Why Intensive Glycemic Control Do More Harm Than Good?

The reason behind the guidelines that recommended lower HbA1c targets (<7% or <6.5%) is that more intensive blood sugar control would reduce risks for cardiovascular, cerebrovascular, neurologic, ophthalmologic, and renal complications.

However, the evidence for reduction is inconsistent, and reductions were seen only in surrogate microvascular measures such as the presence of excess proteins in the urine. 

Clinical trials show that achieving an HbA1c between 7% and 8% will best balance long-term benefits with harms such as low blood sugar, other medication-related adverse effects, medication burden, and costs.

The ACCORD trial, which targeted an HbA1c <6.5% and achieved the lowest target HbA1c level of the included studies (6.4%), was discontinued early because of increased overall death, cardiovascular mortality, and severe low blood sugar events. 

The VADT study in 2009 found that intensive glucose (blood sugar) control in older men with longstanding type 2 diabetes did not significantly reduce their risk of major cardiovascular (CV) events, including heart attack, stroke, and death from CV causes, compared with standard blood sugar control.

Researchers recently reported 15-year follow-up results from VADT. They found that intensive blood sugar control did not exert any “legacy effect”: the intensive blood sugar control group did not enjoy CV benefits 15 years after the start of the study.

The ADVANCE study also failed to find a statistically significant clinical benefit and had more adverse effects with an achieved median HbA1c of 6.4% vs 7.0%. In addition, more intensive treatment to achieve a lower target is more costly and associated with increased patient burden.

The UKPDS 33 trial showed that treatment to a target of about 7% with a sulfonylurea and insulin if needed in adults with newly diagnosed diabetes did not reduce the risk of any diabetes-related end point or all-cause mortality after 10 years but was associated with a small absolute reduction in these outcomes after 17 years of follow-up.

A sub-study (UKPDS 34) also showed a modest reduction in diabetes-related end points and all-cause mortality with metformin treatment in overweight or obese adults (median  HbA1c achieved was 7.4%).

While we acknowledge the damage caused by glucotoxicity, we ignore the insulin toxicity. Multivariate analysis of the EuroDiab study revealed the stunning conclusion that glucotoxicity, as measured by Hemoglobin A1C was not a significant risk factor. 

Multiple other studies confirmed the EuroDiab results. The Golden Years Cohort Study followed 400 type 1 diabetic patients who lived over 50 years managing their disease. This group had beaten the odds and survived. What was their secret? One thing became clear.

The secret was not tight blood glucose control.

The Golden Cohort’s average A1C was 7.6% — well over the standard recommended target of 7.0%. This level could only be described according to standard management as ‘poor’. Some had A1C measurements in the 8.5–9.0% range, yet still far out-lived the average. Strikingly, no Golden Cohort patient had an A1C in the normal range!

Clearly, glucotoxicity was not the major player here.

Recently on march 2018 a new set of global guidelines have been developed to manage diabetes. American College of Physicians (ACP) recommends moderate blood sugar control targets for most patients with type 2 diabetes. 

American College of Physicians (ACP) is asking clinicians to treat adults with Type 2 diabetes less aggressively and targets a Haemoglobin A1c (HbA1c is a test that represents blood glucose control over the preceding three months) of 7% to 8%, against the current recommendation of below 6.5%. It asks clinicians to deintensify drug therapy in patients with HbA1c levels of less than 6.5%.

The new guidance from the American College of Physicians (ACP) supporting higher glycated hemoglobin (HbA1c) targets for pharmacotherapy in adults with type 2 diabetes (T2D), published in the Annals of Internal Medicine, has been the target of criticism from several diabetes organizations including indian doctors.

But till date ADA and AACE guideline is in deep contrast with the ACP 2018 guideline which recommends a HbA1c between 7%-8% for most patients. (6,7,8

A 2021 meta-analysis convincingly highlights that the maximum macrovascular benefits, by way of reduction of non-fatal MI, non-fatal stroke and all-cause mortality are achieved with a target HbA1C between 7 – 7.7%, whether the duration of T2D is less than or more than 10 years. This is in keeping with the ACP guidelines. Physicians should therefore aim for a target HbA1C of 7 – 7.7% regardless of which molecule is used for the treatment of T2D to improve the macrovascular outcomes of T2D.

 ACP guidance focuses on the following four recommendations:

  1. Personalized treatment to minimize harms. Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients’ preferences, patients’ general health and life expectancy, treatment burden, and costs of care.
  2. Target HbA1c to between 7%-8%Clinicians should aim to achieve an HbA1c level between 7% and 8% in most adults with type 2 diabetes.
  3. Back off on intensive treatment. Clinicians should consider de-intensifying pharmacologic therapy in patients with type 2 diabetes who have achieved HbA1c levels less than 6.5%.
  4. Treat older patients’ hyperglycemia. Clinicians should manage patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting HbA1c levels in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, end-stage kidney disease, or severe chronic obstructive pulmonary disease or congestive heart failure) because the harms outweigh the benefits in this population.

So, why do some of us still obsess over blood glucose numbers in Type 2 Diabetes ?

Unfortunately, it’s likely because diabetes specialists have not yet understood that this disease is about hyperinsulinemia, not hyperglycaemia. The drug companies, on the other hand, are all to happy to leave the status quo, which is extraordinarily profitable for them.

By | 2021-04-08T10:48:08+00:00 March 22nd, 2018|Uncategorized|3 Comments

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  1. zen February 7, 2019 at 06:54

    What Is Glucose Toxicity and Why Is It Important?

