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Managing patients with type 2 diabetes mellitus: tight control reduces complications.

In the past 3 years, various publications have raised questions regarding the value of tight glycemic control for people with diabetes, in particular, in relationship to macrovascular disease. These publications were based on several studies that recently appeared in the literature proposing that treating only the cardiovascular risks of people with diabetes--such as dyslipidemia and hypertension--are important in reducing the macrovascular complications of diabetes like heart disease and stroke. These reports raised the question whether intensive treatment for hyperglycemia, per se, is of benefit in terms of cardiovascular outcomes. This point of view ignores the already existing studies demonstrating the cardiovascular benefits of tight glycemic control. (1,2) Furthermore, this point of view ignores, unjustifiably, the proven effects of tight glycemic control in reducing microvascular disease such as neuropathy, retinopathy, and nephropathy. (3,4) Several important, large studies have been published over the past several years that were intended to try to shed light on the role of glycemic control in the comorbidities of diabetes. However, in some cases, the interpretation of early and partial data from these studies have tended to confuse the issue. The goal of this article is to review highlights of these studies and provide clarification that will be helpful in clinical practice.

Large Studies of Intensive Versus Standard Glycemic Control


The first of these studies was the Action to Control Cardiovascular Disease in Diabetes (ACCORD) study. (5) This National Institutes of Health prospective trial, involving more than 10,000 US subjects, was designed to compare the effects of intensive treatment for diabetes control to those of standard care in patients with type 2 diabetes mellitus (T2DM) and cardiovascular risks.

In brief, just over 3 years into the study, the trial was stopped prematurely--and, perhaps, rightfully--because of significant excess mortality in the intensive-treatment group compared to that in the standard-care group. This decision was made before the cause of the excess mortality was known. Interestingly, the data that existed at the time the study was stopped actually showed less incidence of CVD in the intensive-treatment group than in the standard care group. The decision to stop the intensive control arm of the trial led to the false interpretation that the purpose of intensive control is equivalent to a goal of a low glycated hemoglobin (A1C) level and, therefore, created the notion that excess mortality was associated with low A1C levels rather than to the process of achieving tighter control of blood glucose, or even to chance.

Subsequent analysis of the ACCORD data showed that, in fact, of the subjects in the intensive-treatment group, those who achieved lowering of A1C levels to 6.5% or below had better outcomes, particularly with respect to CVD, than the subjects in the standard care group. Of particular interest is that the deaths in the intensive-treatment group occurred in those subjects whose A1C remained above 7% and could not be reduced despite intensive therapy. The correct conclusion is that the mortality in the intensive glucose control arm may have been related to the treatment strategy (perhaps by causing hypoglycemia) or to the refractory nature of hyperglycemia in the group of patients who died (perhaps the result of a different underlying disease process). Clearly, a low target level of A1C, by itself, was not the cause of death.


The similarly large (more than 11,000 subjects) Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study (6) was a multinational trial involving 215 centers in Asia, Australia, Europe, and Canada and was designed to examine intensive control versus standard of care in patients with T2DM. The ADVANCE investigators showed that intensive glucose control resulted in reductions in both microvascular and macrovascular disease, such as kidney disease and CVD, respectively. However, the improvements were primarily the result of a reduction in microvascular disease, namely, proteinuria, which indicates a reduction of progression to kidney disease rather than a reduction in CVD. Hence, as in the ACCORD trial, the cardiovascular (macrovascular) benefits were not immediately evident, demonstrating that longer trials may be necessary.


A third important prospective trial was undertaken concomitantly with ACCORD and ADVANCE: the Veterans Affairs Diabetes Trial (VADT), (7) which also had as its purpose an assessment of the potential cardiovascular as well as microvascular benefits of intensive glucose control. The VADT was a prospective study involving approximately 1,800 subjects with poorly controlled T2DM despite treatment with oral antidiabetes medication or insulin therapy. All patients had A1C levels of at least 7.5%. The study was designed to assess the difference in treatment goals of at least a 1.5% reduction of A1C between the intensive-treatment and the standard-treatment groups in macrovascular and microvascular outcomes. In VADT, a difference was seen between the initial report of data and the final report, which led to misconceptions of the effect of tight glycemic control and, ultimately, low A1C levels on diabetes comorbidities. Initially, the VADT investigators stated, apparently erroneously, that "intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications, with the exception of progression of albuminuria." However, the final results of VADT supported intensive glycemic control to reduce vascular comorbidities in people with T2DM with a duration of less than 15 years.

