Type 2 Diabetes: The Tightrope of Intensive Blood Glucose Control. Part 1
Ian Jackson
Former National Health Service (NHS) Prescribing Adviser and Senior Lecturer in Clinical Pharmacology and Therapeutics at a UK Medical/Pharmacy School
Contact: ian.pharmacist@gmail.com
A Balancing Act
The age-adjusted comparative prevalence of diabetes (20-79 years) in the United Arab Emirates is 16.4% (2021) rising to 18.1% in 2024. (1)
The treatment and management of an increasing number of diabetics is a significant issue for an already over stretched primary care sector as well as an increasing number of hospital admissions due to the complications of diabetes eg. hypoglycaemic episodes adding to the burden of secondary care.
90% of diabetics are type 2 and poor diet and sedentary lifestyles are clearly significant risk factors. An increasingly ageing population is helping drive the increase in numbers. Nearly half of all individuals with diabetes are over the age of 65 years of age and in the over 75s the proportion of people with diabetes rises to 23.8%. (2)
Type 2 diabetes has a huge impact on life expectancy, quality of life of patients and a potentially large economic risk on the Middle East and North Africa (MENA) health economy. When considering these significant issues there is one important question we need to answer:
Does intensive blood control reduce the levels of macrovascular events such as strokes and heart attacks? This is vital as some 60% of type 2 diabetics die of cardiovascular complications.
Candy Crush
The Emirates Diabetes Society Consensus Guidelines for the Man-agement of Type 2 Diabetes Mellitus – 2020 (3) have set the follow-ing glycaemic goals:
• Haemoglobin HbA1c ≤7% (53 mmol/mol) – individualised
• 6.5–7.5% (48–58 mmol/mol) in majority of patients
• Less stringent targets between 7.5 and 8.0% (58–64 mmol/mol) can be recommended for elderly, patients with short life expectan-cy, recurrent hypoglycaemia, and hypoglycaemia unawareness.
These closely follow the American targets (4).
So why have the Americans chosen to produce less intensive blood glucose targets that specifically focus on age and co-morbidities? To understand their approach we need to consider the most robust studies looking at intensive blood glucose control.
So What About the Evidence for Intensive Blood Glucose Control? An Atlantic Accord?
The United Kingdom Prospective Diabetes Study (UKPDS) was a multicentre, open-label, randomized, controlled trial involving 3,867 patients. After a median follow up of 10 years, those patients that had received tighter blood glucose control (HbA1c 7.0%) compared to less intensive control (HbA1c 7.9%) saw a reduction in microvascular complications. This was mainly due to decreased retinopathy requiring photocoagulation. There was no difference in the more important primary endpoint of diabetes-related mortality or all-cause mortality. (5)
One point that needs to be considered with UKPDS is the fact that the median age of the patients in the study was 54 years. This clearly doesn’t reflect the age profile of type 2 diabetics in the typical GP practice where nearly half of all type 2 diabetes are over 65.
There have been several more recent robust studies looking at inten-sive blood glucose control in type 2 diabetics focusing on primary endpoints such as macrovascular complications eg. myocardial in-farctions.
The ADVANCE study looked at over 10,000 patients with type 2 dia-betes and one other risk factor for a cardiovascular (CV) events. (6)
- Intensive blood glucose lowering (including the addition of gliclazide MR) to achieve a target HbA1c of less than or equal to 6.5%
- Standard glucose lowering therapy HbA1c 7.3%
After a mean follow up of 5 years, there were no differences in macrovascular outcomes between the patients with the intensive blood glucose control and standard control. There was some reduc-tion in albuminuria, a surrogate for microvascular complications.
The ACCORD study randomized 10,251 patients with long-standing type 2 diabetes to either intensive (HbA1c <6%) or standard glycae-mic control (HbA1c 7-7.9%). The trial had to be stopped early after 3.7 years because there was a significant increase in the rate of all-cause mortality, one extra death for every 95 patients, in those re-ceiving intensive treatment compared to standard treatment. (7)
The ACCORD study involved older patients (mean age 62 years) who are less healthy, indeed characteristics more typical of people receiving treatment in primary care compared to UKPDS.
A Cochrane review of 28 trials involving 35,000 patients looked at the effects of targeted intensive glycaemic control compared with conventional glycaemic control in patients with type 2 diabetes. (8)
They concluded, “Targeting intensive glycaemic control compared with conventional glycaemic control did not show significant differ-ences for all-cause mortality and cardiovascular mortality. Targeting intensive glycaemic control seemed to reduce the risk of microvascu-lar complications, if we disregard the risks of bias, but increases the risk of hypoglycaemia and serious adverse events”.
