Do we focus enough on clinical outcomes when treating patientswith type 2 diabetes?



Do we focus enough on clinical outcomes when treating patients with type 2 diabetes?

1. A. S. Ametov, Russia
2. Ş. Çetinkalp, Turkey
3. P. Conthe, Spain
4. E. Giorgadze,Georgia
5. H. Iraqi, Morocco
6. M. Kamar, Egypt
7. M. T. Malecki, Poland
8. J. C. Mbanya, Cameroon
9. T. K. Nguyen, Vietnam
10. M. Rizzo, Italy
11. J. E. N. Salles, Brazil
1. A. S. Ametov, Russia

Professor Alexander S. AMETOV, MD
Russian Academy for Advanced Medical
Studies, Moscow, RuSSiA
(email: alexander.ametov@gmail.com)

In an attempt to explain why we are not particularly successful at treating type 2 diabetes mellitus (T2DM), despite the expenditure of enormous effort in achieving and maintaining optimal glycemic control, researchers have proposed the concept of “natural” history of the disease. In my opinion, there is nothing “natural” about the history of T2DM. The diabetes care system is simply too slow. Treatment initiation occurs too late, when a negative “legacy effect” is almost established. Even if glycemic control is achieved, there is little to no chance of changing anything.

Therefore, the time has come to seriously think about primary prevention in T2DM, maximizing early diagnosis and early initiation of the most effective, long-term, and safe ways to manage this severe and chronic disease.

Hyperglycemia is the hallmark of diabetes, and despite some discussion, glycemic control remains a major target for preventing chronic complications. The benefits of glycemic control have been clearly demonstrated in the United Kingdom Prospective Diabetes Study (UKPDS),1 which showed that intensive glucose-lowering treatment aimed at a target glycated hemoglobin (HbA1c) <7% was associated with a reduction in the risk of major vascular events, mainly microvascular, of 37%. A nonsignificant reduction in the relative risk of myocardial infarction of 16% was also observed. Similar results were obtained in the Kumamoto study.2

In ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation),3 the achievement of lower levels of HbA1c in the intensive treatment group compared with the standard treatment group (6.6% vs 7.3%) was associated with a clear reduction in the risk of combined major macro- and microvascular events (hazard ratio [HR], 0.9; 95% CI, 0.82-0.98; P=0.01). However, these results differ to those from other studies, like VADT (Veterans Affairs Diabetes Trial) and ACCORD (Action to Control CardiOvascular Risk in Diabetes).4,5 In the VADT study,4 mean HbA1c was reduced to 6.9% in the intensive group and 8.4% in the standard group. However, there was no significant between-group difference in the risk of cardiovascular events or glycemic control– related mortality (HR, 1.07; 95% CI, 0.81-1.42; P=0.62), as well as in the risk of microvascular events. ACCORD was terminated prematurely due to higher mortality associated with intensive glycemic control.5 Combined analysis of the three studies,6 nevertheless, showed that intensive glycemic control reduces the risk of cardiovascular disease without increasing the risk of mortality and that early intensive therapy delays the development and progression of diabetes complications.

Normal HbA1c values are often considered an indicator of adequate diabetic care, but this is a generalization that could be far from true in daily practice. HbA1c is a cumulative and integral indicator of glycemic status over the past 3 months; it does not reflect glucose fluctuations over 24 hours. 24-Hour variation in glucose level can be substantial and lead to severe complications.

Parameters of glycemic control do not reveal the actual duration of disease or status of pancreatic β cells, which is noteworthy as the efficacy of many treatments depends on the preservation of β cells.

The risk of macrovascular events rises in parallel with progression of diabetes, so it is crucial to take action early to reduce the risk of these events in the earliest stages of glycemic disturbance rather than when diabetes mellitus appears, by which time it is too late to regress the disease.

Long-term glycemic control over ≥11 years, as in the DCCT (Diabetes Control and Complications Trial), UKPDS, Steno-2, EDIC (Epidemiology of Diabetes Intervention and Complications), and ADVANCE-ON (ObservatioNal study)1,7 studies, is associated with a positive “legacy effect,” a reduction in the risk of microvascular events, and improvement in outcomes. ■

References
1. uK Prospective Diabetes Study (uKPDS) Group. intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (uKPDS 33). Lancet. 1998; 352(9131):837-853.
2. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care. 2000;23(suppl 2):B21-B29.
3. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
4. Duckworth W, Abraira C, Moritz T, et al; VADT investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360(2):129-139.
5. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545- 2559.
6. Macisaac RJ, Jerums G. intensive glucose control and cardiovascular outcomes in type 2 diabetes. Heart Lung Circ. 2011;20(10):647-654.
7. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.

 

2. Ş. Çetinkalp, Turkey

Prof Dr Şevki ÇETINKALP, Prof Dr Şevki ÇETINKALP, MD
Department of Endocrinology and
Metabolism, Ege university Faculty of
Medicine, izmir, TuRKEY
(email: scetinkalp@hotmail.com)

Treatment initiation with metformin in patients with newly diagnosed type 2 diabetes is indispensable. All international guidelines have reached a consensus on this, and all combination therapies should contain metformin if there is no contraindication to its use. Is metformin indispensable because it is a more effective antihyperglycemic agent? Not really, according to the United Kingdom Prospective Diabetes Study (UKPDS) 34 report. Metformin couldn’t bring glycated hemoglobin (HbA1c) levels to glycemic target; it only reduced them by 0.6%.However, the use of metformin is justified by the considerable protection it affords from macrovascular complications of diabetes, reducing myocardial infarction by 39% and cerebral palsy by 41%. Moreover, it does this with a tolerable side effect profile and without causing weight gain or hypoglycemia. Despite these positive features and guideline recommendations, metformin was chosen as the first-line drug for only 58% of American type 2 diabetics, according to Berkowitz et al.1 Why is this?