    Normally, your blood glucose is very tightly regulated. It increases after you eat, but your pancreas immediately releases the hormone insulin in response. In people without diabetes, insulin allows cells to take up glucose from the blood, giving them energy and bringing blood sugar back down.

    But as type 2 diabetes develops, this finely tuned system starts to fall apart. Your cells become increasingly insulin resistant, so they don’t take up glucose from the blood as efficiently as they should. The pancreas makes more insulin to try to compensate, but eventually, the organ just can’t keep up. This is what endocrinologists call glucose toxicity.

  2. zen July 10, 2019 at 06:59

    Why tight blood sugar control in older adults with diabetes is dangerous?

    when considering goals for blood glucose in older adults, it is important to ask why we are managing diabetes. As the reason to tightly control diabetes is to prevent complications in the future, tighter control of diabetes could be a goal in an older adults who are in good health and have few risk factors for hypoglycemia. Hypoglycemia risk factors include previous history of severe hypoglycemia that required hospital or emergency department visits, memory problems, physical frailty, vision problems, and severe medical conditions such as heart, lung, or kidney diseases.

    In older individuals with multiple risk factors for hypoglycemia, the goal should not be tight control. Instead, the goal should be the best control that can be achieved without putting the individual at risk for hypoglycemia.

    Lastly, it is important to remember that health status is not always stable as we get older, and the need or the ability to keep tight glucose control may change over time in older adults. Goals for all chronic disease, not just blood sugar control, need to be individualized to adapt to the changing circumstances associated with aging.

  3. zen February 21, 2020 at 08:43

    Intensive blood sugar control doesn’t have lasting cardiovascular benefits for those with diabetes

    In 2009, the New England Journal of Medicine published results from the Veterans Affairs Diabetes Trial (VADT). The study found that intensive glucose (blood sugar) control in older men with longstanding type 2 diabetes did not significantly reduce their risk of major cardiovascular (CV) events, including heart attack, stroke, and death from CV causes, compared with standard blood sugar control.

    Researchers recently reported 15-year follow-up results from VADT. They found that intensive blood sugar control did not exert any “legacy effect”: the intensive blood sugar control group did not enjoy CV benefits 15 years after the start of the study.

    The Veterans Affairs Diabetes Trial
    The VADT study originally enrolled over 1,700 veterans with longstanding type 2 diabetes, who were at high risk of cardiovascular disease, and had poorly controlled blood sugar when they enrolled in the study. At the time of enrollment, study participants had been diagnosed with diabetes for an average of 12 years. Their average A1c level, a measure of average blood sugar levels over the previous two to three months, was 9.4%.

    The participants were randomly assigned to either intensive glucose-lowering therapy or usual care for about 5.6 years. At the completion of the study, there was a significant difference in blood sugar control: the average A1c in the intensive treatment group was 6.9%, while the average A1c in the usual care group was 8.4%.

    Despite the lower A1c levels, there were no benefits shown from intensive treatment on CV outcomes, which included nonfatal heart attack, nonfatal stroke, new or worsening congestive heart failure, amputation for diabetes-related tissue damage, or death from CV causes.

    No long-term cardiovascular benefit of intensive blood sugar control
    A follow-up observational study was then undertaken to assess whether intensive treatment during the 5.6-year study period had any long-lasting effects, after the interventions were completed. The 10-year VADT follow-up showed some benefits to intensive treatment with regard to CV events. At that time, participants in the intensive treatment group still had lower A1c levels compared to the usual care group, despite the gap of several years since the completion of the study.

    However, at the newly published 15-year follow-up, the benefits of intensive control on any of the CV outcomes were lost. By this time, both groups had similar A1c levels of about 8%.

    This phenomenon may suggest that to achieve the CV benefits, blood sugar control needs to be maintained and that the short-term tight control, without lasting blood sugar control, may not have long-lasting effects.

    New evidence supports existing evidence
    The new VADT results add to existing evidence from previous large studies that have failed to show any long-lasting benefits of intensive blood sugar control during observational follow-up. One study, however, did show some beneficial legacy effect. The United Kingdom Prospective Diabetes Study (UKPDS) evaluated intensive treatment versus usual care in adults with newly diagnosed type 2 diabetes. When the UKPDS cohort was evaluated 10 years after the completion of the study, the participants from the intensive treatment arm showed benefits with regard to cardiovascular disease, compared to standard care.

    Taken together, the evidence suggests that older adults with longer duration of diabetes and/or multiple coexisting conditions may not benefit from intensive blood sugar control. On the other hand, intensive treatment might be beneficial in younger patients, with shorter duration of diabetes and fewer coexisting medical conditions.

    Individualize treatment and control other cardiovascular risk factors
    Personalization of goals and treatment regimens that can be maintained safely over the long term by the patient might be the best strategy to lower the risk of cardiovascular disease. As I discussed in a previous blog post, treatment of older adults should consider possible dangers of intensive treatment. For example, intensive blood sugar control can overshoot and lead to hypoglycemia, a potentially dangerous condition in which blood sugar falls too low. Hypoglycemic episodes in older adults are particularly harmful and may negate the possible benefits or tighter diabetes control. In older adults, rather than aiming for tight control, we aim for the best control that can be achieved without increasing the risk of hypoglycemia.

    For reducing CV risk, the authors of an editorial that accompanied the NEJM study recommend prioritizing interventions that address other CV risk factors. That includes quitting smoking, and managing blood pressure and cholesterol levels with medication, if needed. Newer classes of diabetes medications, such as sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists appear to have CV benefits and low risk of hypoglycemia, and may be considered as well.

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