Hypoglycemia, its implications in clinical practice, and possible ways to prevent it

Keywords::

• DPP-4 inhibitors
• Hypoglycemia
• Sulfonylureas
• Type 2 diabetes mellitus

Hypoglycemia is a common, unpredictable and potentially dangerous side effect of anti-diabetic treatment. Hypoglycemic episodes may involve neurogenic symptoms such as palpitations, tremor, hunger, and sweating, as well as neuroglycopenic symptoms including behavioral changes, difficulty thinking, confusion, and possibly seizure, coma, and even death1. According to the American Diabetes Association2, hypoglycemia can be classified as:

• severe hypoglycemia: an event requiring the assistance of another person to actively administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.

• documented symptomatic hypoglycemia: an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L).

• asymptomatic hypoglycemia: an event not accompanied by typical symptoms of hypoglycemia, but with a measured plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L).

• probable symptomatic hypoglycemia: an event during which symptoms typical of hypoglycemia are not accompanied by a plasma glucose determination, but presumably caused by a plasma glucose concentration ≤70 mg/dL (≤3.9 mmol/L).

• pseudo-hypoglycemia: an event during which the person with diabetes reports any of the typical symptoms of hypoglycemia with a measured plasma glucose concentration >70 mg/dL (>3.9 mmol/L), but approaching that level.

There may be important differences in hypoglycemic risk, depending upon the type and duration of diabetes, and the kind of anti-diabetic drug used. Results from the UK Prospective Diabetes Study (UKPDS) indicated that patients receiving intensive drug therapy experienced hypoglycemic episodes with greater frequency than patients randomized to a less aggressive protocol3. This was confirmed by the Action to Control Cardiovascular Disease in Diabetes (ACCORD) study, that was prematurely interrupted because of an excess mortality among intensively treated patients. The study showed that intensive glycemic treatment, targeted to reach a glycated hemoglobin (HbA_1c) less than 6.0%, reduced 5 year non-fatal myocardial infarctions, but increased 5 year mortality compared with standard treatment, targeting a HbA_1c less than 7.0–7.9%. The rate of death from cardiovascular causes was higher in the intensive therapy group than in the standard therapy group (2.6 vs 1.8%; hazard ratio 1.35; 95% confidence interval 1.04–1.76; p = 0.02). This was due to the major incidence of hypoglycemia in the intensively treated group4. Regarding the mechanism throughout which this happens, acute hypoglycemia causes pronounced physiological responses as a consequence of autonomic activation, principally of the sympatho-adrenal system, and results in end-organ stimulation and a profuse release of epinephrine. This autonomic stimulus provokes hemodynamic changes aimed to maintain the supply of glucose to the brain and promote the hepatic production of glucose. Blood flow is therefore increased to the myocardium, the splanchnic circulation, and the brain. The hemodynamic changes associated with hypoglycemia include an increase in heart rate and peripheral systolic blood pressure, a fall in central blood pressure, reduced peripheral arterial resistance, and increased myocardial contractility, stroke volume, and cardiac output5. There is clinical and experimental evidence that hypoglycemia can cause abnormal electrical activity in the heart, strengthening the premise that hypoglycemia can provoke sudden death6. High-resolution electrocardiography, which measures the QT interval precisely, in conjunction with hypoglycemic clamps to control the depth of hypoglycemia, has demonstrated lengthening of the QT interval in both diabetic and non-diabetic individuals7–9, and lengthening of the cardiac repolarization10.

Episodes of hypoglycemia are particularly dangerous in elderly patients, whose care is complicated by chronic medical illness, frailty, isolation, or a shortened life expectancy. Moreover, prior research has also suggested a link between hypoglycemia and fall-related fractures in older patients with type 2 diabetes11. Falls can result in damage to internal organs, traumatic brain injuries, fractures and even death12. Fractures are the most common non-fatal outcome of falls, and falls are the most common cause of fractures12,13. Fractures comprise 61% of fall-related costs, with hip fractures being the most frequent type of fall-related fracture; hip fractures are particularly serious, because they affect patient ability to walk.

