Reduction of Insulin Requirement After Starting Treatment With Sacubitril/Valsartan in a Patient with Diabetes Treated With Continuous Subcutaneous Insulin Infusion (CSII): A case report

Diabetes mellitus increases the risk of heart failure (HF): in the Framingham Study HF risk was increased 2.4-fold in men and 5-fold in women. ¹ Recently Sacubitril/valsartan (Entresto®), a combination angiotensin receptor-neprilysin inhibitor, improved survival and hospitalization of patients with HF with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial, ² showing also potential benefits in glycemic control. ³

Here we describe the case of 62-years-old male patient, BMI 29 kg/m², treated with CSII (Accu-Chek Insight®) for type 2 diabetes (T2D) since 2013 in whom Sacubitril/valsartan for HFrEF since December 2017 was added. T2D was diagnosed in 1981 and treated with oral antidiabetic drugs until 2008. In 2008 after an acute inferior myocardial infarction he underwent coronary artery bypass grafting and started insulin treatment (MDI). He presents several comorbidities as nonproliferative diabetic retinopathy, chronic kidney disease IIIa (eGFR 59 ml/min/1.73m², albuminuria 35 mg/l), and HFrEF secondary to the coronary artery disease.

In December 2017 the ejection fraction (EF) was 30% and patient suffered from stress dyspnea (NYHA class III), so the consultant cardiologist switched him from enalapril to sacubitril/valsartan, starting with 41/59 mg BID until December 2017, when the dosage was increased to 82/118 mg BID. Echocardiography after 3 months of treatment showed a clear improvement of EF (from 30 to 40%) that explained the clinical amelioration of dyspnea (NYHA class II).

At follow-up we observed a progressive reduction (-22%) of daily insulin requirement (mainly for boluses) due to the frequent occurring of postprandial hypoglycemic events, confirmed by the worsening of low blood glucose Kovatchev index (LBGI) (Table 1).

Table 1.

Changes in Diabetes Parameters During and After 4 Months of Sacubitril/Valsartan Treatment.

	Pre-Entresto	+1 month	+2 months	+4 months	Δ
Total insulin requirement (U/die)	100	84	86	78	−22 U/die (–22%)
Basal insulin requirement (U/die)	42	34	36	36	−6 U/die (–14%)
Bolus insulin requirement (U/die)	58	50	50	42	−16 U/die (–28%)
HbA1c (%, mmol/mol)	6.8, 51	6.6, 49	6.9, 52	6.4, 46	−0.4%, –5 mmol/mol
Time in range 70-180 mg/dl (%)	—	48	58	63	+ 31%
Mean glycemia (mg/dl)	—	133	129	114	−19 mg/dl (–14%)
LBGI	—	1.8	2.1	2.9	+ 1.1
HBGI	—	3.9	3.2	1.9	−2
Standard deviation (mg/dl)	—	53	49	45	−8 mg/dl (–15%)
Weight (kg)	96			96	=
BMI (kg/m2)	29			29	=
eGFR (ml/min/1.73 m2)	59			50	−15%
Albuminuria (mg/L)	35.1			8.1	−77%

This occurred without clinical worsening of BMI, eGFR, and background therapy.

Moreover, download of pump data after 4 months of sacubitril/valsartan therapy also showed a greater time in range (70-180 mg/dl), a lower high blood glucose Kovatchev index (HBGI), and a reduction of mean glycemia and standard deviation, resulting in a lower HbA1c value (Table 1).

Discussion

The effect of sacubitril on insulin sensitivity has been investigated in several studies and there are different potential mechanism by which it might lead to improvement in glycemic control such as the breakdown of the biologically active natriuretic peptides, bradykinin, angiotensin I and II, and glucagon-like peptide 1. ²

Recently a post hoc analysis of PARADIGM-HF trial among 3778 patients (98% with T2D), underlines that patients receiving sacubitril/valsartan had a greater long-term reduction of HbA1c than those receiving enalapril (–0.13%, P = .0023). Furthermore the HR for starting insulin therapy in sacubitril/valsartan group was 0.71 (P = .0052). ³

Our report represents the first case of a patient with T2D treated with CSII, where we can accurately assess the insulin dosage change after 4 months of sacubitril/valsartan therapy.

Although it represents an isolated observation, our data could help clinicians who will be using sacubitril/valsartan in patients with diabetes with HF on the assessment of insulin regimen dosage.

Clearly, more data are required to better investigate this particular clinical condition and support diabetologists on being more confident in modifying their advises about insulin therapy for their patients with diabetes.