#17 Lowering HbA1c is Not Enough

Why Chasing Glucose Isn’t Enough

For more than three decades, the conventional wisdom in diabetes management has been straightforward: lower your blood sugar, and you will prevent complications. It is neat, intuitive, and largely correct. We treat HbA1c as the ultimate scorecard of metabolic success, assuming that driving that single number down is the key to protecting our eyes, kidneys, and hearts.

But there are important limitations. Just lowering glucose alone is a bit like putting a bucket under a leaky roof without inspecting the structure above it.

Today, we are going to look at what clinical trials actually tell us about blood glucose control and diabetic complications. We will explore why heart attacks do not always fall when blood sugar does, what happens when fat cells lose their storage capacity, and why true metabolic reversal is about more than just “crossing a threshold”

Don’t worry - this is a good news story. But you need to know what is and isn’t going to give you the best health in the long-term.

Note on terms: marco = large, micro = small, vascular = blood vessels. So, macrovascular diseases are things like heart disease and stroke, where it affects the larger vessels. Microvascular diseases are things like retinopathy and nephropathy, in which the tiny vessels (capillaries) are affected, lowering the ability of blood to reach deeply into tissues and deliver

How You Lower Blood Glucose Matters

What the Big Trials Actually Found

Thirty years of major diabetes trials have shown that lowering HbA1c reduces sight loss (retinopathy), nerve pain (neuropathy), kidney disease and the familiar diabetic symptoms such as excess urination, constant thirst and fatigue. We’ve also learned from several cardiovascular studies that lowering LDL cholesterol reduces heart attacks. These relationships are certainly not speculative - they are causal and replicated.

In the UKPDS trial, newly diagnosed people with type-2 diabetes were followed for over a decade. For every 1% reduction in HbA1c, there was about a 35% reduction in microvascular endpoints - specifically retinopathy and nephropathy (kidney disease) (UKPDS Group, The Lancet, 1998). In terms of physiology, this aligns with what we know: lowering cumulative glucose exposure reduces the amount of glucose that sticks to things it shouldn’t, the formation of ‘advanced glycation endpoints’, and oxidative stress in small vessels.

Long-term follow-up also demonstrated the so-called “legacy effect”: early glycaemic control translated into sustained reductions in complications years later, even after HbA1c levels converged (Holman et al., NEJM, 2008). Early exposure matters.

On the macrovascular (large blood vessel) side with heart attacks and strokes, the story is more complex and, at first sight, less impressive - but bear with me. Trials such as FOURIER showed that aggressively lowering LDL cholesterol (and therefore ApoB-containing particles) reduced major cardiovascular events in a graded, dose–response fashion (Sabatine et al., NEJM, 2017). Lower exposure meant lower risk.

But then came ACCORD. Researchers reduced HbA1c from 8.1% to 6.4% and expected large cardiovascular benefits. Instead, while intensive glucose lowering reduced microvascular progression it did not significantly cut major cardiovascular events and was associated with increased mortality in one treatment arm (ACCORD Study Group, NEJM, 2008). Yikes! Do you have to choose between one set of risks and another? Probably not, thankfully.

Here is what we learnt:

• Glucose clearly drives microvascular damage.

• ApoB clearly drives cardiovascular disease.

• Complications are not explained by one number alone.

The Big But: These Were Drug Trials

There is an important point here: these were pharmacological trials. Unlike many loud voices in the online health space, I am not anti-medicine. It makes sense to use the best tools we have available, but doing so correctly means that we must understand both their benefits and their limitations.

The trials lowered glucose with insulin, sulfonylureas, and other agents. They lowered LDL with statins, bempedoic acid, ezetimibe, PCSK9 inhibitors, etc. This lets us test causality relatively cleanly - by isolating and manipulating one variable.

But these trials managed exposure to glucose and LDL only. In effect, they pulled one sting in a big knotted ball of wool and saw what that one string was attached to. They did not necessarily restore faltering physiology or the upstream drivers of metabolic dysregulation.

Specifically, they did not primarily aim to:

• Restore adipose tissue expandability.

• Clear ectopic fat from liver and pancreas.

• Rebuild skeletal muscle insulin sensitivity.

• Reduce chronic low-grade inflammatory signalling.

• Normalise endothelial nitric oxide responsiveness.

• etc.

Managing exposure reduces load on the system. That can save vision, preserve kidney function, and prevent some heart attacks. It is lifesaving, can rapidly get you out of immediate danger is often essential. That is what doctors do best and they do it well.

But managing load is not the same as repairing the engine.

If we want to understand what deeper prevention looks like, we have to look upstream.

The Underlying Metabolic Stress

In type-2 diabetes, high glucose is not the first domino to fall. It is just the final, visible marker of deeper tissue stress.

Adipose tissue often becomes overwhelmed first. Under chronic energy surplus, fat cells enlarge and lose some of their ability to safely buffer incoming energy. Insulin normally tells fat cells to hold fat in safe storage but insulin resistance in the fat cells means this signal is not fully effective. The result is that fatty acids spill into circulation.