In 2009, an important change was made to the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines. Add-on therapies to metformin were classified into two groups: well-validated core therapies and less-well-validated therapies.2 These evidence-based guidelines focused on the prevention of complications. Data from UKPDS, ACCORD (Action to Control CardiOvascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial) influenced the change in direction.

UKPDS showed that a reduction of 1% in HbA1c was associated with a 37% reduction in development of microvascular complications. However, application of an intensive approach for reaching the HbA1c targets did more harm than good in ACCORD and VADT; in the former study, severe hypoglycemia increased cardiovascular deaths by 35% and total mortality by 22%. In contrast, ADVANCE demonstrated that when HbA1c targets are reached without causing severe hypoglycemia using a safe antidiabetic agent, mortality does not increase and nephropathy and cardiovascular deaths were reduced by 21% and 12%, respectively. The impact of this finding was reflected in the treatment algorithm of the International Diabetes Federation 2011 guidelines on type 2 diabetes: “based on the use of gliclazide in the ADVANCE study, the first add on to metformin therapy should be a sulfonylurea.”3

The favorable effects of gliclazide on nephropathy in ADVANCE and ADVANCE-ON (ObservatioNal study) were similarly reflected in the ADA/EASD 2012-2015 treatment guidelines.4 Their aim was to avoid severe hypoglycemia while treating hyperglycemia (based on individual HbA1c targets) as well as to prefer therapies, such as metformin and gliclazide, that reduce development of complications regardless of glycemic control. However, the new treatment algorithm of the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) 2015 guidelines on type 2 diabetes breaks this trend.5 These hypoglycemia-and-weight– focused guidelines state that the first add-on to metformin therapy should be glucagon-like peptide 1 agonists, dipeptidyl peptidase 4 inhibitors, or sodium/glucose cotransporter 2 inhibitors. Unfortunately, no long-term evidence-based studies exist to demonstrate that these options reduce diabetes complications regardless of glycemic control. Furthermore, the concept of patient-tailored treatment is restricted by reasoning that each diabetic individual is obese and insulinresistant.

In conclusion, current type 2 diabetes treatment algorithms focus on hypoglycemia and obesity, which may lead to a decrease in effective HbA1c reduction and the percentage of patients who reach HbA1c target. When choosing an antidiabetic agent based on a mechanistic approach, not only should antihyperglycemic efficacy be considered, but diabetes complications also. Otherwise, we may in future encounter patients who have regulated blood glucose levels with developed diabetic complications. ■

References
1. Berkowitz SA, Krumme AA, Avorn J, et al. initial choice of oral glucose lowering medication for diabetes mellitus: a patient-centered comparative effectiveness study. JAMA Intern Med. 2014;174(12):1955-1962.
2. Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for the Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009; 32(1):193-203.
3. international Diabetes Federation (iDF). iDF treatment algorithm for people with type 2 diabetes. http://www.idf.org/treatment-algorithm-people-type-2-diabetes. Accessed October 20, 2015.
4. inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55(6):1577-1596.
5. Handelsman Y, Bloomgarden ZT, Grenberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology—clinical practice guidelines for developing a diabetes mellitus comprehensive care plan— 2015. Endocr Pract. 2015;21(suppl 1):1-87.

 

3. P. Conthe, Spain

Dr Pedro CONTHE, MD, PhD
Head of internal Medicine, Gregorio Marañón
Hospital; Associate Professor of Medicine
universidad Complutense, Madrid, SPAiN
(email: pedroconthe@gmail.com)

The most frequent cause of death among patients with type 2 diabetes mellitus (T2DM) is cardiovascular disease, and we all know that today the dramatic increase in the prevalence of T2DM in the world raises the prospect of an increase in cardiovascular morbidity and mortality in the coming decades. Cardiovascular disease, the major cause of morbidity and mortality for individuals with T2DM, is the largest contributor to the direct and indirect costs of diabetes. Common conditions coexisting with T2DM (eg, hypertension and dyslipidemia) are clearly risk factors for cardiovascular disease, and diabetes itself confers independent risk.1,2

The Emerging Risk Factors Collaborators study, which included multiple clinical trial data, estimated that, compared with nondiabetics, a diagnosis of T2DM reduces survival in a middle- aged man and 50-year-old woman by 5.8 and 6.4 years, respectively, and that 50% of the difference is explained by cardiovascular mortality.3

These pieces of evidence suggest that there should be more emphasis on these clinical outcomes when choosing therapy and managing the global risk arising from T2DM in the short and long term. Although it is commonly recognized that diabetes is “glycemic by diagnosis,” but “predominantly cardiovascular” in its complications, management of T2DM in practice sometimes focuses exclusively on glucose lowering. In the majority of available records and surveys in our field, only a minority of patients (<10%) have been found to have all risk factors under control.1,3

Control of individual cardiovascular risk factors prevents or slows cardiovascular disease in people with diabetes.4,5 Large benefits are seen when multiple risk factors are addressed globally. The long-term results of the Steno-2 study5 confirm the importance of multifactorial intervention with a particular focus on established risk factors, and it is now generally accepted that lipid-lowering therapy and blood pressure control are essential for lessening macrovascular risk in T2DM.

