27th September 2020, Dr Chee L Khoo
We know that hyperglycaemia is associated with increased cardiovascular mortality. We also know that in patients with diabetes, hypoglycaemia is also associated with increased cardiovascular morbidity and mortality. What about patients who don’t have diabetes and have low blood glucose (<4.0 mmol/L)? I am sure we all have patients who do not have diabetes but on screening blood tests, have BSL lower than 4.0 mmol/L. We normally just pat them on the back and say, “…your blood sugar is better than good”. Are we correct? Why do they even have hypoglycaemia? Is hypoglycaemia totally harmless in these patients?
Hypoglycaemia in the absence of diabetes is also referred to as reactive, postprandial, or idiopathic hypoglycaemia [1]. Now, we are not talking about patients on drugs that may cause hypoglycaemia, patients with insulinoma, critically ill patients and patients who are malnourished. We don’t actually know how common the problem is as there are currently no standard diagnostic criteria for this syndrome. We have even less evidence about its potential health implications. In fact, the health relevance, and indeed existence, of this condition has been controversial for decades [2-4]. The current paradigm assumes that low glucose outside the context of clinical hypoglycaemia is healthy. Is it that harmless?
Reactive hypoglycemia is sometimes thought to be associated with obesity and an exaggerated insulin response. However, Brun et al. conclude that the majority of cases are actually in the context of high insulin sensitivity accompanied by defects in counter-regulation, most likely a blunted glucagon response [5]. The role of adrenaline and other counter-regulatory hormones in reactive
hypoglycaemia and the relation with other potentially heterogeneous hypoglycaemic conditions remain mostly theoretical. They also criticised the use of oral glucose tolerance test (OGTT) to diagnosed or exclude reactive hypoglycaemia as the hypoglycaemia during OGTT was due to the “unphysiologic stress, seldom encountered outside the laboratory setting”.
To explore the real connection between true hypoglycaemia and reported hypoglycaemic symptoms Mongraw-Chaffin et al used Dexcom G4 continuous glucose monitoring (CGM) in 8 otherwise healthy women who self-reported hypoglycaemia symptoms (headache, trouble concentrating or confusion, irritability, blurred vision, weakness, fatigue, nervousness, palpitations, tremor or shakiness, or dizziness) (6). The average age was 29 years. Six were Caucasian and two were African American. Six had normal weight (18.5 < BMI < 25.0 kg/m2) and two had obesity (BMI > 30 kg/m2). An average of 1994 glucose values were measured from each participant across the 7-day follow-up period.
Participants reported regularly experiencing hypoglycaemic symptoms. All participants had measured hypoglycaemia (≤ 3.9 mmol/L) and half had clinically significant hypoglycaemia (≤ 3.0 mmol/L) during the 7 days of blinded continuous glucose monitoring. Lower glucose levels were significantly associated with reported hypoglycaemic symptoms, as was length of time since previous meal, and participants unanimously reported engaging in defensive eating to avoid symptoms.
The International Hypoglycaemia Study Group (there is such a group?) deemed that blood glucose values <3.0 mmol/L is associated with “immediate and long-term danger to the individual” [7]. They further suggest that glucose levels in this range “cause defective glucose counter-regulation and impaired awareness of hypoglycaemia” and have been associated with cardiac arrhythmias and mortality in individuals with type 2 diabetes [7-9].
Hypoglycaemia and CV harm – does it matter whether you have diabetes or not?
Chevli et al analysed sample data from the third National Health and Nutrition Examination Survey (NHANES-III) in the USA (10). Participants aged 20-90 years who did not have diabetes or CVD were considered. The NHANES-III participants were followed up for mortality from the initial exam (1988 and 1994) through 31 December 2006.
The key findings were as follows: (1) low FPG (<4.4mmol/L) was significantly associated with increased risk of both CVD and all-cause mortality; (2) this association was stronger among males than females for both CVD and all-cause mortality; and (3) diabetic range FPG (⩾7.0 mmol/L) was significantly associated with increased risk of all-cause mortality.
The relationship between hypoglycaemia and poor cardiovascular outcomes in diabetics is thought to be due to the unfavourable impact of lower levels of fasting plasma glucose (FPG) on the inflammation, sympatho-adrenal activation, increased platelet and neutrophil activation, endothelial function, coagulation, and inflammatory mediators or cytokines. Catecholamines also directly affect cardiac myocytes and cause them to become calcium overloaded, which can lead to prolongation of the corrected QT (QTc) interval in conjunction with catecholamine-induced hypokalaemia.
Furthermore, sympathetic stimulation of the heart directly increases cardiac contractility and heart rate, which in turn increases cardiac demand and risk of cardiac ischaemia. These systemic changes increase the risk of cardiovascular events, such as fatal ventricular arrhythmias. Hypoglycaemia also impairs autonomic function by decreasing cardiac vagal baroreflex sensitivity as a result of sympathoadrenal activation. Such physiologic responses can occur in the absences of symptoms commonly experienced during hypoglycaemia.
Thus, does it matter where we draw a line somewhere and call someone a diabetic or not? Hypoglycaemia causes the same physiological response in an individual whether we call them diabetic or not. There is evidence to show that low FPG is a strong risk factor for both CVD and all-cause mortality in the nondiabetic population. These findings add to the potential of FPG screening in seemingly healthy individuals to identify those at increased risk of CVD and all-cause mortality.
References:
- Chalew SA, McLaughlin JV, Mersey JH, Adams AJ, Cornblath M, Kowarski AA. The use of the plasma epinephrine response in the diagnosis of idiopathic postprandial syndrome. JAMA, J Am Med Assoc 1984;251(5):612–5.
- Service FJ. Hypoglycemic Disorders. N Engl J Med 1995;332(17):1144–52.
- Ng CL. Hypoglycaemia in nondiabetic patients – an evidence. Aust Fam Physician 2010;39(6):399–404.
- Yager J. Non-Hypoglycemia is an Epidemic Condition. N Engl J Med 1974;291(17):907–8.
- Brun JF, Fedou C, Mercier J. Postprandial reactive hypoglycemia. Diabetes Metab 2000;26(5):337–51.
- Mongraw-Chaffin M, Beavers DP, McClain DA. Hypoglycemic symptoms in the absence of diabetes: Pilot evidence of clinical hypoglycemia in young women. J Clin Transl Endocrinol. 2019 Jul 24;18:100202. doi: 10.1016/j.jcte.2019.100202. PMID: 31428564; PMCID: PMC6695274.
- Glucose Concentrations of Less Than 3.0 mmol/L (54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care 2017; 40(1):155-7.
- Chow E, Bernjak A, Williams S, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014;63(5):1738–47.
- Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ (Clinical research ed) 2010;340:b4909.
- Chevli PA, Ahmad MI, Hari K, Anees MA, Soliman EZ. Impact of low fasting plasma glucose on mortality in the general population. Diab Vasc Dis Res. 2020 May-Jun;17(3):1479164120930599. doi: 10.1177/1479164120930599. PMID: 32720509.