expectancy to close to normal levels – especially if prediabetes is identified early.

It’s certainly possible to prevent, delay or change the course of diabetes. However, this depends on a robust and accurate assessment of prediabetes and the timely prescription of medication and lifestyle interventions.

Defining Prediabetes

People don’t become diabetic overnight. Before diabetes is established, individuals go through a stage of prediabetes that can last anywhere between 2 to 5 years. The effects of prediabetes are largely asymptomatic or invisible, and it’s often flagged on coincidental or routine blood tests.

The CDC estimates that 96 million adults in the US – over a third of the population – likely have prediabetes. Similar levels are observed across other developed countries.

In the USA, incidence rates of diabetes have doubled in the last 20 years, and diabetes is the 7th leading cause of death, and this is likely underreported.

Harvard Health cites that many people totally miss prediabetes or don’t take sufficient action to prevent it from developing into full-blown diabetes. As few as 10% of people with prediabetes are aware that they have it. Around 5 to 10% of cases of prediabetes convert into diabetes annually.

On the positive side, lifestyle changes can prevent as many as 70% of cases of prediabetes from turning into diabetes. As such, accurate and timely diagnosis and intervention are a top priority. But as ever, it isn’t as straightforward as some perceive.

Testing and Diagnosing Prediabetes and Diabetes

Testing blood glucose levels and response is critical for diagnosing prediabetes, as prediabetes is usually asymptomatic and neurologic and vascular pathology are absent.

Recommendations for who and when to screen for diabetes and prediabetes have been provided by several authoritative organizations and are summarized by metabolism.com in an earlier article.

However, capturing blood glucose levels and robustly diagnosing prediabetes is challenging, and leading health authorities provide varying and non-consistent advice.

There are four main ways to test and measure blood glucose to diagnose prediabetes and diabetes. Here’s an overview of each:

1: HbA1C Test

The HbA1C test (glycosylated hemoglobin A1c) measures average blood sugar level over a long period, typically the past 2 or 3 months. It achieves this by measuring the amount of hemoglobin in the red blood cells coated with glucose (HbA1c).

An HbA1C below 5.7% is considered normal, between 5.7 and 6.4% indicates prediabetes, and 6.5% or higher indicates diabetes.

2: Fasting Blood Sugar Test

A fasting blood sugar test measures impaired fasting glucose (IGT). The blood test is taken after an overnight fast (not eating).

The American Diabetes Association defines a fasting blood sugar level of 99 mg/dL or lower to be normal, 100 to 125 mg/dL indicates prediabetes, and 126 mg/dL or higher indicates diabetes.

3: Glucose Tolerance Test

Glucose tolerance tests measure impaired glucose tolerance (IGT). This blood test measures your blood sugar before and after drinking a solution containing glucose. The WHO advises that the test is taken 2 hours after ingestion of 75 g of oral glucose.

Additional measurements may be taken at 1 and 3 hours or at 30 to 60-minute intervals. Similarly to a fasting blood test, individuals must fast overnight before the test.

At 2 hours, a blood sugar level of 140 mg/dL or lower is considered normal, 140 to 199 mg/dL indicates prediabetes, and 200 mg/dL or higher indicates diabetes.

4: Random Blood Sugar Test

In some cases, clinicians may choose to take blood sugar randomly, known as a random blood sugar test. This is taken at any point, with no fasting.

It’s not robust but indicates diabetes with a blood sugar level of 200 mg/dL or higher. This often initiates other blood investigatory tests for diabetes.

Diagnostic Criteria for Diabetes vs Prediabetes

Hb A1c  Fasting glucose    OGTT (2 hours)
Diabetes 6.5% or higher 126 mg% or higher 200 mg% or higher
Prediabetes 5.7% to 6.4% 100 to 125 mg% 140 to 199 mg%
Normal 5.7% or less 99mg% or less 140 mg% or less

Debates Surrounding Diabetes Diagnostics

Measuring glucose levels is one thing, but relating findings to prediabetes on a patient-by-patient basis is another.

First off, there are four tests to choose from, and global health authorities don’t advise the same test, let alone the same test result criteria.

● The World Health Organization (WHO) defines prediabetes with two parameters. First, they use impaired fasting glucose (IFG), defined as 6.1-6.9 mmol/L (110 to 125 mg/dL). Secondly, they use impaired glucose tolerance (IGT), defined as 2 h plasma glucose of 7.8-11.0 mmol/L (140-200 mg/dL).

● The American Diabetes Association (ADA) uses the same cut-off for IGT but a lower cut-off for IFG (100-125 mg/dL). The hemoglobin A1c test is common in the US, with 5.7% to 6.4% indicating prediabetes.

Then, there are debates surrounding the efficacy and reliability of the tests and their ability to corroborate results. For example, a review of prediabetes found evidence of poor correlation between A1C, IFG and IGT results.