Also, the metabolic complications of hyperglycemia and hypoglycemia are a rare cause of hospitalization today and, as such, affect the cost of disease less than they once did. Patients are far more likely to be admitted for cardiovascular complications that are more costly and that require longer stays in hospital, specialized monitoring, and multiple treatments.

In 2008, the Food and Drug Administration established guidance for industry to ensure that drugs in development for T2DM should have a beneficial, or at least neutral, effect in relation to cardiovascular outcomes.6 This guidance had consequences on the practice activity of clinicians, by making them reconsider management in terms of a comprehensive strategy rather than one objective, normoglycemia, which had been shown to be too simplistic in the light of available evidence.

Randomized controlled trials have demonstrated that metformin and sulfonylureas are safe and that they reduce micro and macrovascular complications. In contrast, the impact of new diabetes drugs on cardiovascular outcomes remains unclear, as novel drugs should in theory outperform current treatment strategies by providing evidence for efficacy in lowering clinically relevant end points.

It seems clear that a “glucocentric” approach alone is not enough to improve cardiovascular outcomes. The real challenge is to transmit to patients what diabetes means in terms of cardiovascular risk. It is crucial to make patients properly understand the benefit of optimal cardiovascular risk control with different measures, such as making healthy dietary choices, reducing excess weight, and participating in regular physical activity. All this, of course, without them forgetting to control blood glucose, blood pressure, and lipids by taking prescribed medication with good adherence and motivation to achieve personalized goals agreed with their doctors. ■

References
1. inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
2. Stratton iM, Adler Ai, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (uKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-412.
3. Danesh J, Erqou S, Walker M, et al; Emerging Risk Factors Collaborators. The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. Eur J Epidemiol. 2007;22(12):839-869.
4. Menon V, Lincoff AM. Cardiovascular safety evaluation in the development of new drugs for diabetes mellitus. Circulation. 2014;129(25):2705-2713.
5. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580-591.
6. US Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER). Guidance for industry. Diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: Food and Drug Administration; December 2008. http://www.fda.gov/downloads/Drugs/guidanceComplianceRegu latoryinformation/guidances/ucm071627.pdf. Accessed October 21, 2015.

 

4. E. Giorgadze, Georgia

Prof Elene GIORGADZE, MD, PhD
Founding Director of the National institute
of Endocrinology; Associate Professor
iv. Javakhishvili Tbilisi State university
Tbilisi, GEORGiA
(email: elengiorgadze@gmail.com)

In 2015, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) published an updated position statement for the management of patients with type 2 diabetes mellitus.1 The update was necessary due to the growing number of new glucose lowering medications and new data available from outcome trials and meta-analyses of big, randomized clinical trials in the previous three years. As Georgia does not have its own guidelines, doctors mostly use the ADA/EASD position statement. The new position statement, like the previous one, emphasizes personalization and individualization of treatment. Glycemic control remains a major focus of the treatment of patients with type 2 diabetes mellitus (T2DM). However, the pathogenesis of T2DM is complex, with multiple defects in numerous organs, and antihyperglycemic drugs are designed to target one or more of these pathophysiological defects. The number of noninsulin antihyperglycemic drugs is quite high; the most frequently prescribed ones are metformin, sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon- like peptide 1 (GLP-1) agonists, pioglitazone, and most recently sodium/glucose cotransporter 2 (SGLT-2) inhibitors. Importantly, antihyperglycemic medication chosen must be effective and well-tolerated, while avoiding hypoglycemia and weight increase.

Patients with diabetes are at increased risk of mortality and morbidity compared to the rest of the population. So, it is important that alongside good efficacy and tolerability, antidiabetic medication is safe. Based on the meta-analyses of rosiglitazone studies, the American Food and Drug Administration adopted guidance on evaluating cardiovascular risk in new antidiabetic therapy for T2DMin December 2008.2 Older drugs, such as metformin and sulfonylureas, have a long record of use in clinical practice. It is known from UKPDS (United Kingdom Prospective Diabetes Study) that metformin is likely to have a cardiovascular benefit. Sulfonylureas were once viewed with great concern with regard to increased risk of heart disease, but a recently performed meta-analysis of 28 trials with 34 912 patients proved that sulfonylureas do not increase the risk of all-cause mortality.3 Intensive glycemic control reduced the risk of nonfatal myocardial infarction, amputation of a lower extremity, and microvascular complications, but increased the risk of severe adverse events and severe hypoglycemia. There was no significant difference in health related quality of life between the targeting of intensive versus conventional glycemic control.3 The ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial has also demonstrated that an intensive strategy with conventional agents can achieve mean HbA1c levels of 6.5% safely, with no increase in mortality. It is true that there was no significant reduction in macrovascular disease, but the reduction in diabetic nephropathy of approximately 20% was evident.4 DPP-4 inhibitor trials show that these agents, with the exception of saxagliptin, do not increase the risk of hospitalization for heart failure; however, they showed no benefit regarding cardiovascular safety compared with placebo either. GLP-1 agonists and SGLT-2 inhibitors similarly have no cardiovascular safety benefit compared with placebo. Moreover, in rare cases, SGLT-2 inhibitors increase the risk of euglycemic ketoacidosis.

