While the UKPDS has shown us that glycemic control will improve the toll of microvascular disease, the main cause of death in diabetics is cardiovascular disease; outcomes of which are less affected by glycemic control. There is something strange about diabetics that makes diabetics more likely than others to develop cardiovascular disease; and when they do develop this disease, it is more likely to kill them. Most diabetics die a cardiovascular death.

      Some of the explanation for the excess mortality in Type 2 Diabetics may be linked to the fact that 50-70% of Diabetics have abnormal lipids. While the incidence of elevated Cholesterol and LDL is about the same as the general population at 44%; the hallmark of Diabetic Dyslipidemia is an elevated Triglyceride level frequently coupled with low HDL. While studies have shown us that a 1% increase in LDL is associated with a 2% increase in cardiovascular disease; an even more dramatic relationship exists with HDL where a 1% lowering of HDL  is associated with a 3% increase in cardiovascular disease risk.

The Canadian working group on Hypercholesterolemia and Other Dyslipidemias has recommended that Patients with Diabetes Mellitus over the age of 30 be classified as being at very high risk for Coronary Artery Disease.

Achieving Goals:

1998 clinical practice guidelines from the CDA recommend a healthy lifestyle including diet, weight loss and physical exercise. Various studies have shown than on average, lifestyle changes will only achieve a 5% cholesterol reduction so in most cases pharmacotherapy will be required.

The data for the benefits of LDL lowering are very consistent & robust. I usually suggest  starting  with a statin if LDL>3.0. If Total Chol & LDL are normal or controlled, we look at HDL and Triglycerides. We know that a 1% reduction in HDL is associated with a 3% increase in risk of cardiovascular events. Statins produce a small 5-10% increase in HDL, this increase is generally unrelated to drug dose. The characteristic hypertriglyceridemia seen in hyperglycemia will respond to some extent to improved glycemic control but the depressed HDL is more resistant. Medications with beneficial effects on raising HDL and lowering Triglycerides are the fibrates and Niacin. Fibrates also have a beneficial effect on glycemic control because they act as PPAR-a agonists. Bezafibrate can decrease fasting Triglyceride by 50%, reduce Cholesterol by 12%,  increase  HDL by 20% and decrease Fasting Plasma Glucose by 16%. 3  In the DAIS study 4 treatment with Fenofibrate decreased Triglyceride by 30%, decreased Cholesterol by 10%, increased HDL by 10% and slowed the reduction of coronary artery lumen size. At what point should we pharmacologically treat isolated low HDL ? My threshold is HDL<0.8.

Fibrates:

Increase lipoprotein Lipase, thereby lowering  Triglyceride up to 50%, lower Cholesterol +/- 10% and increase HDL by up to 20%. They are ppar-a agonists and may also modestly lower glucose. Do not use in renal or hepatic failure (Gemfibrozil safer in renal compromised patient). Interaction with warfarin causes prolonged INR. Possible myositis when administered with statin. Check liver functions & CK.

• Bezafibrate (Bezalip) 400 mg SR once daily
  
• Fenofibrate (Lipidil Micro) 200 mg OD
  
• Fenofibrate (Lipidil Supra) 160 mg ) 160 mg OD
  
• Gemfibrozil (Lopid) 300-600 mg BID (safer in renal compromise)

Statins:

HMG-CoA Reductase inhibitors. Reduce biosynthesis of Cholesterol. May reduce cholesterol up to 60%,  may reduce LDL up to 50%, reduce Trig up to 25% and raise HDL up to 6%. In high dosage may lower HDL . Do not use in patients with liver disease, check liver functions and discontinue if liver functions >3 times ULN. May cause myositis with fibrates or niacin, monitor CK. Metabolized by C-P450, may increase INR with coumadin.
 

• Atorvastatin (Lipitor) 10 mg OD to 80 mg OD (10,20,40,80 mg tabs)
  
• Fluvastatin (Lescol) 20-80 mg  (20 & 40 mg caps)
  
• Lovastatin (Mevacor) 20-80 mg  (20 & 40 mg tabs)
  
• Pravastatin (Pravachol) 10-80 mg  (10,20,40 mg tabs)
  
• Rosuvastatin (Crestor) not yet available in Canada
  
• Simvastatin (Zocor) 5-80 mg  (5, 10, 20, 40 mg tabs)
  

Resins:

Bile acid sequestrants. Absorbs cholesterol containing bile acids which are then excreted in feces. May cause steatorrhea, may cause constipation. May impair absorption of fat soluble vitamins. May reduce absorption of warfarin.

• Cholestyramine (Questran) 4 gm 1-6 times/day
  

Niacin:

Water soluble B-complex vitamin. Reduces hepatic synthesis of VLDL and LDL, increases HDL. Lowers Chol  by 10-15%,  lowers Trig by 20-30%, raises HDL 30%. Do not use in liver disease, check liver functions; may worsen peptic ulcer; elevates uric acid; may worsen glucose control (doses >1500 mg). Frequently causes flushing which may be attenuated by taking ASA before niacin. May cause myositis if given with statins.

• Niacin  100-1500 mg/day  (tabs of 100 & 500 mg)
  
• Niacin 500 mg sustained release 500-1500 mg/day  (tabs of 500 mg)

Other Agents: Salmon Oil

References

1. Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. CMAJ 1998;159(8 suppl)
   
2. Fodor J, Frolich J,Genest J, et al. Reccomendations for the management & treatment of dyslipidemia. CMAJ 2000;162 (10)1441-7
   
3. Ogawa S, Tekeuchi K, Sugimura K, et al. Bezafibbrate reduces blood glucose in Type 2 Diabetes Mellitus. Metabolism 49;331-334, 2000
   
4. Ercsson C, Hamsten A, Nilsson J, et al. Angiographic assessment of effects of Bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 347;849-853, 1996

Case Study #1

Mr. F.

• age 54, Statistician
  
• Ht 5'10, Wt 212 lb, BMI 43, Waist 44"
  
• Diabetic for 7 years, on metformin glyburide
  
• HgbA1c 7.2%
  
• BP 142/86
  
• Chol 6.24,Trig 4.68, HDL 0.76, LDL 3.42

• Glycemic Control?
  
• BP Control?
  
• Lipid Control?
  
• Lifestyle?
  
• Thrombosis prevention?

Mr. F. Lipids
Chol 6.24, Trig 4.68, HDL 0.78, LDL 3,42

• Goals?
  
• Treatment?

Mr. F. after 3 months on statin

• Chol 5.25, Trig 4.02, HDL 0.79, LDL 2.57
  
• Where do we go from here?
  
• HDL 33% below goal of 1.2
  
• Trig  50% above goal of 2.0

Case Study #2

Mrs. G. Age 49, accountant

• Ht 5’6”, Wt 159 lb, BMI 27, Waist 37”
  
• Diabetic x5 yrs, on Gliclazide 160 mg BID
  
• Av FBS 7.6, HgbA1c 7.4%
  
• Chol 5.52, Trig 4.66, HDL 0.52, LDL 3.2,
  
• Treated with Bezalip 400 mg SR x3 mo
  
• Chol 4.98, Trig 2.40, HDL 0.76, LDL 2.58
  
• What do we do now?