"Landmark trials are very important in clinical practice because they practically guide the clinician on how to choose the right modality of treatment, based on evidence-based facts," said Dr. Marie Yvette Rosales-Amante, an endocrinologist at Asian Hospital. "On the other hand, it can prove to be confusing to the doctor who does not have a keen eye for analyzing medical literature, since there are just too many clinical trials out there."
She added: "If we indiscriminately accept all the data presented to us, our patients will likely end up with multiple drugs for any purpose under the sun."
Rosales-Amante's caution is understandable: the management of diabetes mellitus (DM) continues to evolve, with perspectives shifting regularly with the currents of numerous completed, ongoing, and planned large-scale trials.
MEDICAL OBSERVER offers a summary of the ways some landmark trials have shaped and are continuing to shape the landscape of diabetes care.
Evolving guidelines: Blood-pressure control
The UK Prospective Diabetes Study (UKPDS) is arguably the landmark of landmark diabetes studies. First presented in September 1998, the results of UKPDS laid down some of the foundations for basic principles of diabetes management still in use today.
"UKPDS was the first large clinical trial of type 2 DM which provided proof that sugar and blood-pressure control are vital in preventing complications," said Rosales-Amante.
The 20-year trial involved 5,102 patients with type 2 diabetes in 23 clinical centers in England. Its latest arm, UKPDS 75, looked into 4,320 patients from the main arm, and its results were published earlier this year.
In a nutshell, UKPDS demonstrated that better blood-glucose and blood-pressure (BP) control reduces the risk of complications due to diabetes, raising the oft-repeated question: how low should you go?
"For the first time there were targets for sugar and BP control in type 2 DM, the values of which continue to decrease over the years," Rosales-Amante noted. "It also showed us that type 2 DM is a truly progressive disease, that patients will need multiple medications over the years in order to achieve the target goals of sugar and BP."
UKPDS 75 found that glucose and BP control together reduced risks better than either treatment approach alone. Specifically, the study found that the effects of glucose and BP control were additive, with a 21-percent reduction in risk per one-percent reduction in glycosylated-hemoglobin (HbA1c) levels, and an 11-percent risk reduction per 10 mm Hg reduction in systolic BP.
"UKPDS is important because it was able to prove many concepts about type 2 DM complications," said Rosales-Amante.
For BP control, it is now generally accepted that systolic BP levels of 135 mm Hg or lower and diastolic BP levels of 80 mm Hg or lower are ideal, but the exact number for glucose control remains uncertain. Current evidence suggests that the lower you go with blood glucose in diabetics the better, and current treatment targets glucose levels of six mmol/L or less.
UKPDS used a beta-blocker and an angiotensin-converting-enzyme (ACE) inhibitor to control BP, and found no difference between the two families of antihypertensive agents, concluding that what matters is BP control itself, not the agent. However, the results of more recent studies, such as the Irbesartan in Diabetic Nephropathy Trial (IDNT), the Irbesartan in MicroAlbuminuria type 2 (IRMA 2) and Reduction in Endpoints in Non-insulin-dependent diabetes mellitus with the Angiotensin-II-Antagonist Losartan (RENAAL) suggest that angiotensin-receptor blockers (ARBs) may provide reductions in risk beyond that explained by their antihypertensive effects.
"We cannot ignore the fact that many studies provide evidence that there is protection provided by ACE inhibitors and ARBs independent of BP control," Rosales-Amante commented on the latter studies. "What we need is more head-to-head studies of ACE inhibitors v. ARBs v. beta-blockers v. calcium-channel blockers v. diuretics, all in one study."
Lipid control
With obesity now implicated in the pathogenesis of diabetes, lipid levels have come into focus as another target of diabetes management. Not that the idea is all that new. According to Dr. Ruby T. Go, chief of endocrinology at Chinese General Hospital, who talked about lipid trials at the annual convention of the Philippine Diabetes Association (PDA) held in November, the concept goes as far back as 1927.
"From an excess of fat diabetes begins, from an excess of fat diabetics die," she quoted Dr. E.P. Joslin, a diabetologist from Boston who has also been recognized by Dr. Frederick Banting, who in turn is best known for coining the term Syndrome X, the intertwining of heart disease and diabetes that still sparks controversy today.
The value of lipid control has been further highlighted by recent landmark clinical trials. Over the years, the World Health Organization (WHO), International Diabetes Foundation (IDF), and National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) have all formulated guidelines for cholesterol levels based on the results of several lipid trials. The most notable of these trials are the following-the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT), the Heart Protection Study (HPS), the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT), the PRavastatin or atorVastatin Evaluation and Infection Therapy (PROVE-IT) trial, the REVERSal of Atherosclerosis with Lipitor (REVERSAL) trial, the Myocardial Ischemia Reduction with Aggressive Cholesterol Reducation (MIRACLE) trial, and the Collaborative AtoRvastatin and Diabetes Study (CARDS).
Based on these studies, the most recent guidelines for lipid control provided by NCEP-ATP III recommend low-density-cholesterol (LDL-C) levels less than 100 mg/dl, with an optional goal of less than 70 mg/dl for patients at particularly high risk for cardiovascular disease.