Every day we come to the conclusion that each patient differs and that every diabetes case is unique. Every time we are face to face with a patient in our office, we have to compare the risk and the benefit of each class of antidiabetic agent, taking into account all the data from randomized controlled trials and meta-analyses, and make a decision that best fits this individual patient. ■

References
1. inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
2. uS Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER). Guidance for industry. Diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Silver Spring, MD: Food and Drug Administration; December 2008. http://www.fda.gov/downloads/Drugs/guidanceComplianceRegulatoryinformation/ guidances/ucm071627.pdf. Accessed October 21, 2015.
3. Hemmingsen B, Lund SS, Gluud C, et al. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;11:CD008143.
4. Heller SR; ADVANCE Collaborative Group. A summary of the ADVANCE trial. Diabetes Care. 2009;32(suppl 2):S357-S361.

 

5. H. Iraqi, Morocco

67

Professor Hinde IRAQI, MD
Department of Endocrinology and Diabetology
ibn Sina Hospital, Rue Lamfadel Cherkaoui
Rabat, MOROCCO
(email: hinde.iraqi@gmail.com)

The publication of the United Kingdom Prospective Diabetes Study (UKPDS) in 1998 provided strong support to clinical practice that vigorous treatment of diabetes can decrease the morbidity and mortality of type 2 diabetes mellitus (T2DM) by decreasing its chronic complications. UKPDS also demonstrated that metformin reduced cardiovascular disease in a small subgroup that was overweight, and its postintervention follow-up demonstrated the long-term beneficial effects of intensive glucose control on macrovascular and microvascular events in patients with newly diagnosed type 2 diabetes at study entry.1

Other studies, however, in participants who had more advanced T2DM than those in UKPDS, such as ACCORD (Action to Control CardiOvascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial), suggested no significant reduction in cardiovascular outcomes with intensive glycemic control.

Glucose control remains a major focus in the management of patients with T2DM, but its achievement should always be in the context of a comprehensive cardiovascular risk factor reduction program, which should include smoking cessation, the adoption of healthy lifestyle habits, blood pressure control, and lipid management. In general, guidelines on the management of T2DM recommend metformin as the first-line glycemia- lowering drug because of its possible beneficial impact on all-cause and cardiovascular mortality. In addition, this low cost drug carries a low risk of hypoglycemia and is weight neutral. If glycated hemoglobin (HbA1c) target is not achieved after approximately 3 months, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend considering a combination of metformin and one of these six treatment options: sulfonylurea, thiazolidinedione, dipeptidyl peptidase 4 (DPP-4) inhibitor, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagonlike peptide 1 (GLP-1) receptor agonists, or basal insulin.2 In the latest World Health Organization model list of the most efficacious, safe, and cost-effective medicines—based on the needs of a basic health-care system—only two oral antidiabetic drugs are included: gliclazide and metformin.3

Ideally, glycemia-lowering drugs should be investigated and compared for their effects on hard end points, such as cardiovascular disease, death, and micro- and macrovascular complications. New studies suggest that commonly prescribed drugs for T2DM may not all be equally effective at preventing death and renal or cardiovascular diseases. Each drug has unique advantages and disadvantages, and the question is whether specific types of drugs should be preferred over others in terms of a better efficacy or safety profile.

Randomized controlled trials with DPP-4 inhibitors demonstrated no improvement in cardiovascular outcomes in patients receiving add-on therapy with saxagliptin, alogliptin, and recently sitagliptin versus placebo.4 The studies with saxagliptin and linagliptin showed that active treatment increased the risk of hospitalization for congestive heart failure.

The ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial demonstrated in patients with T2DM that an intensive strategy with conventional agents (including gliclazide MR) can achieve mean HbA1c levels of 6.5% safely, with no increase in mortality. Despite no significant effect in reducing macrovascular disease, diabetic nephropathy was reduced by ≈20%.5 The follow- up study, ADVANCE-ON (ObservatioNal study), demonstrated a persistent reduction in renal failure 5.5 years after return to usual care, without any increase or decrease in the risks of death or cardiovascular disease.6

If clinical practice guidelines are designed to facilitate informed decision-making, clinicians should perhaps focus more on the reduction of diabetic nephropathy and cardiovascular neutrality in patients with T2DM. ■

References
1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15): 1577-1589.
2. inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
3. World Health Organization (WHO). WHO Model Lists of Essential Medicines. 19th list. http://www.who.int/medicines/publications/essentialmedicines/en/index.html. Published April 2015. Amended August 2015. Accessed October 26, 2015.
4. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015; 373(3):232-242.
5. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
6. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow- up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.

 

6. M. Kamar, Egypt

Dr Mohamed Kamar, MD
Professor of Diabetes and Endocrinology
Faculty of Medicine, Zagazig university
President of the Delta Diabetes Association
(DDA), EGYPT
(email: moh_kamar@hotmail.com)

Since the encouraging results of the United Kingdom Prospective Diabetes Study (UKPDS)1 for type 2 diabetes mellitus, health-care providers looking after diabetic patients have become more aware of their responsibility in preventing chronic diabetic complications: for instance, a 1% reduction in glycated hemoglobin (HbA1c) in UKPDS was associated with 37% reduction in microvascular complications. However, macrovascular complications did not benefit from tight glucose control. Nevertheless, it is worth noting that in the 10-year follow-up study of UKPDS,2 there was a significant reduction in myocardial infarction with tight glucose control (15%) compared with conventional therapy. The Steno-2 study3 showed that by simultaneously addressing several modifiable risk factors, ie, hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, patients receiving intensive therapy along with aspirin had a 53% lower risk of cardiovascular disease than those who received conventional treatment after a mean follow-up of 7.8 years.