For all these reasons, physicians should try every possible effort to reach adequate glycemic control without causing hypoglycemia. In elderly subjects this can be achieved by approaching the patients with a more realistic therapeutic goal, and reducing the signs and symptoms of hyperglycemia such as polyuria, fatigue, and weight loss, rather than attaining euglycemia14. Another strategy to reduce hypoglycemia is using an adequate anti-diabetic treatment: the majority of diabetes societies agree that metformin monotherapy is effective and associated with a low risk of hypoglycemia15–17. However, as diabetes progresses, metformin must be combined with other anti-hyperglycemic drugs to achieve the desired HbA_1c; the risk of hypoglycemia linked to the different anti-diabetic agents is different. An analysis conducted by Bron et al. showed that insulin use was most frequently associated with increased risk of developing hypoglycemia, followed by use of sulfonylureas, meglitinide and α-glucosidase inhibitors. The impacts of thiazolidinediones, metformin, and dipeptidyl peptidase-4 inhibitors on hypoglycemia risk, instead, were relatively small18. Despite that evidence, in clinical practice a lot of physicians still use sulfonylureas over DPP-4 inhibitors as second-line choice of oral glucose-lowering treatment after metformin, probably because of their lower cost, and also because, at least in Italy, DPP-4 inhibitors can be prescribed only by specialists, and not by general practitioners. Sulfonylureas act primarily by blocking ATP-sensitive potassium channels in the pancreatic β-cells, which stimulates insulin secretion19, while DPP-4 inhibitors act by inhibiting the enzyme dipeptidyl peptidase-4, increasing incretin levels. Hypoglycemia is less frequent with DPP-4 inhibitors because they act in a glucose dependent manner, differently from sulfonylureas20. This was also confirmed when sulfonylureas and DPP-4 inhibitors were compared by Mintz et al.21; the authors conducted a post hoc analysis of a 52 week trial and its long-term extension22,23 to compare the incidence, timing, and severity of hypoglycemic episodes with saxagliptin + metformin compared to glipizide + metformin. This analysis showed that the saxagliptin + metformin combination was associated with fewer patients reporting hypoglycemia and fewer and less severe hypoglycemic events in those experiencing hypoglycemia compared with glipizide + metformin21.

All things considered, surely DPP-4 inhibitors are more expensive than sulfonylureas, but the total cost of hypoglycemic events must also be included in the analysis, as it may surpass drug cost savings. Patients with hypoglycemia showed significantly higher annual all-cause and diabetes-related health care costs than patients without hypoglycemia18. Moreover, we need to consider that having a hypoglycemic event is associated with significantly increased risk of anti-diabetic treatment discontinuation. On the other hand, it has to be said that sulfonylureas are surely effective in reducing HbA_1c, and if they continue to be widely used and prescribed, and no official guidelines of the most important societies for the management of diabetes have taken a position against it, we should find the right place for these drugs among the numerous anti-diabetic drugs. It also has to be said that not all sulfonylureas are the same, with newer generations being safer than the older ones24. In this regard, sulfonylureas can be used keeping in mind that the risk of hypoglycemia is high, and, in our opinion, they should be managed only by specialists, and not by general practitioners. Sulfonylureas should not be used in older people25, or in patients with chronic kidney disease, because of their renal excretion, or in patients with cardiac problems. We think that the ideal patient for sulfonylureas could be a relatively young subject with a newly diagnosed, not well controlled, type 2 diabetes taking a limited amount of drugs: in this subject we should start sulfonylureas, both alone or in combination with metformin, for a limited period of time, maybe 3–6 months, in order to rapidly achieve adequate glycemic control. In this way we can avoid starting insulin, that is associated with an even higher risk of hypoglycemia compared to sulfonylureas; we can improve patient’s quality of life and compliance. After 3–6 months, if an adequate glycemic control has not been achieved, we should start insulin treatment; on the other hand, if we have reached the desired HbA_1c value, we should switch to another oral anti-diabetic agent, such as pioglitazone or DPP-4 inhibitors, that are protective of β-cell function26,27.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

P.M. and G.D. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this editorial.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.