Hypoglycemia is an essential issue for patients with diabetes and is often considered as a limiting factor in glycemic management. Heterogeneity of disease in type 2 diabetes can affect the frequency and severity of hypoglycemia, and several factors can affect the risk of hypoglycemia such as sulfonylurea or insulin therapy and physical exercise. Hypoglycemia may also have adverse cardiovascular (CV) and psychological consequences. Focused education about hypoglycemia is needed in order to minimize the impact of this important complication.

• Data from several studies has suggested that rates of hypoglycemia are higher in real-life than in clinical trials, and in one study on patients with type 2 diabetes almost 50% of patients on insulin for more than 12 months reported hypoglycemia.
• The high rates of hypoglycemia in real-world experience was confirmed in the latest HAT study, the largest trial on hypoglycemia carried out to date; in that trial, 52% of patients on insulin experienced a mild-moderate hypoglycemic event, and 21% a severe event.
• Despite this, in some regions, the rates of hypoglycemia seem to be gradually declining over time, which may be explained at least in part by changes in prescribing practices, favoring other agents over sulfonylureas.
• However, this is not the case in all settings.
• There are also large variations in hospital admission rates from ambulance call outs and visits to the emergency department across various studies.
• Such variations may be due to differences in study design, type of diabetes, exclusion and inclusion criteria, differences in treatments, definitions of hypoglycemia, and possible differences due to ethnicity.
• Nonetheless, it is clear that hypoglycemia remains a clinical problem of significant relevance, and the physician’s ultimate aim should be to reduce the rates of hypoglycemia through educational and pharmacological interventions, given the rising trends of risk factors such as aging, frailty, and comorbidities.

• At present, there is a suggestive link between clinical CV disease and severe hypoglycemia, although there is little data about such an association in community-based populations.
• In the ARIC study, which surveyed emergency department visits, ambulance calls, and hospitalizations, there was indeed evidence that a single episode of severe hypoglycemia gives rise to a high-risk state, with 3-year mortality of about 30%.
• The risk appears to be highest in the first year after a hypoglycemic episode, showing robust independent associations with CV mortality and coronary heart disease.
• Elevated high sensitivity cardiac troponin (hs-cTnT) is a biomarker of chronic subclinical myocardial damage, and elevations in hs-cTnT in asymptomatic persons are thought to reflect chronic subclinical myocardial damage.
• There is now evidence suggesting that severe hypoglycemia may lead to increased levels of hs-cTnT, but this requires further study.
• Another important aspect to consider is cognitive impairment as related to hypoglycemia.
• Indeed, an increased prevalence of both mild cognitive impairment and dementia has been significantly associated with history of severe hypoglycemia, and the link between hypoglycemia and cognitive outcomes appears to be strong.
• Any documented hypoglycemia event should trigger re-evaluation of risk factor management and attention given to the possible negative effects of polypharmacy.
• Providers should frequently screen for hypoglycemia history, and assessment of cognitive function, especially in older adults with history of hypoglycemia, is important.
• Therapy should always be tailored to prevent hypoglycemia in adults with cognitive impairment.
• Lastly, intensive control may be counterproductive in high-risk patients, and especially in older adults.

• There are many ways that hypoglycemia can affect psychological outcomes in patients with type 2 diabetes.
• These include, but are not limited to, unpleasant physical and emotional symptoms, loss of consciousness leading to physical harm, creation of embarrassing situations, lowered self-esteem, decreased quality of sleep, and concerns about future events.
• Indeed, multiple studies have demonstrated that fear of hypoglycemia is much higher in those who have experienced severe hypoglycemia events compared to those who have not.
• Despite its importance on patient outcomes, there is still insufficient data on the impact of mild hypoglycemia on psychological outcomes, although it seems certain that severe hypoglycemia has a clear negative effect.
• The strongest and most consistent effect is fear of hypoglycemia, general worsening of well-being, and health status.
• Moreover, it should be kept in mind that the negative psychological impact of hypoglycemia is not restricted to patients who use insulin.

• Adjunctive therapies refer to another treatment used together with the primary therapy.
• In type 2 diabetes, adjunctive therapies are used to help patients achieve optimal or near normal glycemic control.
• However, currently available insulins and other glucose-lowering therapies do not perfectly mimic normal physiology, with the consequence that severe hypoglycemia may occur.
• Current approaches to glucose lowering utilize therapies that minimize the risk of hypoglycemia using more physiological insulins (i.e. basal or rapid analogs), as well as oral and injectable drugs with a low risk of hypoglycemia using glucose dependent mechanisms to lower glucose.
• Moreover, new technological solutions have been developed for better delivery of insulin and improved monitoring of glucose levels.
• Other aspects to consider are that patients should be educated about avoidance and management of hypoglycemia using diet and exercise education, structured education programs, and cognitive behavioral therapy.
• For the future, new insulin formulations are under development and novel combination therapies that may help to further lower the risk of hypoglycemia.