Achieving a glycemic target of HbA1c <7% seems to be reasonable to minimize microvascular complications as much as possible. However, should a drug be selected based on its specific ability to prevent these complications?

In the ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) study,4 a glycemic goal of HbA1c <6.5% was achieved safely with intensive glucose control without the occurrence of severe hypoglycemia. In addition to the overall reduction of microvascular complications (16%; P=0.01), a specific renal benefit was obtained (21% relative reduction in the risk of nephropathy) in favor of the use of intensive glucose control, which included gliclazide modified release (MR). A legacy effect was also noted, since there was a persistent reduction (46%) in end-stage kidney disease over 10 years in patients with type 2 diabetes on the intensive, gliclazide MR–based treatment in ADVANCE, even after the patients shifted from intensive to standard therapy in ADVANCE-ON (ObservatioNal study).5

Experimental findings and preliminary clinical data suggest that DPP-4 (dipeptidyl peptidase 4) inhibitors, in addition to improving metabolic control, have the potential to interfere with the onset and progression of diabetic microangiopathy.6 However, these effects have not been confirmed in three large DPP-4 cardiovascular outcome studies—SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus),7 EXAMINE (EXAMINation of cardiovascular outcomes with alogliptin versus standard of care in patients with type 2 diabetes mellitus and acute coronary syndromE),8 and TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin).9

Health-care providers looking after diabetic patients should not only focus on the management of hyperglycemia, but should also address other cardiovascular risk factors to prevent cardiovascular disease. In addition to adequate glucose control, regular screening for retinopathy, measurement of microalbuminuria and estimated glomerular filtration rate, and foot examination can improve patient outcomes. Furthermore, the use of antidiabetic medications with microvascular benefit that has been proven in large randomized studies would be a valuable option. ■

References
1. uK Prospective Diabetes Study (uKPDS) Group. intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (uKPDS 33). Lancet. 1998;352 (9131):837-853.
2. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes N Engl J Med. 2008;359(15):1577- 1589.
3. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383-393.
4. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
5. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow- up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.
6. Avogaro A, Fadini GP. The effects of dipeptidyl peptidase-4 inhibition on microvascular diabetes complications. Diabetes Care. 2014;37:2884-2894.
7. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TiMi 53 Steering Committee and investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
8. Zannad F, Cannon CP, Cushman WC, et al; EXAMiNE investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMiNE: a multicentre, randomised, double-blind trial. Lancet. 2015; 385(9982):2067-2076.
9. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373 (3):232-242.

 

7. M. T. Malecki, Egypt

Professor Maciej T. MALECKI, MD, PhD
Department of Metabolic Diseases
Jagiellonian university Medical College
Krakow; and
university Hospital, Krakow, POLAND
(email: mmalecki@cm-uj.krakow.pl)

Type 2 diabetes mellitus is one of the most important challenges facing contemporary medicine. There are about 400 million patients affected by this disease worldwide and its morbidity is constantly rising on all continents. The causes behind this growth in morbidity are complex: they involve population aging—a nonmodifiable phenomenon— but also factors like unhealthy diet, sedentary lifestyle, and obesity— all of which can potentially be modified or prevented. Type 2 diabetes is associated with premature mortality, mainly due to cardiovascular causes, as well as with disability, due to foot amputation, end-stage renal disease, or blindness.

The controversial question concerns whether in treating patients with type 2 diabetes, we are doing all that is possible to protect their health, prolong their life, and maintain their quality of life. Where should we look for answers to this question? The most important sources of information include large randomized controlled clinical trials whose aim was to examine the impact of various therapeutic interventions in patients with type 2 diabetes on clinically important end points, including mortality, cardiovascular events, microvascular complications, etc. It is key to emphasize that we are speaking about clinical studies that have evaluated outcomes that are important for patients and not just surrogates, for example, glycated hemoglobin level. Articles presenting the outcomes of such trials, with the exception of the United Kingdom Prospective Diabetes Study, have only been published recently, from 2008 onwards.1,2 What can we learn from their results?

Firstly, we have learned that while intensification of hypoglycemic therapy reduces the incidence of microvascular complications, like diabetic kidney disease (with its most advanced form, end-stage renal disease), these is no convincing evidence that proves that intensification reduces the risk of cardiovascular events or extends life expectancy, particularly in patients with longstanding type 2 diabetes with macroangiopathy. Secondly, when considering important clinical outcomes, it is difficult to prove the superiority of a specific glucose- lowering agent, including the newest generation ones, over other glucose-lowering agents.3 Although, there are very recent promising data that require further confirmation.4 Finally, it is important to treat typical comorbidities, in particular arterial hypertension, because this helps reduce cardiovascular morbidity.5 Although, in this case, therapeutic goals should be individualized and rational, as “the lower, the better” strategy has its limitations.6

Returning to the initial question—do we pay enough attention to the long-term clinical benefits of the therapeutic measures we apply in type 2 diabetes patients?