The Fenofibrates Intervention and Event Lowering in Diabetes (FIELD) trial is a recent study that looked into the possible addition of fenofibrates in the lipid-lowering armamentarium of diabetics. Go, who also presented the results of the trial to the local medical community at the 11th joint convention of the Philippine Society of Hypertension and Philippine Lipid Society earlier this year, called FIELD the "largest study concentrating purely on diabetics."
However, clinicians are divided over the results of FIELD in terms of the use of fenofibrates. On the results of FIELD, Rosales-Amante was herself cautious: "Personally, I did not change the way I treat my patients with type 2 DM with dyslipidemia based on the FIELD study. Again, we would like to see head-to-head studies of gemfibrozil v. fenofibrate v. atorvastatin, etc."
Nonetheless, the study does provide further evidence for the value of controlling lipid levels to lower cardiovascular risks in diabetics, further consolidating lipids as an important target for comprehensive diabetes management.
Intensive glycemic control
While recent studies highlight strict control of blood pressure and lipid levels as integral to complete diabetes management, there is no doubt that the control of blood-sugar levels remains at the heart of diabetes treatment. Dr. Roberto Mirasol, an endocrinologist at St Luke's Medical Center who also established the diabetes clinic of Rizal Medical Center, also talked at the PDA annual convention about landmark clinical trials and intensive diabetes management.
Among the more influential of recent studies he cited were the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial and several studies done on intensive-care-unit (ICU) patients and post-CABG patients. Based on these studies, said Mirasol, current guidelines for glycemic control as provided by the American Diabetes Association (ADA) and the American College of Endocrinology (ACE) target maximal glucose levels of less than 180 mg/dl. The ADA specifically recommends a range of 90 to 130 mg/dl for diabetic patients in general wards, with 180 mg/dl as an acceptable upper limit, and blood-glucose levels less than 110 mg/dl for ICU patients. The ACE prefers target levels of less than 110 mg/dl for both ICU and general-ward patients.
Diabetes prevention
Clinicians have often wondered whether diabetes can, in fact, be prevented. Until relatively recently, diabetes had been seen as a chronic progressive disease that seemed an inevitable fact of life for people predisposed to the condition. As the pathogenesis of the disease becomes clearer, however, with advancing discoveries such as the identification of obesity as a significant etiological factor, the perspective of clinicians and researchers on the matter now faces a significant shift.
"Several prevention trials in type 2 diabetes have shown that intensive lifestyle modification, metformin and acarbose can prevent the progression of patients with prediabetes, IGT (impaired glucose tolerance) or IFG (impaired fasting glucose) to type 2 diabetes," said Dr. Edith Arceo-Dalisay. Arceo-Dalisay, chair of the Nutrition Council of the PDA, talked about the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial at the 2006 PDA convention.
According to Arceo-Dalisay, DREAM is the largest diabetes-prevention trial to date, coming at the heels of several other studies including the following: Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), which focused on the use of acarbose for preventing diabetes progression; ACE inhibitor studies including the Heart Outcomes Prevention Evaluation (HOPE) trial, the Prevention of Events with Angiotensin-Converting-Enzyme Inhibition (PEACE) trial, the EUropean trial On Reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA), and the Studies Of Left Ventricular Disfunction (D-SOLVD); and ARB trials, particularly the Study on Cognition and Prognosis in the Elderly (SCOPE) and the Candesartan cilexitil in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM). Other prevention studies that have shown promising results include the Finnish Diabetes Prevention Study and the US-based Diabetes Prevention Program (DPP).
DREAM compared the ACE-inhibitor ramipril with the thiazolidinedione (TZD) rosiglitazone in preventing diabetes progression. The DREAM researchers found that rosiglitazone has "a substantial benefit on the prevention of diabetes and regression to normoglycemia," while ramipril has a "modest benefit on regression to normoglycemia." Specifically, while the researchers could not recommend ramipril for preventing diabetes, their data showed that rosiglitazone reduced progression to diabetes, the study's primary outcome, by more than 60 percent. They concluded that "for every 1,000 people treated with rosiglitazone for ~3 years, 144 cases of DM will be prevented with an excess of ~4 cases of CHF (Congestive Heart Failure)," thereby providing a candidate drug for diabetes prevention.
While the evidence of DREAM and other trials show that diabetes can be prevented, the question remains: how do clinicians identify candidates for receiving treatment to prevent diabetes? How should patients be chosen for screening and what is the best method for screening for prediabetes, a concept that, while still controversial, is currently gaining ground in endocrinological practice? What parameters should be measured, what limits should be used to identify a patient as "at risk" without yet being diagnosed as a diabetic?
More questions will no doubt arise as we learn more about this condition, and clinicians will continue to look to RCTs, the landmarks of medical science to guide the way to better diabetes management.
"There are more diabetes drugs coming out, completely new classes of drugs," said Rosales-Amante, contemplating the landscape of research. "This may mean more sophisticated options for treatment, but the bottom line will not change: diabetes still has no cure, we need to control sugar, BP, and lipids so patients will live better and longer."
She concluded: "We need more research for a cure: islet cell transplant, gene therapy," hinting at the possible shape of diabetes research and management to come. M
