Correction of Over-Dosed Insulin in a Type-2-Diabetic Associates With a Better Control of Glycemia and Arterial Hypertension: A Case Report

Background: An association between hypoglycemia and arterial hypertension is unknown. Here, we report a case of a chronically over-dosed insulin therapy in conjunction with uncontrolled hypertension. Case Presentation: A 73-year-old, male diabetic of Caucasian ethnicity was admitted to a neurological intermediate-care unit of a university hospital for progressive weakness due to diabetic polyneuropathy. Besides obesity (body-mass index: 31 kg/m²) and type-2 diabetes, an uncontrolled arterial hypertension was present. Diabetes therapy consisted of xed-dose insulin (160 units QD). Symptomatic or documented hypoglycemic episodes were not reported. Hemoglobin A1c was 11.2%. Prior to hospitalization, a urapidil (60 mg thrice a day), was added to his antihypertensive medication with valsartan (160 mg BID) and bisoprolol (5mg BID). During hospitalization, metformin, empagliozin, and dulaglutide (1.5 mg per week) were added to insulin. An intensied conventional therapy with a cumulative daily dose of 46 units was introduced. 22 months after discharge, the medical therapy consisted of metformin (1 g BID), liraglutide (1.8 mg QD), and insulin glargine (26 units QD). The antihypertensive medication was reduced to bisoprolol and valsartan, urapidil was discontinued. The follow-up visit showed Hemoglobin A1c of 6.6%, and a well-controlled blood pressure. The patient’s physical activity improved with the patient being able to leave his at alone for the rst time within 6 years. Conclusions: Undocumented, asymptomatic hypoglycemic events and post-hypoglycemic hormonal stimulation were the likely cause for the poor glycemic and blood-pressure control. A step-wise reduction of insulin concurrently translated into a better glycemic and blood-pressure control.

mg thrice a day), was added to his antihypertensive medication with valsartan (160 mg BID) and bisoprolol (5mg BID). During hospitalization, metformin, empagli ozin, and dulaglutide (1.5 mg per week) were added to insulin. An intensi ed conventional therapy with a cumulative daily dose of 46 units was introduced. 22 months after discharge, the medical therapy consisted of metformin (1 g BID), liraglutide (1.8 mg QD), and insulin glargine (26 units QD). The antihypertensive medication was reduced to bisoprolol and valsartan, urapidil was discontinued. The follow-up visit showed Hemoglobin A1c of 6.6%, and a well-controlled blood pressure. The patient's physical activity improved with the patient being able to leave his at alone for the rst time within 6 years.
Conclusions: Undocumented, asymptomatic hypoglycemic events and post-hypoglycemic hormonal stimulation were the likely cause for the poor glycemic and blood-pressure control. A step-wise reduction of insulin concurrently translated into a better glycemic and blood-pressure control.

