CAN STATINS HAVE A BENEFIT IN THE REDUCTION OF PLASMA KETONE BODIES IN PATIENTS WITH UNCONTROLLED TYPE 2 DIABETES MELLITUS AND MIXED HYPERLIPIDEMIA? Spyridon Karamagkiolis 1,2, Eleni Sogka 1, Nikolaos Aggelis 1, Ourania Triantafyllou 1, Flora Koumoutsou 1, Vasiliki Mintza 1, Polyxeni Choussi 1,2 1 Department of Internal Medicine, General Hospital of Larissa, Larissa, Greece 2 Diabetes Mellitus Outpatient Clinic, General Hospital of Larissa, Larissa, Greece

BACKGROUND (1) In diabetic patients, high blood levels of ketone bodies are an early sign of Diabetic Ketoacidosis (DKA), a potentially life-threatening condition. DKA is a less common occurrence in patients with Type 2 Diabetes Mellitus (T2DM) in contrast to patients with Type 1 Diabetes Mellitus. DKA precipitating factors  Infection, new diagnosis of diabetes mellitus, insulin omission, myocardial infarction, abdominal crisis, trauma,pregnancy Ketone bodies : acetone, acetoacetic acid and beta – hydroxybutyrate.

BACKGROUND (2)

BACKGROUND (3)

OBJECTIVES To study whether treatment with statins in insulin-treated patients with uncontrolled Type 2 Diabetes Mellitus (T2DM) and Mixed Hyperlipidemia (MHL) decreases the blood levels of β-Hydroxybutyrate (B-OHB), the predominant ketone in Diabetic Ketoacidosis (DKA).

METHODS (1) Patients profile Total Number = 12, 8 Males - 4 Females Age = 59.5 ± 5.5 years old, BMI = 37.5 ± 5.5 Diet Rich in fat (> 40% fat,mostly saturated) Daily use of alcohol Sedentary life style Refusal to comply to medical suggestions 1.T2DM Duration 12.5 ± 3.5 years HbA1c = ± 1.02% Antidiabetic treatment for the past year  7 patients = Basal Insulin q.d. (Glargine or Detemir) + Metformin ± DPP-4-I  5 patients = Premixed Insulin b.i.d. + Metformin ± DPP-4-i None of the subjects accepted a change in treatment or insulin dose titration No daily blood glucose (SMBG) check –Frequent insulin omission 2. Mixed Hyperlipidemia Duration 6.5 ± 2.5 years No systematic hypolipidemic treatment by choice

METHODS (2) At the time of the study none of the subjects were acutely ill and all declined hospital admission Capillary blood glucose and capillary blood β-OHB were measured (twice) All patients exhibited β-OHB values > 0.6 mmol/L Method used for determining capillary blood β-OHB = Test strips Abbott ® FreeStyle-Precision-β-Ketone ® Blood β-OHB normal values < 0.6 mmol/L  values 0.6 – 1.5 mmol/L and blood glucose ≥ 300 mg/dL→ Risk for DKA  values > 1.5 mmol/L and blood glucose ≥ 300 mg/d→ High Risk for DKA

METHODS (3) Patients agreed to follow a hypolipidemic regimen They were randomly selected to receive either Simvastatin 40 mg q.d. or Atorvastatin 20 mg q.d. 15 days later capillary blood glucose and capillary blood β-OHB were measured (twice) in an outpatient setting

METHODS (4) Statistical Analysis: Due to the small number of patients, the non- parametric Wilcoxon matched-pairs signed- ranks test was used. Software Program: GraphPad-InStat® (version 3.10)

RESULTS (1) TablesTables –Table 1: parameters prior to treatment with statins –Table 2: parameters prior to and 15 days after initiating treatment with statins

Pts (n=12) GenderAgeHbA1c (%) Random BG (mg/dL) β-OHB (mmol/L) CHOL (mg/dL) TRG (mg/dL) 1F F F F M M M M M M M M Pts = Patients, F = Female, M = Male, BG = Blood Glucose, β-OHB = β- Hydroxybutyrate, Chol = Cholesterol, TRG = Triglycerides

Pts (n=12) GenderAgeHbA1c (%) Random BG (mg/dL) β-OHB (mmol/L) 15 days after statins use Random BG (mg/dL) β-OHB (mmol/L) 1F Simv 40mg ↓ 2F Atorv 20mg ↓ 3F Atorv 20mg ↓ 4F Simv 40mg ↓ 5M Simv 40mg ↓ 6M Simv 40mg ↓ 7M Atorv 20mg ↓ 8M Atorv 20mg ↓ 9M Atorv 20mg ↓ 10M Simv 40mg ↓ 11M Atorv 20mg ↓ 12M Simv 40mg ↓

RESULTS (2) Blood levels of B-OHB were significantly reduced after treatment with statins in all the patients. The mean values (±SD) of blood B-OHB levels before the initiation of treatment with statins,were 0.80 ± 0.20 mmol/L; 95% confidence intervals (CI) = 0.68 – 0.94 mmol/L –[Std error = 0.05, Minimum = 0.60 mmol/L, Maximum = 1.20 mmol/L, Median = 0.75 mmol/L] The mean values of blood B-OHB levels 15 days after the introduction of statins,were 0.45 ± 0.19 mmol/L, 95% CI = 0.33 – 0.57 mmol/L –[Std error = 0.05, Minimum = 0.20 mmol/L, Maximum = 0.80 mmol/L, Median = 0.40 mmol/L] Mean Difference: 0.35 ± 0.12 mmol/L; 95% CI = 0.28 – 0.44 mmol/L, p = (two-tailed). –[Std error = 0.03, Minimum = 0.20 mmol/L, Maximum = 0.60 mmol/L, Median = 0.40 mmol/L]

RESULTS (3) In 67% (n=8) of the patients studied, blood B-OHB concentrations returned to normal levels (< 0.6 mmol/L) No statistically significant differences were noticed in relation to  Sex,  Age,  Levels of HbA1c, Blood Glucose, Cholesterol, Triglycerides,  Type of antidiabetic regimen,  Treatment with simvastatin 40 mg/d or atorvastatin 20 mg/d.

RESULTS (4) Study’s Disadvantages: Patients sample small in number, non randomized Absence of a control group The method for determining β-OHB levels lacks a high degree of exactitude Lack of evidence that the study’s results apply to a longer time frame (months,years).

CONCLUSIONS The novel finding of this study is that in patients with uncontrolled T2 Diabetes Mellitus and Mixed Hyperlipidemia, treatment with statins may reduce blood B-OHB-levels. A larger study with a control group is required to confirm these findings. Prompt initiation, appropriate titration of insulin treatment and mainly,patient compliance,remain the corner stone for the reduction of HbA1c and pathological values of β-OHB.

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