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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - Canadian Cardiovascular Congress 2009

Edmonton, Alberta / October 24-28, 2009

A large multicentre study conducted in a family practice setting in Canada has associated a simple algorithm with very high success rates in placing patients with type 2 diabetes mellitus (DM2) at the currently recommended LDL target of <2.0 mmol/L. In the prospective, open-label study, patients were started on one of two doses of rosuvastatin based on their baseline LDL. If not at goal at six weeks, the statin dose was doubled. At 12 weeks, 82% of patients were at goal without any further step.

“This approach was very effective and it was safe,” reported Dr. David C. W. Lau, Chair, Diabetes and Endocrine Research Group, University of Calgary, Alberta. Although there may be several reasons why a large proportion of high-risk patients are not treated to goal, Dr. Lau speculated that one reason might be an inadequate starting dose and then a slow upwards titration so that the goal is not achieved in a reasonable period of time, often discouraging patients.

ADAPT Findings

In this study, called ADAPT (A Diabetes study to treat A Population previously not at Target), DM2 patients were enrolled at 122 family practices across Canada. The patients were required to be on a commonly accepted dose of a statin for at least four weeks prior to enrolment but still have LDL levels greater than those currently recommended by the Canadian Diabetes Association (CDA). This recommended level, <2.0 mmol/L, is the same as that recommended by the Canadian Cardiovascular Society (CCS) for high-risk patients, including those with established cardiovascular disease.

Of those enrolled, 598 discontinued their previous statin therapy and were allocated to one of two doses of rosuvastatin determined by their baseline LDL. Approximately 60% of patients had been taking 10 mg atorvastatin previously, while the remaining patients were taking one of the other currently available statins. Among those with LDL <2.5 mmol/L, the starting dose of rosuvastatin was 10 mg once daily; if >2.5 mmol/L, 20 mg rosuvastatin once daily was initiated. At six weeks, the dose in each group was doubled if LDL remained >2.0 mmol/L. At the end of 12 weeks, the proportion of patients with LDL <2.0 mmol/L was evaluated. Whether or not an upwards titration was needed at six weeks, 84% of those who initiated therapy on 10 mg and 79% of those who initiated therapy on 20 mg had achieved the goal of <2.0 mmol/L.

The average LDL in both groups was 1.7 mmol/L. More than 90% of patients who achieved the LDL goal also achieved an apolipoprotein B (apoB) level <0.8 g/L, which was defined in the newly released CCS Cholesterol Guidelines as an alternative goal for high-risk patients. The total cholesterol:HDL ratio of <4.0, which has been defined as a secondary goal of therapy in the new CCS guidelines, was reached at the end of 12 weeks by 86% and 85% of the 10-mg and 20-mg groups, respectively. Of the 307 patients in the 10-mg arm who completed the 12-week study, 232 (76%) achieved the goal on the starting dose. In the 20-mg group, 182 (70%) reached the goal without the need for an upward titration.

“With either no titration or just a single titration, the majority of DM2 patients can reach the current treatment goals if they are provided with an adequate starting dose,” Dr. Lau told delegates here at the CCC. He emphasized that the therapy, whether or not the dose was doubled, was well tolerated with no difference in adverse events when the two arms were compared. There were no cases of rhabdomyolysis or clinically significant elevations for liver enzymes or creatine kinase.

The safety data were not unexpected based on previous studies, but Dr. Lau speculated that physicians might not be treating to LDL goals because they start with low doses and uptitrate slowly due to safety concerns. He questioned this practice, noting that numerous large trials have eliminated the concern over the potential for dose-related risks such as rhabdomyolysis. Rather, significant side effects have been rare and sporadic, appearing to be equally common on lower doses of early-generation statins as they are on the most potent newest statins. In patients who develop one of the uncommon adverse events associated with statins, it is often possible to switch statins without recurrence of the event.

According to Dr. Lau, “There is no justification for not using the most potent statin to reach treatment goals. Physicians should be using adequate doses, including an adequate starting dose, to reach treatment goals efficiently and effectively.”

LAP2 Survey

In the most recent data from the Lipid Treatment Assessment Project 2 (LAP2), a multinational survey to assess the proportion of patients at lipid goals in nine countries, including Canada, 67% of high-risk patients were at LDL goal (Waters et al. Circulation 2009;120:28-34). While this is a major improvement from previous surveys, including LAP1, which found that less than 40% of high-risk patients were at goal, it means that one-third of high-risk patients, almost all of whom are already taking a statin, have not reached a level of LDL defined in evidence-based trials as protective from vascular events. The authors of LAP2 further noted that only 30% of coronary heart disease (CHD) patients with two or more risk factors were at a goal of <1.8 mmol/L, which has been associated with even greater benefit than <2.0 mmol/L in several studies, including TNT (Treatment to New Targets).

As experts discussed here at the CCC, failure to reach treatment goals appears to be largely the result of physician-driven decisions to introduce statins at doses that are too low and then to uptitrate too slowly. As statins are extremely well tolerated even at relatively high doses, physicians rather than patients are implicated as the major factor in the failure to treat to goal. The benefit of reaching the goals includes the potential of protection from fatal events. In the new CCS Cholesterol Guidelines, monotherapy with a potent statin in an adequate dose is recommended as the preferred strategy. The guidelines state that most patients can expect to reach goals on a single agent, but Dr. Lau suggested that the goals are important and adequate therapy should be pursued even when monotherapy is not sufficient.

Based on ADAPT, which suggests that a small but substantial proportion of DM2 patients will not be able to reach treatment goals on 40 mg rosuvastatin, Dr. Lau stated that he would add a second agent if needed because of the evidence that a LDL level <2.0 mmol/L is protective, independent of the means with which it is reached. He indicated that other agents, such as ezetimibe, are indicated when rosuvastatin alone is not sufficient. He reiterated that second agents could be avoided in the majority of patients if an effective dosing scheme such as the one described in ADAPT is provided.

Summary

A multicentre Canadian study has demonstrated that most patients with diabetes can reach an LDL goal of <2.0 mmol/L if started on an adequate dose of a potent statin. The proportion rises to >80% with a single upwards titration. These findings are likely to be relevant to the management of other high-risk groups who are indicated for the same LDL goal. Like previous surveys, the most recent data suggest that substantial proportions of high-risk patients on a statin are not currently at the treatment goal with the potential for avoidable vascular events, including those that are life-threatening. The lack of adequate statin therapy appears to be a major factor in the substantial numbers of high-risk individuals with LDL above goal.