In their study, Pyorala et al. in 1998 examined total mortality as a primary end point. Major CHD events (death) or non-fatal MI constituted the secondary end point. As their tertiary end point, they examined any CHD event, arteriosclerotic event (including death from hospital admission for such event), revascularization procedure, coronary artery bypass grafting or angioplasty. Mortality and occurrence of different forms of non fatal artherosclerotic events during follow-up were as follows: 578(27.2%) in non diabetics, 407 (19.25) in placebo group. In the simvastatin group: Diabetic patients 44(45.5%) in placebo group and 24 (22.9%) in the simvastatin group. Over the 5.4 year follow up period (median), the RR of main endpoints in simvastatin treatment –diabetic group were (total mortality) 0.57 (95% CI,0.30-1.08;P-0.087). Major CHD events 0.45(95% CI, 0.27-0.74; P<0.002) and for any artherosclerotic event 0.63 (95% CI, 0.43-0.92; P<0.018). The corresponding RR in non diabetic patients were as follows: 0.71 (95% CI, 0.58-0.87; P<0.001), 0.68(95% CI, 0.60-0.77; P<0.0001) and 0.74 (95% CI, 0.68-0.82; P<0.0001). Analysis of the 4S study suggests mortality benefit in lowering cholesterol in diabetics and also non-diabetics. Keech et al ^{2003 in their results observed that for the primary combined outcome of CHD death or non-fatal MI, Pravastatin therapy reduced the risk among all patients from 15.9 % to 12.3% (RRR 24%, P<0.001). In diabetics, the RRR was 19%. Also, Pravastatin reduced the risk of stroke from 9.9% to 6.3% in diabetic group. According to Collins et al in Heart Protection Study Collaborative Group, 2002, observation was made in their results of significant reduction of mortality (1328:12.9% ) deaths among 10,269 patients in the simvastatin group versus 1507: 14.7% among 10,267 patients in the placebo group, P<0.003. Other studies (ALLHAT, 2002, Colhoun et al, 2004, Goldberg, et al, 1998, Sommeijer, et al, 2004) also reported significant or near significant reduction in mortality or death rate. Most studies reported mortality or death rate as a primary end point.}

Virtually all studies examined this as a secondary end point. Colhoun et al in 2004 ^{believed that there is an association of a 2-4 fold increased risk of both CHD and stroke. In their study, acute CHD events were reduced 36% (-55 to -9), coronary revascularization by 31% (-59 to 16) and rate of stroke by 48% (-69 to -11), in the Artovastatin group. Goldberg et al,1998 reported reduction in relative risk for revascularization procedures by 32% (P< 0.04) in diabetic patients. However, when grouped together such as CHD, death, non fatal MI, CABG, Pravastatin group was associated with a 25% reduction of risk of coronary events. In CARDS, 2004, the investigators showed that patients with T2DM and other risk factor of coronary artery disease, or retinopathy, had a 35% relative risk reduction in CVD attributed to Atorvastatin 10 mg daily, which was similar to a 33% relative risk reduction in CVD with Simvastatin 40 mg. In the ALLHAT-LLT study 2002, Pravastatin did not reduce CHD significantly (or all cause mortality) compared with usual care in older participants with hypertension or moderately elevated LDL-C. Note: total T2DM population was about 35% of total participants. In the Heart Protection Study 2002, there was prepartial reduction in incidence rate of first stroke, following randomization 144, (4.3%) in Simvastatin versus 585(5.75%) in placebo; P<0.001 for revascularization. Overall, the simvastatin group produced a highly significant (24%, SE 4; 95% CI 17-30) proportional reduction in incidence rate of first revascularization procedure following randomization -939(9.1%) simvastatin versus 1205(11.7%) placebo, P<0.0001.}

The Heart Protection Study in 2002, specifically looked at the following outcomes:

Neropsychiatric: observational studies have suggested that lowering cholesterol might slow cognitive decline. However, no significant differences were found between treatment groups after being administered the well validated modified telephone interview for cognitive status (TICS-M) questionnaire.

On respiratory disease: Increased mortality from Chronic Obstructive Pulmonary disease (COPD) has been a concern for low cholesterol, an association sometimes linked to observational studies too. However, no significant differences were found in Forced Expiratory Volume (FEV1) 2.06L in the simvastatin group versus 2.05L in the placebo group.

On cancer; No significant difference occurred between the simvastatin group 814, 7.9% of new cancers versus 803, 7.8% in placebo.

Wanner et al in 2005, examined prospectively 1255 patients with T2DM, on maintenance hemodialysis, randomly assigned 20 mg Atorvastatin or placebo. With a primary end point of composite of death from cardiac causes, non-fatal MI or stroke, and a secondary endpoint of death from all causes-cardiac or cerebrovascular, they observed that Atorvastatin had no significant effect on individual components of primary end point, except the relative risk of fatal stroke among those receiving the drug (2.03) CI 95% (1.05-3.93), P<0.04. Atorvastatin reduced the rate of all cardiac events combined (RR 0.82, CI 95%, 10.68-0.99, P<0.03.

From results of more than 20000 patients, the statins seem to be relatively well tolerated, with slight or moderate increases in liver function enzymes (ALT and AST). Rises above three times the upper limit are considered high. Rhabdomyolysis remains rare in both diabetics and non diabetics regardless of lipid profile, receiving a statin therapy.

Biases to this review may emanate on selection of studies. Some studies selected, which contained sets of diabetic patients, may have actually contained non T2DM subjects. However, with T2DM constituting a huge majority of diabetics in general (85-90%) and with type 1 diabetes mellitus almost exclusively in juneveniles, it is assumed that subjects recruited for these studies were almost exclusively T2DM patients, since their average age was beyond 40 years. Also, some landmark studies involving statin therapy and T2DM may have been favorably recognized in the literature selection process.

There seem reasonable evidence to suggest that the statins have benefits beyond mere lowering of cholesterol, both in T2DM patients, and non diabetic patients. The evidence suggests mortality benefit in controlling diabetic dyslipidemia, or in the absence of dyslipidemia. This therefore, lends credence to an early treatment regimen in order to reduce long-term mortality. A question therefore arises “should we place all T2DM patients on statins regardless of their cholesterol level? The simple answer may not be easily comprehended, but good evidence suggest that even non-diabetics patients, with minimal CHD risk, may live longer with early statin therapy. T2DM patients being in a higher risk group of CHD events, it may be wise to initiate statin therapy as early as possible, in order to benefit from a greater long-term effect. Therapy should be encouraged in all T2DM patients above 40 years, and who can tolerate it. On going studies may hopefully explain better the benefits of statin therapy in all groups. Some studies have reported positive effects on Angiotensin 2 enzyme, as well as Thromboxane A2, suggesting a positive effect on hypertension and anticoagulation, respectively.