Controversy Surrounding the HbA1C Test

The HbA1C test has come under particular scrutiny. This study in the American Journal of Medical Sciences found that the HbA1C test was poor at predicting prediabetes and that clinicians should refer patients for additional oral glucose testing.

Other findings suggest a strong genetic component in HbA1C, concluding that it’s inherently imprecise. Similarly, another study in Metabolic Syndrome and Related Disorders concluded: “It is important to consider that HbA1c values below 6.5% (for diabetes) and 5.7% (for prediabetes) do not reliably exclude the presence of diabetes and prediabetes, respectively.”

Since the A1C test measures glycated hemoglobin (HbA1c), it’s vulnerable to a myriad of factors affecting HbA1c lifespan and function.

Adding another twist to the debate is a study published in March 2023 which found that the HbA1c test was superior to the IFG (impaired fasting glucose) test for predicting severe diabetic complications, in this case adverse cardiovascular outcomes, in vulnerable individuals.

Contradictions in the Literature

To further salt the wound, evidence surrounding the testing and diagnosis of prediabetes is often contradictory.

● For example, this study from the American Journal of Hypertension says: “The combination of FPG and HbA1c is a reasonable alternative to the generally recommended OGTT for the screening of diabetes”. The authors found the use of the OGTT as the gold standard warrants skepticism.

● Whereas, this one in the American Journal of Medical Science says, “Patients with HbA1c of 5.7% to 6.4% should undergo OGTT to confirm diagnosis of dysglycemia.” The authors reinforce the OGTT as the gold standard.

IGT and IFG are also affected by those who are hypoglycemic, anemic, exhibit altered hematocrit (percentage of red blood cells in the blood), and hypotensive. As such, this study published in Clinical Chemistry and Laboratory Medicine found poor replicability for both of these tests, advising caution for interpreting a single test result.

To further muddy the waters, test conditions are highly influenceable. For example, we know that, for example, eating dinner early improves 24-hour blood glucose levels. Fasting overnight after eating salads all day is likely more favorable for a fasting glucose test than fasting overnight after consuming sodas and fast food all day.

Hormones concentrations in the morning, the “Dawn Phenomenon,” can also affect test results, particularly in those with hormonal conditions. The Dawn Phenomenon is a normal hormonal reflex which increases blood sugar levels in the early morning. For most, this peaks around 3 am to 4 am, but it can extend to 8 am for some, which may feasibly impact glucose test results.

Moreover, diabetes tests often use subsidized rapid test strips with short expiry dates. They’re also affected by variables like temperature, humidity, and quality of blood samples, with error rates of around 12 to 15% in some cases.

In summary, the evidence suggests prediabetes diagnosis is highly sensitive to diagnostic and individual factors.

A review of prediabetes published in the World Journal of Diabetes concludes, to this effect, “the criteria used to define prediabetes needs to be refined in accordance to the long-term medical outcomes.”

Prediabetes Diagnosis: An Opportunity for Positive Change?

Prediabetes screening and diagnosis are becoming more common worldwide, but this presents new challenges for clinicians and health management.

For example, in the UK, the national rollout of the new Diabetes Prevention Programme (DPP) has vastly increased the number of people diagnosed with prediabetes. Clinicians are now raising concerns about the tests and criteria used to define prediabetes and also the social ramifications of creating a ‘new disease’ that may cause depression, anxiety, and stigma.

Harnessing prediabetes diagnosis for positive change is essential. That includes establishing clear guidelines for testing, effectively communicating results with patients, and establishing personalized treatment strategies.

Among all of this, there is at least one positive thing about prediabetes: it’s reversible.

Lifestyle changes such as diet and exercise can reduce risk by 40% to 70% or more, with the added bonus of reducing risk factors for numerous other diseases and disorders.

Stay tuned for our next article to learn about changing the course of prediabetes.

Unmasking the Dark Side of the Ozempic Craze

Unmasking the Dark Side of the Ozempic Craze

By Gary M. Pepper, M.D. Ozempic, Rybelsus, Trulicity, Wegovy, Saxenda are the central players in the weight loss craze sweeping across the globe. Metabolisim.com has been monitoring this phenomenon from its beginnings in 2008 with its report “Lizard Spit Reduces Blood Sugar and Appetite”, regarding the first drug in this class, Byetta (exenatide). Caught In the middle of the current chaos are the medical experts who treat diabetes and have been prescribing these medications for more than a decade. Here is a brief commentary from one such board certified endocrinologist; “I started treating Type 2 diabetics with GLP-1 agonists more than 10 years ago. In some respects, these medications have revolutionized the treatment of diabetes by lowering blood sugar effectively and promoting weight loss at the same time, a unique combination of benefits. Not everyone benefits from these drugs to the same degree unfortunately, and I have seen lots of patients experience unacceptable side effects from them. Nothing though, has prepared me for what is happening now. Too often, I find myself confronting someone who expects me to prescribe one of these drugs just so they can lose weight. Sadly, one extreme example was someone who, despite battling a life threatening medical condition, was insistent on getting a prescription. At the same time my diabetic patients are scrambling to find a place to buy their medications if they can even afford it. It is disheartening, to say the least, and I dread the negative interactions with some of my patients I now face almost daily.”

