By Jeff Unger, MD

Director, Unger Primary Care Concierge Medical Group, Rancho Cucamonga, CA

Dr. Unger does research for Novo Nordisk, Lilly, Sanofi-Aventis, Janssen, GSK, Itarcica, Dance Pharma, Proteus Pharma, and Abbott Diabetes, is a consultant for Novo Nordisk, Janssen, Itarcica, Dance Pharma, Proteus Pharma, and Abbott Diabetes, is on the speaker’s bureau for Novo Nordisk, Janssen, and Valeritas, and is a stockholder for Novo Nordisk.

SYNOPSIS: A retrospective analysis of data from the UK Clinical Practice Research Datalink found that hypoglycemia increases the risk of both cardiovascular disease and all-cause mortality in patients with diabetes.

SOURCE: Khunti K, et al. Hypoglycemia and risk of cardiovascular disease and all-cause mortality in insulin-treated people with type 1 and type 2 diabetes: A cohort study. Diabetes Care 2015;38:316-322.

This is a retrospective analysis of data from the UK Clinical Practice Research Datalink which includes 265,868 insulin-treated patients age > 30 years diagnosed with diabetes between 2001 and 2007. 3260 were diagnosed with T1DM and 10,422 had T2DM. During a median follow-up of 5 years for type 1 diabetes patients and 4.8 years for those with type 2 diabetes, hypoglycemia was experienced by 573 (18%) and 1463 (14%) of patients, respectively. Compared with patients who did not experience hypoglycemia, the hazard ratio (HR) for CV events among T1DM patients who experienced hypoglycemia was 1.51 (not significant) and 1.61 for those with and without a history of CVD. For T2DM patients, the respective HRs were 1.60 and 1.49. The median time interval between the first hypoglycemia event and the first CV event was 1.5 years for all diabetes patients. Thus, hypoglycemia increases the risk of both CV and all-cause mortality in patients with diabetes.


The intensive treatment arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was terminated early due to a 22% increased risk of all-cause mortality compared with the standard arm in patients with T2DM. One hypothesis for the increased risk of mortality centers around the role of hypoglycemia as a contributor to incident sudden death in “high-risk” patients. The risk of severe hypoglycemia in ACCORD was associated with higher rather than lower A1C levels in both arms of the study. Hypoglycemia can incite a number of physiologic events, including increased platelet adhesion, increased heart rate, and vasoconstriction. Repeated mild or moderate hypoglycemia can suppress the usual counterregulatory response of catecholamines. A single episode of severe hypoglycemia in a patient who rarely experiences glucose levels < 60 mg/dL is likely to result in a more intensive release of catecholamines, which may trigger malignant arrhythmias in a patient with prolonged Q-T interval. Thus, blunting the catecholamine response may have a protective effect, as well as limit the risk of potentially fatal arrhythmias during a severe hypoglycemic event. This hypothesis is known as “hypoglycemia preconditioning.”

Clinically, patients with A1C levels > 8.5 % who have known coexisting cardiovascular disease should be treated to glycemic targets designed to minimize their risk of severe hypoglycemia. Consider prescribing medications that limit inducing hypoglycemia in high-risk patients, such as metformin, DPP-4 inhibitors, GLP-1 receptor agonists, bromocriptine, and SGLT-2 receptor agonists. Basal and prandial insulin analogues are less likely to result in hypoglycemia than human insulin. The use of disposable patch pumps (V-Go pumps) provide an attractive alternative to mixed insulin for patients with T2DM.

Patients with T1DM are not immune to CV death and all cause mortality. Our goal with T1DM patients is to limit the amount of variability experienced by these individuals. One should remember that T1DM is a bihormonal disease state consisting of loss of insulin production by the pancreatic beta-cell, and excessive glucagon production via hypertrophied islet alpha cells. Thus, the off-label use of GLP-1 receptor agonists alone or in combination with an SGLT-2 inhibitor may reduce the postprandial and fasting effects of glucagon excess in patients with T1DM. T1DM patients with hypoglycemia awareness autonomic failure should also be encouraged to use continuous glucose sensors, which will alarm in response to a fall in interstitial glucose levels.

Although long-term exposure to hyperglycemia is a known cause of mortality in patients with diabetes, the immediate risk of acute and severe hypoglycemia cannot be ignored. This study suggests that all patients treated with insulin should be monitored closely for evidence of hypoglycemic events. Clinicians should adjust treatments and glycemic targets for patients at high risk for cardiovascular mortality. 


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