Marcus Cuffie Pharm. D. Candidate Preceptor: Dr. Ali Rahimi September 23, 2011

1. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised[sic] trial Griffon S, Borch-Johnsen K, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. Lancet. 2011 July 9; 378(9786): 156-167. Funding: National Health Service Denmark, Various Research Councils, Novo Nordisk, Astra, Pfizer, GSK, Merck, et al. Marcus Cuffie Pharm. D. Candidate Preceptor: Dr. Ali Rahimi September 23, 2011

2. Class I, Level A

3. Background • Type 2 diabetes is increasingly prevalent in the United States • 25.8 million Americans have diabetes • An estimated 79 million people have prediabetes • Type 2 diabetes leads to many detrimental complications. • Leading cause of kidney failure • Leading cause of blindness • Leading cause of nontraumatic lower-limb amputations

4. Background • Risk of cardiovascular events and death can be halved among patients with longstanding diabetes and microalbuminuria by intensive multifactorial treatment. • Type 2 diabetes is detectable well before it is clinically diagnosed. • No research into whether intensive multifactorial treatment has a benefit in early type 2 diabetes

5. Objective • To investigate whether early intensive multifactorial treatment improves outcomes when started between detection by screening and clinical diagnosis.

6. Patient Population Exclusion Criteria • 3055 Registered patients in 343 general practices • Men and Women Ages 40-69 Predominantly white (around 90%) • BMI: 31.6 • Average systolic BP of 150 • Average total cholesterol of 5.6mmol/L • Average HbA1c of 6.6% • (Denmark, n=1533; Cambridge, UK, n=867; Netherlands, n=498; and Leicester, UK, n=159). • Illness with a life expectancy of <12 months • Psychological or psychiatric disorders • Pregnant /Lactating • Housebound • Already diagnosed with diabetes Methods - Population

7. Methods - Design • Two phases: • Screening phase: varied from site to site • Treatment phase: Randomized, parallel-group trial in Denmark, the Netherlands, and the UK. • Provided either routine diabetes care or intensive multifactorial treatment in a 1:1 ratio. • Randomization included stratification • Patients were unaware of their general practice’s group assignment.

8. Intervention HbA1c= glycosylated hemoglobin,. CCB = calcium channel blocker. ACE = angiotensin converting enzyme. IHD = ischemic heart disease, CVD = cardiovascular event. BP = blood pressure.

9. Intervention • For the routine care group, family physicians were only provided with diagnostic test results. Patients received standard diabetes care, according to the recommendations applicable in each center.

10. Endpoints • Primary endpoint: • A composite of first cardiovascular event: including cardiovascular mortality, cardiovascular morbidity (non-fatal myocardial infarction and non-fatal stroke), revascularization, and non-traumatic amputation. • Secondary endpoint: • The individual components of the primary endpoint and all-cause mortality • Assessed after 5 years

11. Statistical Analysis • To assess intervention effects Cox’s regression was used to estimate hazard ratios and 95% CI within each center. • For total mortality, Kaplan-Meier estimates of cumulative incidence were calculated.

12. Statistical Analysis Cox regression model: • A regression technique that allows adjustment for known differences in baseline characteristics between intervention and control groups applied to survival data • Survival analysis takes the survival times of a group of subjects and generates a survival curve, which shows how many of the members remain alive over time.

13. Statistical Analysis Kaplan Meier Curve • Used to measure the fraction of patients living for a certain amount of time after treatment • In most studies, you don’t have the luxury of waiting until the very last subject has died of old age; you normally have to analyze the data while some subjects are still alive. Kaplan Meier also takes into account subjects that may have moved away, and may be lost to follow-up.

14. Statistical Analysis • Number Needed to Treat: 78 • Hazard ratio: 0.84 • Relative risk reduction: 16% • Absolute risk reduction: 1.3%

15. Results • Cardiovascular events and all cause mortality. • 138 first time cardiovascular events occurred • 117(8.5%) in the Routine Care group • 121(7.2%) in the Intensive Treatment group • Reported Hazard ratio: 0.83 (0.65-1.05), p value= 0.12. • The combined HR for death in the intensive treatment group compared with the routine care group was 0.91 (95% CI 0·69–1·21). • 6.7% died in routine care • 6.2% died in intensive treatment

16. Discussion • Associated with slightly, but significantly, increased prescription of treatments and improvements in cardiovascular risk factors. • Non-significant relative reduction in the incidence of cardiovascular events at 5 years between groups.

17. Conclusion • This trial shows that screening for type 2 diabetes and early intensive multifactorial treatment of the detected patients are feasible in general practice. • In both study groups, cardiovascular risk factors, such as blood pressure and cholesterol concentrations, improved notably after diagnosis and glycemia and weight did not increase. • Small incidence of primary risk factor may be due to improved treatment in the routine care group • Based on this trial, intensive treatment is not necessary in early diagnosed type 2 diabetes patients.

18. Evaluation • Strengths • Large sample size • Patient sample representative to European population • Controlled and blinded • Limitations • Non-standard treatments • Lower than expected event rates • Variability between and within sites. • What was the routine care group like?

19. Evaluation • Intense treatment showed no benefit • Not statistically or clinically significant • The importance of screening • Decreased the expected endpoint • ACCORD trial • Intensive blood pressure and combination lipid therapies do not reduce combined cardiovascular events in adults with diabetes • More people in the intensive blood sugar group died

20. References • Griffon S, Borch-Johnsen K, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. Lancet. 2011 July 9; 378(9786): 156-167.