Background
Hypoglycemia represents a life-threatening hazard of insulin therapy, especially in cardiovascular high-risk patients (1,2). According to a recent consensus recommendation for the therapy of type-2 diabetes, glucagon-like-peptide-1 (GLP-1) agonists and sodium-glucose transporter-2 (SGLT-2) inhibitors are preferred alternatives, when hypoglycemic episodes occur or atherosclerotic vascular disease is present (3).
Hypoglycemia unawareness is associated with increased glucose concentrations in the brain most likely due to an up-regulation of insulin-independent glucose-transport mechanisms to the brain (4). The avoidance of neuroglycopenia during subsequent hypoglycemic episodes seems to be a plausible explanation. An autonomic neuropathy or polyneuropathy does not associate with hypoglycemia unawareness (5). In geriatric diabetes patients on insulin therapy, glycated hemoglobin A1c (HbA1c) does not correlate with less hypoglycemic episodes suggesting that a higher HbA1c goal does not su ce to reduce the risk for hypoglycemia in this cohort (6).
In patients experiencing hypoglycemic episodes, it is unclear whether post-hypoglycemia-induced catecholamine release and/or the activated sympathetic nervous system contribute to the development of arterial hypertension (7). In a small cohort study, the hypoglycemic burden in insulin-treated diabetics with hypertensive crisis or with hypoglycemia as the cause of hospital admission was similar (8).
In general, the average use of insulin per capita of the population is very high in Germany (9) and the adoption of novel therapy guidelines to reduce the risk for hypoglycemia is still challenging (10)(11)(12). Here, we present a type-2 diabetic with an elevated HbA1c, despite an ongoing high-dose insulin therapy, who had a hypertensive crisis prior to hospitalization. Although hypoglycemic episodes were not proven, the steady reduction of insulin dose over 22 months led to an improved glycemic control and allowed for reduction of antihypertensive medication.  Tables 1 and 2. The patient was admitted to an Intermediate-Care Unit initially, due to hyperglycemia, based on intermittent blood glucose, and hypertensive crisis. The insulin therapy was switched to intensive conventional therapy resulting in a cumulative insulin dose of 46 units per day after 11 days in the hospital. In addition, metformin, empagli ozin, a sodium-glucose transporter-2 inhibitor (SGLT-2i), and dulaglutide, a subcutaneously applied, once-a-week glucagon-like-peptide-1 (GLP-1) agonist, were added. In follow-up visits during the ensuing 22 months following the discharge (Table 3), diabetes therapy ultimately consisted of metformin (2 g/d), the GLP-1 agonist liraglutide (1.8 mg/d) and insulin glargine (26 units QD). The SGLT-2 inhibitor was discontinued due to side effects. The HbA1c was 6.6%, body weight decreased to 94.7 kg (body-mass index: 28.0 kg/m²). Strikingly, the patient was switched from a 3-fold to a 2-fold combination of antihypertensive drugs. The corresponding daily de ned dose (DDD) of antihypertensive medications changed from a DDD of 7 at hospital admission to a DDD of 2 at the last follow-up visit, 22 months after discharge. Although the insulin dose was reduced from 160 units/d to 46 units/d during the index hospitalization, further reductions were achieved during the 22 ensuing months during 9 follow-up visits (Fig. 1). The decrease of antihypertensive medication as shown in Fig. 1 lagged behind insulin reduction and HbA1c normalization considerably. However, an ambulatory blood-pressure recordings over 24 hours after 3 months proved a normal blood pressure (mean day-time systolic blood pressure (mean day-time systolic 131 mmHg, diastolic blood pressure 88 mmHg, reverse dipper). Likewise, the patient's mobility improved for one year following insulin reduction. For the rst time in 6 years, the patient was able to leave his at alone using a walking aid. Lastly, troponin T elevation at index hospitalization normalized with a period of 10 months following the discharge (troponin T levels dropped to 19.5 ng/L, normal reference: < 14.0). During the observation period in hospital and after discharge, coronary angiography was not performed. Transthoracic echocardiography, performed 22 months after discharge, revealed a normal systolic left-ventricular function, moderate left-ventricular hypertrophy and a moderate mitral stenosis. After 22 months, the patient was rehospitalized for minor stroke with a fully reversible facial paresis on the right and dysphasia. Additional exams suggested a cerebral ischemic event in the cerebral media artery, proved bilateral carotid sclerosis without need for intervention. The stroke prevention was changed from Aspirin to Clopidogrel. Holter electrocardiogram showed sinus rhythm and a reduced heart rate variability (standard deviation of normal beats: 64 ms). The patient was discharged with the same diabetic and antihypertensive medication like 22 months after discharge of index hospitalization (Table 3).    (9), more comprehensive management of type-2 diabetes is needed, which includes the correction of possibly over-dosed insulin therapy.

Case Presentation
As conclusion, an association of asymptomatic hypoglycemic episodes due to over-dosed insulin therapy and hypertension is suggested. More clinical data using continuous glucose monitoring are needed to substantiate the suspected association between reduction of asymptomatic hypoglycemic episodes and improvement of uncontrolled arterial hypertension.