The Cochrane review and the ACCORD study add credence to the US approach of less tight blood glucose targets for elderly patients with short life expectancy, recurrent hypoglycaemia, and hypoglycaemia unawareness.
Hypoglycaemia and Risk
One of the main outcomes from the ADVANCE study was an in-creased risk of hypoglycaemia with intensive treatment (HR 1.86; P < 0.001). This is a worrying nearly doubling of risk. The ACCORD study showed that hypoglycaemic attacks, requiring medical assistance, are more frequent with tighter blood glucose control compared to standard therapy 10.5% vs. 3.5% (P<0.001).
A meta-analysis of studies involving 903 510 patients showed that severe hypoglycaemia was strongly associated with a higher risk of cardiovascular disease. (9)
When diabetic patients have a hypoglycaemic attack they activate their sympathetic system. The increased levels of adrenaline lead to the quickening of the heart rate and vasoconstriction of peripheral blood vessels. Patients with type 2 diabetes are already at a higher risk of cardiovascular events so repeated sympathetic stimulation will only increased that risk.
The risk of hypoglycaemia increases markedly with age and can have serious consequences eg. an increased risk of falls, cardiovascular disease and dementia. Could this account for the differences in the ACCORD study compared to UKPDS where the trial population was older and at a greater risk of hypoglycaemia but more reflective of the diabetic populations we see in primary care? (10)
Discussion
There are many issues we need to consider when managing type 2 diabetes. The growing level of type 2 diabetes is having a significant impact on the MENA area and we must ensure that therapies that we offer to these patients are evidence based and appropriate for each individual.
Several studies have should that intensive blood glucose control pro-duces no reduction in major adverse cardiac events (MACE), such as cardiovascular death, non-fatal myocardial infarction, and stroke, compared to standard control. Considering that 60% of type 2 dia-betics die of cardiovascular complications the findings of these stud-ies should have a significant impact on clinical practice. One major study, ACCORD, actually showed an increased mortality risk with in-tensive control.
American Diabetes Association (ADA) have made an important point about these landmark trials. (6) Newer drugs such as glucagon like peptide 1 (GLP-1) receptor agonists and sodium–glucose co-transporter 2 (SGLT2) inhibitors were not approved at the time of these trials. These agents have established cardiovascular and renal benefit appear (we will review the evidence behind these agents in future articles). The clinical trials involving these agents where not designed to test higher versus lower HbA1c so as such we don’t have the evidence that it is the glucose lowering action that confers their renal and CV benefit.
The ADA state that “on the basis of physician judgment and patient preferences, select patients, especially those with little comorbidity and long life expectancy, may benefit from adopting more intensive glycemic targets if they can achieve them safely without hypoglyce-mia or significant therapeutic burden.” Give the dangers from hypo-glycaemia this pragmatic and evidence based approach seem sensi-ble.
References
1) International Diabetes Federation. IDF Diabetes Atlas. Available from: https://diabetesatlas.org/data/en/compare/208-209/idf-country-data-comparision.html
2) Rosenstock J. Management of type 2 diabetes mellitus in the elderly: special considerations. Drugs Aging 2001;18(1):31–44.
3) Alawadi F, et al. Emirates Diabetes Society Consensus Guidelines for the Management of Type 2 Diabetes Mellitus – 2020. Dubai Diabetes Endocrinol J 2020;26:1-20.
4) American Diabetes Association. Older Adults: Standards of Medical Care in Diabetes—2021. Diabetes Care 2021;44(Supplement_1):S73–S84
5) Turner R, et al. Intensive blood-glucose control with sulphonylu-reas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 1998;352(9131):837-53.
6) Patel A, et al. Effects of a fixed combination of perindopril and in-dapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370(9590):829-40.
7) Gerstein HC, et al. “Effects of Intensive Glucose Lowering in Type 2 Diabetes”. The New England Journal of Medicine 2008;358(24):2545-59.
8) Hemmingsen B, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2013, Issue 11. Art. No.: CD008143. DOI: 10.1002/14651858.CD008143.pub3.
9) Severe hypoglycaemia and cardiovascular disease: systematic re-view and meta-analysis with bias analysis. BMJ 2013;347:453.
10) Lehman R. Tight control of blood glucose in long standing type 2 diabetes BMJ 2009;338:b800.
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