INTERVIEW




Lawrence A. LEITER, MD, FRCP, FACP
Endocrinology and Metabolism Division
St Michael’s Hospital University of Toronto
Toronto, Ontario CANADA

What are the most important breakthroughs of the last 25 years in the field of diabetes?

Interview wi th L. A. Leiter, Canada

Diabetes mellitus, the most rapidly evolving pathology in the world, is associated with staggering costs and burdens due to diabetic complications that lead to consequent morbidity and mortality. Fortunately, over the past twenty-five years, diabetes has been a field characterized by major breakthroughs in several areas, including its pathophysiology, diagnosis, prevention, and clinical management. Over this time period, we have also benefited from the results of a large number of well-conducted randomized clinical trials, which have provided important evidence of the optimal management of diabetes, both to help improve glycemic control as well as to prevent the potentially devastating long-term complications of diabetes. These trials have served to inform evidence-based diabetes clinical practice guidelines that have been introduced in most jurisdictions around the world. Finally, we have also had a large number of new therapies and technologies introduced, which have also helped to revolutionize the management of diabetes.

Medicographia. 2011;33:72-76 (see French abstract on page 76)



WHAT ARE THE MOST IMPORTANT BREAKTHROUGHS OF THE PAST 25 YEARS…


…in the field of diabetes pathophysiology?
First of all, over the past 25 years, the “glucose hypothesis” has finally been proven. Based on clinical trial evidence in both type 1 and type 2 diabetes (Diabetes Control and Complications Trial [DCCT], United Kingdom Prospective Diabetes Study [UKPDS], Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation [ADVANCE], etc) on the value of glucose reduction in the prevention of the complications of diabetes, especially microvascular ones, there is no doubt that hyperglycemia plays a direct role in the pathophysiology of diabetic complications. At the same time, a number of putative mediators have been proposed, including increased levels of sorbitol and increased advanced glycation end products. Work from Michael Brownlee et al has resulted in a socalled “unifying hypothesis.” It has been shown that glucose-induced activation of protein kinase C isoforms, increased glucose flux through the aldose reductase pathway, and increased formation of glucose-derived advanced glycation end products all lead to increased reactive oxygen species. There has also been much interest in insulin resistance as a pathogenetic abnormality. There remains controversy with regard to the exact pathophysiology of metabolic syndrome and whether it, by itself, imparts additional risk above and beyond that of its component risk factors. There is no doubt, however, that there is clustering of abnormalities in glucose intolerance, dyslipidemia, and hypertension and that these are commonly associated with increases in insulin resistance, increases in visceral fat, and a proinflammatory state. Meta-analyses have suggested that the presence of metabolic syndrome is associated with about a 1.5- to 2-fold increase in cardiovascular risk above and beyond that imparted by traditional risk factors. There is also a better understanding that increases in visceral fat may be associated with these various metabolic abnormalities, leading to increased risk for cardiovascular (CV) disease, although some recent data suggest that it might actually be increases in hepatic fat rather than visceral fat that are the key pathogenetic abnormality.

One of the many key contributions of UKPDS was the clear description of the progressive nature of type 2 diabetes as a result of progressive β-cell failure. It now appears that this is multifactorial in origin and results from glucose toxicity, lipotoxicity, deposition of amyloid, as well as other factors. There has also been increasing evidence on the importance of glucose toxicity in contributing to both β-cell failure as well as insulin resistance. The improvement in β-cell function and insulin resistance associated with the new sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitors has helped to confirm this hypothesis in humans.

Over the past 25 years, we have also accrued a huge body of evidence on the role of the incretin system in the pathophysiology of not just type 2 diabetes, but perhaps also its complications. Patients with type 2 diabetes have decreased levels of the two major incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory poly-peptide (GIP), leading not just to decreased insulin secretion, but also increased levels of glucagon.

…in the field of diabetes diagnosis and prevention?
The criteria for diabetes and earlier states of glucose abnormalities have evolved.We now donot just have impaired glucose tolerance (IGT), reflective of a postprandial glucose abnormality, but also impaired fasting glucose (IFG), reflective of borderline high fasting glycemia. Although they have been collectively termed prediabetes, there has been opposition to this term, and thus alternate terms are being discussed. Nonetheless, there is no doubt that there is much greater awareness that glucose tolerance should not be considered a dichotomous variable and that intermediate states of glucose intolerance, or “dysglycemia,” can be associated with increased risk for cardiovascular disease as well as diabetes. This has led to a series of diabetes prevention studies. Evidence from three large randomized controlled trials, the Chinese Da Qing Study, the US Diabetes Prevention Program, and the Finnish Diabetes Prevention Study, have provided compelling evidence that intensive lifestyle intervention can prevent or delay the development of diabetes in individuals with IGT. In addition, we now have data that antihyperglycemic agents, including metformin, acarbose, rosiglitazone, and pioglitazone, can also reduce progression of IGT to diabetes mellitus. The most recent of the diabetes prevention trials, the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, was the first diabetes prevention trial to be designed and powered to find out whether the prevention of diabetes is also associated with a reduction in CV disease risk. Although valsartan exerted a modest 14% reduction in the development of new diabetes, neither valsartan nor nateglinide had any impact on CV events.