But the story does not end in adipose tissue.

Excess fatty acids accumulate in the liver, promoting hepatic insulin resistance. The liver begins exporting more glucose and more VLDL particles (which will evolve into LDL particles as they drop off cargo). Triglycerides rise. ApoB levels increase along with it.

In the pancreas, ectopic fat and chronic hyperglycaemia strain beta cells. First-phase insulin secretion weakens so the signal that normally shuts down liver glucose release becomes faulty. Glucose rises too high after meals and stays too high in between. Widespread glucotoxicity - persistent exposure to elevated glucose - increases oxidative stress inside cells and impairs mitochondrial function. Your bloodstream has become a bit of a toxic soup, if you’ll forgive the casual speech.

In skeletal muscle, lipid intermediates such as diacylglycerol and ceramides interfere with insulin signalling pathways, reducing glucose uptake. Combine all these sffects and you have achieved diabetes take-off.

Across all of these tissues, chronic nutrient excess drives:

• Oxidative stress

• Mitochondrial strain

• Endoplasmic reticulum stress

• Low-grade inflammatory signalling

The endothelium (the thin cellular lining of blood vessels) sits downstream of all of this. It is exposed to elevated glucose, circulating lipoproteins, fatty acids, and inflammatory signalling molecules.

Complications arise not because “sugar is toxic” in isolation, but because multiple tissues are operating under sustained metabolic load for too long. Maybe that makes it more reasonable that just changing a few numbers, even important ones, can only achieve so much.

Drug trials reduce specific exposures. They can lower glucose and that is good. They can lower LDL and that is good. They reduce the burden on stressed tissues.

But they do not necessarily restore buffering capacity in adipose tissue, clear ectopic fat from liver and pancreas, or normalise intracellular stress pathways.

If you want to regain more control of your health, this distinction matters.

4. The 53% Signal: What Reversal Changes

The 5-year follow-up of the DiRECT trial provides an important clue (Lean et al., The Lancet Diabetes & Endocrinology, 2024).

Participants randomised to the weight-loss remission programme had 4.8 serious medical events per 100 patient-years, compared with 10.2 in the control group receiving best-practice care - a roughly 53% lower rate of serious adverse events.

This was not a dedicated cardiovascular outcomes trial, and the absolute event numbers were modest. But the strength of the signal is difficult to ignore.

Earlier DiRECT and related studies showed that:

• Liver fat falls rapidly with substantial calorie restriction (Lim et al., Diabetologia, 2011).

• Pancreatic fat can decrease in responders, allowing partial recovery of first-phase insulin secretion (Al-Mrabeh et al., Lancet Diabetes & Endocrinology, 2020).

Weight loss reduces liver glucose output, lowers fasting insulin, reduces triglycerides, and often significantly improves blood pressure.

In other words, remission does not simply lower blood glucose. It reduces multiple drivers of vascular stress simultaneously and that is the key difference. With the right approach:

• Glucose exposure falls.

• Hyperinsulinaemia diminishes.

• Fatty acid ‘leakage’ decreases.

• Lipoprotein (e.g. LDL) production often improves.

• Inflammatory tone declines.

We do not yet have decades-long outcome trials of lifestyle-induced remission. But we do know which exposures cause harm and how. When we reduce several of them together, the biological direction of travel is favourable. Best of all, unlike intensive use of certain medications, making sensible diet and lifestyle changes has almost zero downside (if done appropriately and working with your doctor if on medications).

Like I said above, this is not an anti-medicine stance; it’s a best-of-both-worlds one.

5. Restoration vs Suppression

Being it all together, microvascular complications track closely with glucose exposure. If you want to protect your retinas and kidneys, controlling glycaemia matters. Macrovascular disease is multifactorial. You can have a near-perfect HbA1c, but if ApoB remains high and vascular stress persists, cardiovascular risk does not disappear.

Medication can reduce specific exposures and save lives. It is often necessary and appropriate. But upstream metabolic restoration reduces the drivers of those exposures.

Reversal is not merely about lowering HbA1c or discontinuing prescriptions. It is about reducing cumulative metabolic stress across interconnected systems. When we clear liver fat, improve muscle insulin sensitivity, calm adipose tissue, and restore vascular responsiveness, we are not simply adjusting laboratory numbers. We are actually altering the physiology that produces those numbers. And physiology, over time, determines risk.

So, don’t lose sight of what you’re aiming for. It is within reach. Redouble your efforts today. Let’s get this done!

Just before you go.

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Acknowledgements 

I would like to express my gratitude to the following artists & platforms for making this newsletter a nicer place to rest your eyes.

1.  Thumbnail: Photo by Fredrik Ivansson on Unsplash

2. “Why Chasing Glucose Isn’t Enough”: Photo by Daniel Kraus on Unsplash

3. “How you lower HbA1c Matters”: Photo by Sweet Life on Unsplash

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