I believe this question is rhetorical—if the answer is to be given from the perspective of the entire system of diabetes care, it has to be negative. Many patients do not achieve glycemic goals and, moreover, for many they are incorrectly set (either too high or too low). It is not rare for comorbidities to be underdiagnosed and improperly treated. We must also keep in mind that the majority of type 2 diabetes patients are treated by primary care physicians, who might not be up to date with the newest information in diabetes treatment research, are often overworked, and are only able to devote a limited amount of time to diabetic patients. What can be done during this short visit to make these physicians look a couple or tens of years ahead?

There is no universal answer to this question. We need greater funds for diabetes care and changes in its organization, like giving greater responsibility and independence to educational nurses.7 We also need education at a number of levels— for society as a whole, health-care policy makers, all professionals caring for diabetes patients (diabetologists, primary care physicians, nurses, and dieticians)—and, last but not least, patients. After all, as Dr E. P. Joslin said many years ago, “The person with diabetes who knows the most, lives the longest.”! ■

References
1. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
2. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545- 2559.
3. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373 (3):232-242.
4. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OuTCOME investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Sep 17. Epub.
5. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829-840.
6. Cushman WC, Evans GW, Byington RP, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575-1585.
7. den Engelsen C, Soedamah-Muthu SS, Oosterheert NJ, Ballieux MJ, Rutten GE. improved care of type 2 diabetes patients as a result of the introduction of a practice nurse: 2003-2007. Prim Care Diabetes. 2009;3(3):165-171.

 

8. J. C. Mbanya, Cameroon

Jean Claude MBANYA, MD, PhD, FRCP (uK)
Professor of Medicine and Endocrinology
Faculty of Medicine and Biomedical Sciences
university of Yaounde i, BP 8046, Yaounde
CAMEROON
(email: jcmbanya@hopitcam.net)

The ultimate aim of any approach in the management of diabetes is to enable patients to achieve better clinical outcomes and a better quality of life in the long term. For almost two decades, we have used the level of glycated hemoglobin (HbA1c) to reflect chronic glycemic control and assumed that reduction in HbA1c during treatment always translated into better clinical outcomes. This is not really true because we know from large clinical trials that clinical outcomes are influenced by: the history of previous glycemic control, baseline HbA1c, duration of diabetes, existing clinical complications, the methods by which lower HbA1c levels are obtained, and the side effects of the therapeutic agents; and not just by intensive glycemic control alone.1,2

There is evidence to demonstrate that the benefits of early and intensified control of diabetes on cardiovascular complications persist long after the cessation of intervention, despite the loss of within-trial differences in HbA1c levels. This implies that the effect of glycemic control on chronic vascular complications, in large part, depends on the previous history of glycemic control.3,4

Targeting intensive glycemic control in patients with diabetes and significant cardiovascular disease increases the risk of hypoglycemia and serious adverse clinical outcomes. Therefore, the choice of agents is very important if we must improve clinical outcomes in such patients.5 Nevertheless, in resource constrained settings there is a need to balance the achievement of clinical outcomes while maintaining patient quality of life with the availability and affordability of antidiabetic agents. We have evidence from a large clinical trial and follow-on study, in which cheap antidiabetic drugs like metformin and a sulfonylurea demonstrated cardiovascular benefits.2,4

Standards in current type 2 diabetes guideline recommendations and the US Food and Drug Administration approval of new therapies for diabetes treatment base their conclusions on the premise that the level of HbA1c is equivalent to the rate of development of chronic diabetic vascular complications. However, they do not focus on the practicality of choosing drugs that reduce clinical outcomes.

The selection of any treatment for type 2 diabetes should focus on the achievement of better clinical outcomes and quality of life in the context of an individualized, patient-centered approach taking into consideration the stage of vascular disease at the time of glycemic control. It should incorporate evidence on treatment efficacy, proven benefits, and potential side effects. Furthermore, shared decision-making that includes the patient’s profile, needs, preferences, values, ability to pay, and beliefs are essential components of such an approach.

The major complication of type 2 diabetes is the development of cardiovascular disease, yet it is questionable whether our current glucose-lowering approaches focusing on surrogate markers of cardiovascular disease risk translate into a reduction in cardiovascular complications and cardiovascular mortality. The logical conclusion is that treatment and management of type 2 diabetes should be optimized towards reducing cardiovascular risk rather than simply focusing on reducing HbA1c and glucose levels to target values. ■

References
1. Gerstein HC, Miller ME, Byington RP, et al; ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545-2559.
2. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
3. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577- 1589.
4. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.
5. Zoungas S, Patel A, Chalmers J, et al; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med. 2010;363 (15):1410-1418.

 

9. T. K. Nguyen, Vietnam

Dr Thy Khue NGUYEN, MD, PhD
Active Emeritus Associate Professor, Ho Chi
Minh City university of Medicine and Pharmacy,
Ho Chi Minh City, ViETNAM
(email: drthykh@gmail.com)

The major aim of treating diabetes is to improve prognosis by decreasing micro- and macrovascular complications as well as other diabetes-related problems. Clinical trials of new medications have focused mostly on surrogate end points, such as blood sugar and glycated hemoglobin (HbA1c), and adverse effects related to them. However, to assess the clinical outcomes of any treatment strategy, time is necessary. This is illustrated by the decrease in cardiovascular disease in the newly diagnosed diabetic patients of the United Kingdom Prospective Diabetes Study, which only became evident after 30 years.1

Cardiovascular safety is the major concern of physicians in diabetes treatment because cardiovascular disease is the leading cause of morbidity and mortality in diabetes. The US Food and Drug Administration requires that the cardiovascular safety profile of every new diabetic medication must be assessed.