…in the field of diabetes clinical management?
The increased use of self-monitoring of blood glucose (SMBG) has allowed us to improve glycemic control while minimizing risk for hypoglycemia in our insulintreated patients. At the same time, it has recently been questioned whether the use of SMBG actually improves glycemic control in non–insulin-treated patients. Many of these stud- ies have not adequately assessed this question, as patients were not necessarily provided with adequate information as to what to do with the results of their testing. Nonetheless, these studies have certainly raised awareness that the use of SMBG by itself may not necessarily improve glycemic control. Rather, it is a tool to provide information that can be utilized by a properly educated patient in collaboration with a diabetes healthcare team to improve glycemic control.

Another major advance has been the routine use of glycated hemoglobin (HbA1c) to monitor glucose control in patients with diabetes. There is no doubt that the routine use of this test has revolutionized diabetes care in that it has provided both clinicians and patients with a proper estimate of overall glycemic control. …in the field of diabetes clinical trials?

Over the past 25 years, evidence-based medicine has entered the diabetes world, and we now have the results of a large number of clinical trials to help influence clinical practice as well as guideline recommendations. The 1993 publication of the main results of the DCCT proved convincingly for the first time that improved glycemic control could prevent the long-term microvascular complications of diabetes. In the original trial period, however, there was no reduction in macrovascular events. With passive follow- up of patients for an additional ten years, it become evident that intensive insulin therapy was also associated with a 42% reduced risk for the primary CV composite end point and a 57% reduced risk for the typical major adverse clinical event (MACE) composite of nonfatal myocardial infarction, stroke, or CV death. This long-term influence of early good glycemic control on clinical outcomes has been termed “metabolic memory” or “glycemic legacy.” More recent results from three large trials designed to look at the effects of intensive glycemic control on the macrovascular complications of diabetes, the Action to Control CardiOvascular Risk in Diabetes (ACCORD), ADVANCE, and the Veterans Affairs Diabetes Trial (VADT), confirmed the benefit of good glycemic control on microvascular complications, but did not show significant benefit in any of these studies individually on macrovascular events. When the results of these studies were meta-analyzed, however, an overall 15% reduced risk of myocardial infarction was observed. Furthermore, these study results probably minimized the potential benefits of improved glycemia as the difference in HbA1c between the intensive and standard therapies was only about 1%. The results of the extended follow-up of UKPDS, which demonstrated a significant reduction in risk for myocardial infarction and for total mortality that was not observed at the end of the initial intervention, were not only consistent with glycemic legacy, but also demonstrated that the reduction in CV events with improved glycemia may take longer than that observed with reduction in low-density lipoprotein cholesterol (LDL-C) or blood pressure lowering. Although an increase in mortality was observed in the ACCORD study, which has led some individuals to back away from striving for good glycemic control, the ADVANCE study, using gliclazide-based therapy, did not have a similar increase in mortality, despite the achievement of relatively similar HbA1c levels. The most recent analyses from ACCORD would suggest that the increased mortality was not, as initially suggested by some observers, a result of HbA1c targets that were too low, achieved too quickly, or a consequence of hypoglycemia, but rather a result of “unsuccessful” intensive therapy.

…in the field of diabetes complications?
One of the major paradigm shifts in diabetes care over the past 25 years has been a shift away from the “glucocentric” approach to the prevention of diabetes complications. The dramatic benefit of lipidloweringwith statins to reduce macrovascular risk has been demonstrated in patients without known coronary artery disease (CAD), in studies like the Collaborative AtoRvastatin Diabetes Study (CARDS), and in those with known CAD, in studies like the Treating to New Targets (TNT) study. Nonetheless, there have been more, recent attempts at further reducing the high residual risk observed in diabetes by using combinations of lipid-lowering drugs. In the ACCORD Lipid trial, no additional benefit was observed with the routine addition of fenofibrate to simvastatin in about 5500 patients with type 2 diabetes (although there was potential benefit in the subgroup of patients with high triglyceride and low high-density–lipoprotein cholesterol [HDL-C] levels). Studies investigating combinations of statins with various other HDL-C–raising therapies, including niacin and cholesteryl ester transfer protein inhibitors, are ongoing.

