CAN STATINS HAVE A BENEFIT IN THE REDUCTION OF PLASMA KETONE BODIES IN PATIENTS WITH

UNCONTROLLED TYPE 2 DIABETES MELLITUS AND MIXED HYPERLIPIDEMIA?

Spyridon Karamagkiolis1,2, Eleni Sogka1, Nikolaos Aggelis1,Ourania Triantafyllou1, Flora Koumoutsou1, Vasiliki Mintza1,Polyxeni Choussi1,2

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 = 12.98 ± 1.02%

Antidiabetic treatment for the past year 7 patients = Basal Insulin q.d. (Glargine or Detemir) + Metformin ± DPP-4-I5 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)

• Tables

– Table 1: parameters prior to treatment with statins

– Table 2: parameters prior to and 15 days after initiating treatment with statins

Pts (n=12)

Gender Age HbA1c(%)

Random BG(mg/dL)

β-OHB(mmol/L)

CHOL(mg/dL)

TRG(mg/dL)

1 F 54 11.8 306 0.6 248 305

2 F 60 13.7 345 1.2 237 330

3 F 61 13.5 351 1.1 256 321

4 F 65 13.2 338 0.8 241 265

5 M 55 13.3 364 0.6 230 292

6 M 56 12.9 327 0.7 250 340

7 M 57 14.0 372 1.0 246 310

8 M 58 12.1 296 0.7 237 288

9 M 59 12.8 321 0.6 251 290

10 M 62 12.5 340 0.9 260 345

11 M 63 13.0 368 0.7 258 276

12 M 64 12.9 370 0.8 280 322

Pts = Patients, F = Female, M = Male, BG = Blood Glucose, β-OHB = β-Hydroxybutyrate, Chol = Cholesterol, TRG = Triglycerides

Pts (n=12)

Gender Age HbA1c(%)

Random BG(mg/dL)

β-OHB(mmol/L)

15 days after statins use

Random BG(mg/dL)

β-OHB(mmol/L)

1 F 54 11.8 306 0.6 Simv 40mg

312 0.4 ↓

2 F 60 13.7 345 1.2 Atorv 20mg

330 0.8 ↓

3 F 61 13.5 351 1.1 Atorv 20mg

362 0.7 ↓

4 F 65 13.2 338 0.8 Simv 40mg

336 0.6 ↓

5 M 55 13.3 364 0.6 Simv 40mg

347 0.3 ↓

6 M 56 12.9 327 0.7 Simv 40mg

339 0.5 ↓

7 M 57 14.0 372 1.0 Atorv 20mg

359 0.6 ↓

8 M 58 12.1 296 0.7 Atorv 20mg

305 0.4 ↓

9 M 59 12.8 321 0.6 Atorv 20mg

289 0.2 ↓

10 M 62 12.5 340 0.9 Simv 40mg

352 0.4 ↓

11 M 63 13.0 368 0.7 Atorv 20mg

380 0.3 ↓

12 M 64 12.9 370 0.8 Simv 40mg

354 0.2 ↓

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 = 0.0005 (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.

Thank you for your attention