Most diabetic patients would die of cardiovascular diseases before reaching the end stage of renal disease (ESRD). ESRD and other microvascular complications have a huge impact on the quality of life of diabetic patients; retinopathy is the leading cause of blindness, while neuropathy is an important risk factor of foot ulcers. Approximately 40% of diabetic patients will have nephropathy, and half of this cohort will progress to ESRD in developed countries.2 Microvascular complications correlate strongly with blood sugar, and studies have shown that lowering blood sugar will significantly improve retinopathy, nephropathy, and neuropathy.1 The ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) study,3 a randomized controlled, 2×2 factorial design trial comparing intensive glucose lowering to standard blood glucose control in chronic diabetic patients, showed that after a median follow-up of 5 years, proteinuria decreased significantly in the intensive treatment group, with an HbA1c of 6.5% vs 7.3% in the standard group.

The posttrial follow-up study, ADVANCE-ON (ObservatioNal study), found that progression to ESRD was 46% lower in the intensive group after another 5 years.4

However, there are still many other risk factors for micro- and macrovascular complications that must be considered, such as blood pressure, dyslipidemia, smoking, physical inactivity, and unhealthy diet. The Steno-2 study in type 2 diabetes with microalbuminuria reported a significant reduction in all cardiovascular risk factors. Nephropathy, retinopathy, and cardiovascular events decreased in the intensive treatment group when compared to the standard treatment group in the first 7.8 years of randomized controlled multifactorial intervention.5 These beneficial effects were sustained and continued to improve in the subsequent 5.5-year observational follow-up period in the intensive group, even though the two groups (intensive and standard control) had similar profiles with regards to HbA1c, blood pressure, and lipids. During the entire 13.3-year follow-up, the absolute reduction in death from any cause was 20%.6 Multiple targets must be reached in order to control diabetes effectively.

Diabetes is a very complex disease. Although randomized controlled trials are highly valued as a way of guiding the choice of medication to control blood sugar, these studies cannot cover all aspects of type 2 diabetes. Analysis of post hoc observational data provides the specialty with a broader view of daily practice. Consequently, clinical outcomes in cardiovascular disease as well as microvascular complications should be taken into account in order to obtain comprehensive care for diabetic patients. ■

References
1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577- 1589.
2. Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic Kidney Disease: a report from an ADA Consensus Conference. Diabetes Care. 2014;37(10):2864-2883.
3. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
4. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow- up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.
5. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383-393.
6. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6):580-591.

 

10. M. Rizzo, Italy

Professor Manfredi RIZZO, MD, PhD
Associate Professor of internal Medicine
Biomedical Department of internal Medicine
and Medical Specialties, university of
Palermo, Palermo, iTALY
(email: manfredi.rizzo@unipa.it)

Type 2 diabetes (T2DM) is increasing worldwide. Among clinicians and in international guidelines, there is generally agreement on the first-line use of metformin; however, it is still uncertain what constitutes an ideal drug sequence after metformin. Sulfonylureas, such as gliclazide, still have a big place. In addition, the rapid development of new drugs targeting pancreatic islet dysfunction, in particular gutderived incretin hormones, has marked the field of diabetes in the last decade. Incretin-based therapies not only improve glycemic control, but can also induce weight loss and reduce hypoglycemia and cardiovascular risk.1,2

Cardiovascular outcome remains a crucial point for patients with T2DM. Trials with high insulin use in higher risk patients with T2DM have shown either no cardiovascular benefit or an association between severe hypoglycemia and increased cardiovascular mortality, while in contrast long-term clinical trials have shown improved cardiovascular outcome. Such controversial data do not allow a final conclusion to be drawn about insulin therapy. Elsewhere, rosiglitazone has been shown to have an adverse cardiovascular risk profile and consequently it has been withdrawn from the market in most countries. Most of the cardiovascular outcome trials of incretinbased therapies are still ongoing, such as the trials of the new sodium glucose transporter 2 inhibitors.3 In 2008, the ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) study provided important data on cardiovascular outcome in T2DM patients receiving intensive blood glucose control.4 In this study, 11 140 T2DM patients were randomly assigned to either standard glucose control or intensive glucose control (defined as the use of gliclazide modified release, plus other drugs as required, to achieve a glycated hemoglobin value of 6.5% or less). After a median of 5 years of follow-up, the strategy of intensive glucose control with gliclazide yielded a significant reduction in the combined outcome of major macrovascular and microvascular events.

It is clear that diabetes management does not only require glycemic control, but also the achievement of other therapeutic goals targeting all parameters that may reduce cardiovascular risk; monitoring such parameters in T2DM patients helps estimate the risk for the development of future complications. This also leads to treatment toward individualized clinical targets. Indeed, in clinical practice, physicians should consider the pharmacodynamic and pharmacokinetic properties of the drug and take into account all the patient’s other comorbidities, such as heart failure, renal disease, and liver disease, as well as his phenotype and social background. The advantages and disadvantages of a specific drug should be considered for each patient and, in this way, the eventual therapeutic approach chosen, including healthy lifestyle recommendations, will be individualized (patient-centered).