A large number of blood pressure–lowering trials, including the Hypertension Optimal Treatment (HOT) trial and UKPDS, have demonstrated the value of intensive blood pressure lowering in diabetes. Furthermore, in the ADVANCE trial, a combination of perindopril and indapamide was associated with a significant reduced risk of complications in a group of patients whose blood pressure averaged 135/75 mm Hg versus the standard treatment group, in whom the average blood pressure was 140/77 mm Hg. In contrast, in the ACCORD Blood Pressure trial, using a combination of various antihypertensives, no additional overall benefit was observed when a systolic blood pressure of 120mmHg versus 140mmHg was aimed for, although a 41% reduced risk for stroke was observed. The results with the angiotensin-converting enzyme (ACE) inhibitors ramipril and perindopril in the Heart Outcomes Prevention Evaluation (HOPE) and ADVANCE trials, respectively, and with the angiotensin receptor blocker (ARB) telmisartan in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study, have also demonstrated the vascular protective benefits of these drugs, even in patients with diabetes without hypertension. The Steno 2 trial highlighted the importance of a multifactorial approach to cardiovascular risk reduction with a 50%-60% reduced risk for both micro- and macrovascular complications over the initial 8 years of follow-up and a 46% reduced risk of mortality after an additional 5 years of follow-up.

The risk of kidney complications was also dramatically reduced. The glycemic control and blood pressure–lowering trials mentioned above were all associated with renal benefits as well. Furthermore, a large number of trials, employing primarily ACE inhibitors in type 1, and ARBs in type 2, diabetes, have shown reductions in proteinuria and progression of renal disease. Although the ONTARGET trial did not show a benefit in adding an ARB to an ACE inhibitor on renal or cardiovascular end points, the ongoing ALiskiren Trial In Type 2 diabetes Using carDio-renal Endpoints (ALTITUDE) will address the potential additional benefit of adding the direct renin inhibitor aliskiren to an ACE inhibitor or ARB on cardiorenal end points.

Finally, the treatment of diabetic retinopathy has also dramatically altered over the past 25 years. Both strict glycemic and blood pressure control have been shown to prevent the onset and progression of retinopathy. Laser photocoagulation has been demonstrated to benefit both severe nonproliferative and proliferative retinopathy as well as clinically significant macular edema, while surgical vitrectomy has been shown to result in better visual recovery in patients with advanced proliferative retinopathy. More recently, intraocular injections of pharmacologic interventions, including anti–vascular endothelial growth factor (anti-VEGF) agents and steroids, have also shown promise for the treatment of macular edema and retinal neovascularization.

…in the field of diabetes clinical management?
Multiple new medications have become available for the treatment of type 2 diabetes. While metformin and the sulfonylureas continue to be widely utilized, new classes of antihyperglycemic agents that have been launched over the past 25 years include alpha glucosidase inhibitors (acarbose), thiazolidinediones (rosiglitazone, pioglitazone), dipeptidyl peptidase 4 (DPP-4) inhibitors (sitagliptin, vildagliptin, saxagliptin), and GLP-1 analogues (exenatide, liraglutide). There has also been a move towards early combination therapy of antihyperglycemic agents. The greater number of available medications has provided the clinician with more therapeutic choices and more opportunities to individualize therapy. At the same time, we are still lacking the clinical trials to guide us on how best to utilize these medications, in terms of which drugs to use and in what therapeutic order.

Another major advance has been the availability of newer insulin analogues. The rapidly acting analogues (aspart, lispro, glulisine) are associated with greater convenience for our patients as well as better postprandial control and reduced risk of hypoglycemia. Similarly, the long-acting insulin analogues (detemir, glargine) are also associated with a reduced risk for hypoglycemia as well as less day-to-day glycemic variability. Insulin pens have made it easier for our patients to use insulin.

There has been increasing use of insulin pumps, primarily in the treatment of type 1 diabetes, as well as of the somewhatless- complex patch pumps. Pump therapy is associated with better glycemic control for patients with increased HbA1c levels, reduced frequency of hypoglycemia, less glycemic variability, and a general improvement in quality of life. The more recent availability of real-time continuous glucosemonitors has further improved our ability to properly assess and minimize glycemic excursions. As a result, there is increasing optimism that the integration of continuous glucose monitors into insulin pumps will result in the availability of the long-awaited “closed-loop” insulin pump in the not too distant future.

A major change in the way that we have managed diabetes over the last 25 years has been the emergence of clinical practice guidelines. Guidelines from various organizations from around the world have suggested treatment targets, algorithms, and other treatment recommendations to help improve outcomes in patients with diabetes. Unfortunately, there remains ongoing evidence of a significant treatment gap, with many of our patients not reaching treatment targets. Renewed efforts at knowledge translation must be employed in order to get more patients to goal and subsequently improve clinical outcomes. _

Keywords: diabetes mellitus; breakthroughs; pathophysiology; diagnosis; prevention; clinical management; clinical practice guidelines