Off- Label Use

The FDA is the U.S. government’s department tasked with evaluating and approving drugs for specific medical conditions. When a new medication is approved for treating a medical condition by the FDA the agency will, at the same time, set strict guidelines for exactly which patients may use the newly approved drug. When a medication is used “off-label” it means that these limitations are being overridden by the provider for a potential benefit which outweighs the drugs risks. It is a general misconception that off-label means illegal; it does not. This practice has been going on for ages and more than 20% of prescriptions in the United States are prescribed off-label. A common example is the use of beta-blockers (approved for heart problems) for the treatment of performance anxiety.

GLP-1 agonist drugs, as discussed recently by metabolism.com. were originally approved for the treatment of Type 2 diabetes in adults. In the past few years most of these same medications have gained unprecedented popularity for their “off-label”  weight loss benefit. Of the 5 GLP-1 agents presently in U.S. pharmacies only Wegovy (semaglutide) and Saxenda (liraglutide) are FDA approved for treating obesity. Of these two, Wegovy is the newer and had been much more popular that its sister drug Saxenda, probably due to being dosed only once weekly compared to daily for Saxenda and less likely to cause side effects. Due to Wegovy’s soaring popularity, its manufacturer, Novo Nordisk, increased the price of Wegovy two times since its initial release. (more…)

Anti-obesity Medications 2023: The Controversy Continues

Anti-obesity Medications 2023: The Controversy Continues

by Gary M. Pepper, M.D. and Sam Jeans, MSc The global anti-obesity drug market, in 2021was valued at over $2 billion. Within one year this figure had skyrocketed to $8 billion and is expected to climb to nearly $ 20 billion by 2027. This astounding growth is a reflection of soaring obesity rates, and the arrival of a new class of weight loss medication fueling a craze both in the USA and across the world.

The FDA and global health regulators, until very recently, had maintained a very tight ship when it comes to treating obesity with medication, placing the emphasis on diet and exercise rather than weight loss drugs. Since the 80s, anti-obesity drugs continued to be controversial, and a more stringent FDA  implemented ongoing safety trials along with other precautions.   There is some speculation that a shift in attitude toward approval of weight loss medication by the FDA , is underway

Weight loss drug controversies are far from over and, in fact, may soon rival the amphetamine crisis of the 70’s. For that reason, metabolism.com has felt it important to provide our guide to weight loss drug issues, past and present.

Anti-Obesity Drugs Timeline

Prescription drugs for lifestyle diseases such as obesity were marketed heavily throughout the 1950s to the 1970s. Amphetamines entered the public domain after the Second World War where they were used extensively in the military.

In the 50s, walk-in clinics prescribed diet pills with other medications almost at random, with or without genuine concern for one’s weight. These brightly colored pills became known as “rainbow pills”.

In the 1960s and 1970s, the so-called “rainbow pill diet” of pills was finally coming to an end as the FDA began to systematically ban many of the drugs involved. A high-profile expose by investigative journalist Susanna Mcbee, published in Life magazine, brought attention to this new modern public health crisis.

The rainbow pill diet combined amphetamines, laxatives, thyroid hormones, and even diuretics to produce extreme weight loss, combined with benzodiazepines, barbiturates, and steroids to reduce side effects, and antidepressants to suppress medication-induced insomnia and anxiety.

In 1968, rainbow pills were linked to over 60 deaths, with numerous accounts of their devastating impact surfacing in the news and media. Within just two months, 48 million pills were seized and destroyed. Nevertheless, amphetamine-based diet pills remained extremely popular throughout the 1970s. In 1978, some 3.3 million prescriptions for amphetamines were written each year, with some 50 million pills a year ending up in the black market.

In 1979, the FDA banned amphetamines as a weight loss aid, but that is hardly the end of the USA’s love affair with obesity medication.

Here’s a brief timeline of recent anti-obesity drugs:

(more…)

Weight Loss Drugs: An Overview for 2022

Weight Loss Drugs: An Overview for 2022

By Gary M. Pepper, M.D. , Sam Jeans MSc

To help clarify the effectiveness, side effects and cost of weight loss drugs now available,  Metabolism.com is providing this breakdown for consumers.

According to the CDC, the prevalence of obesity in the USA is ever-increasing and reached an all-time high of 42.4% of adults over the age of 20 in 2017 to 2018.

Obesity carries a vast range of health risks that need little introduction. Obesity alone reduces life expectancy by around 3 to 10 years, or longer.

Weight Loss Drugs and Insurance

Despite the prevalence of obesity in the USA, only around 3% of sufferers take medication. Low uptake of obesity medication is partly due to patchy insurance coverage, as about 1/3rd of insurers don’t cover obesity drugs at all, including Medicare and Medicaid in around half of all states. (more…)

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