In the last few years, it has been suggested that cardiovascular medications, such as statins, may increase the development of new-onset diabetes; yet, data are still not conclusive.5,6 In summary, cardiovascular outcome remains a crucial point for T2DM patients that always needs to be considered in our daily clinical practice. ■

References
1. Rizzo M, Chandalia M, Patti A, et al. Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study. Cardiovasc Diabetol. 2014,13:49.
2. Rizzo M, Abate N, Chandalia M, et al. Liraglutide reduces oxidative stress and restores heme oxygenase-1 and ghrelin levels in patients with type 2 diabetes: a prospective pilot study. J Clin Endocrinol Metab. 2015;100(2):603-606.
3. Rizzo M, Al-Busaidi N, Rizvi AA. Dapagliflozin therapy in type-2 diabetes: current knowledge and future perspectives. Expert Opin Pharmacother. 2015; 16(3):281-284.
4. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
5. Rizzo M, Spinas GA, Rini GB, Berneis K. is diabetes the cost to pay for a greater cardiovascular prevention ? Int J Cardiol. 2010;144(2):309-310.
6. Katsiki N, Rizzo M, Mikhailidis DP, Mantzoros CS. New-onset diabetes and statins: throw the bath water out, but, please, keep the baby! Metabolism. 2015; 64(4):471-475.

 

10. J. E. N. Salles, Brazil

Dr João Eduardo N. SALLES, MD
Assistant Professor of Endocrinology
Santa Casa de São Paulo Medical School
São Paulo, BRAZiL
(email: jensalles@yahoo.com.br)

Intensive glycemic control has been extensively studied in recent years. The results of large trials, such as ACCORD,1 ADVANCE,2 and VADT,3 which compared strict versus conventional glycemic control, showed no difference in the incidence of cardiovascular disease or mortality (except in the intensive treatment arm of ACCORD,1 where mortality was higher). In contrast, the UKPDS study showed that intensive treatment was better at preventing heart attacks and reducing all-cause mortality. Similar data in type 1 diabetes were found in EDIC,4 a continuation of DCCT. With similar glycated hemoglobin levels in both groups, mortality was lower and cardiovascular disease progressed less with intensive treatment. The terms “metabolic memory” and “glycemic legacy” were used to describe the lower risk of complications and mortality with better early glycemic control. Chronic hyperglycemia may lead to the formation of mitochondrial reactive oxygen species (ROS) and the alteration of respiratory chain proteins.5 This alteration allows continuous ROS formation, even after correction of hyperglycemia, which promotes endothelial dysfunction and leads to diabetic complications, cardiovascular disease, and nephropathy. This being the case, early, intensive control of blood glucose is an important target in preventing mortality and complications in patients with diabetes.

Cardiovascular safety of oral antidiabetic agents

Clinical trials that assessed the cardiovascular safety of oral antidiabetic agents have also proven useful for assessing their possible side effects and benefits. For dipeptidyl peptidase 4 inhibitors, cardiovascular safety—but not reduction in diabetes-related complications—was demonstrated in SAVOR-TIMI,6 EXAMINE,7 and TECOS.8

The cardiovascular safety of gliclazide modified release (MR) was shown in ADVANCE in patients with established type 2 diabetes and cardiovascular disease,2 a result that differentiates gliclazide MR from other sulfonylureas. In the 10-year follow-up trial, ADVANCE-ON,9 mean glycated hemoglobin was similar in both randomized groups (7.4%), allowing investigators to ascertain outcome benefits related to intensive treatment (including gliclazide MR) and not glycemic control.

The rate of insulinization was no greater with intensive versus standard treatment. No difference in the incidence of cardiovascular disease was observed between the groups, indicating that gliclazide MR does not increase medium- or long term cardiovascular risk. The most important finding, however, was the large reduction in nephropathy in the intensive treatment group, in which end-stage renal disease (ESRD) was significantly reduced by 46% after ten years.

Diabetes is increasing exponentially as an important cause of hemodialysis in Brazil. Such a situation exists due to the lack of early, effective metabolic control of diabetes and because half those with diabetes do not know they have the disease. Early glycemic control in diabetes is a critical strategy for reducing ESRD. Nevertheless, blood glucose reduction should not be our sole focus; thought should also be given to the other beneficial effects of treatments. ADVANCE-ON9 shows that metabolic control can effectively be obtained with an oral antidiabetic agent (gliclazide MR), with additional benefits including low risk of hypoglycemia, good tolerability, and reduction in specific microvascular diseases, such as terminal kidney disease.

So, yes, we should focus more on clinical outcomes when treating patients with type 2 diabetes. ■

References
1. Gerstein HC, Miller ME, Genuth S, et al; ACCORD Study Group. Long-term effects of intensive glucoselowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818-828.
2. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
3. Duckworth W, Abraira C, Moritz T, et al; VADT investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360(2):129-139.
4. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes interventions and Complications (DCCT/EDiC) Study Research Group. intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2553.
5. Ceriello, A, ihnat MA, Thorpe JE. Clinical review 2: The “metabolic memory”: is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab. 2009;94(2):410-415.
6. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TiMi 53 Steering Committee and investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-1326.
7. White WB, Cannon CP, Heller SR, et al; EXAMiNE investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013; 369(14):1327-1335.
8. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373 (3):232-242.
9. Zoungas S, Chalmers J, Neal B, et al; ADVANCE-ON Collaborative Group. Follow- up of blood-pressure lowering and glucose control in type 2 diabetes. N Engl J Med. 2014;371(15):1392-1406.