The initially reported results of VADT, taken together with the initial results of the ACCORD and ADVANCE trials, led many clinicians to the wrong conclusion that intensive control of hyperglycemia in individuals with diabetes to achieve lower A1C goals should not be practiced. However, further analysis of the VADT results has shown that intensive glycemic control was especially beneficial among the subjects in the intensive-treatment group who had had diabetes for fewer than 15 years; the subjects in this subgroup had less microvascular disease as well as less CVD. However, the subgroup of patients with a diabetes duration of more than 21 years had some worsening of cardiovascular status, with a higher mortality rate, perhaps resulting from intensive treatment. (An increase in hypoglycemia was also seen in the intensive-control group in the ACCORD trial, but that finding could not be correlated with an increase in mortality.)


The study with the longest duration is the United Kingdom Prospective Diabetes Study (UKPDS), which involved more than 5,000 patients with newly diagnosed T2DM, enrolled in 23 centers in the United Kingdom between 1977 and 1991. (4) Patients were followed for an average of 10 years, with the objectives of determining whether intensive therapy would reduce macrovascular--that is, cardiovascular--and microvascular complications (nephropathy, neuropathy, retinopathy), as well as comparing three types of treatments: sulfonylureas, metformin, and insulin. In addition, subjects who had concomitant hypertension were randomized to receive treatment aimed at either "tight" or standard blood pressure control; the purpose of this arm was to determine the effect of tight control on outcomes and to compare an angiotensin-converting enzyme inhibitor (in this case, captopril) to a [beta]-blocker (atenolol).

In the UKPDS, the patients in the intensive-therapy arm had lower A1C levels (median, 7.0%) than did those who received conventional therapy (median, 7.9%), with an overall decrease of 25% in the rate of microvascular complications. Here again, the benefits of tight glucose control with respect to CVD were not seen immediately but emerged during an extended (10-year) posttrial follow-up period. The reductions in cardiovascular morbidity and mortality were reported by Holman and colleagues (1) in 2008. These findings are consistent with the long-term follow-up results (ie, of at least 10 years) reported in other trials. (8-10)

Implications for Treatment: Conclusions From Large, Prospective Trials

What is the clinician to make of these findings, and how are these discrepancies to be resolved? Good guidance comes from the meta-analysis published by Ray and colleagues in 2009. (9) These investigators analyzed five prospective, randomized trials (ACCORD, ADVANCE, VADT, and UKPDS, discussed above, as well as the prospective pioglitazone clinical trial in macrovascular events [PROactive] (11)) and concluded that intensive glucose control reduces cardiovascular events significantly better than standard control, but with an important caveat: the optimum mechanism, speed, and extent of A1C reduction might be different in differing populations.

The overriding lesson is that the goal of diabetes treatment should be individualized. No patient should be treated based solely on average reported results. Treatment should be tailored to individual patients' circumstances. It seems clear that a large majority of patients will benefit from achieving the current goals of A1C ([less than or equal to] 6.5% per the AACE or [less than or equal to] 6.9% per the American Diabetes Association), provided these levels are achieved safely. It is hoped that most patients who achieve the appropriate goals safely will experience less microvascular disease and, over the long term, will also benefit in regard to macrovascular disease. However, other patients may require different goals.

A subset of patients with T2DM--those with early disease, who are relatively young and otherwise healthy--will probably benefit with treatment to bring A1C levels as close to 5% as possible, provided this can be achieved safely, without resulting in side effects such as hypoglycemia or obesity.

Two other subsets of patients--those with long-standing disease (more than 15 to 20 years) who also have comorbid conditions such as heart disease, or those with a shortened life expectancy--probably should not be treated as intensively. No specific goals have been recommended for these patients, but reasonable A1C targets range from 7% to 8% or even 8.5%, with blood sugar levels ranging from a minimum of 100 or 120 mg/dL to a maximum of 250 mg/dL.

Current and Upcoming Treatment Options

This approach of intensive treatment for tight control--or at least, tighter control--is quite possible today because of the availability of medications that do not cause significant side effects and complications. For example, in patients without kidney disease, metformin can be used safely to achieve target goals without causing hypoglycemia. Thiazolidinediones (TZDs) are associated with a risk for weight gain and bone fractures, but when used in patients who are relatively young and healthy, at reasonably low dosages, and in a setting of good clinical follow-up, TZDs can be used safely without causing hypoglycemia.

Newer therapeutic agents in current use and in various stages of development and clinical testing include two classes of incretin-based therapies, the glucagon-like peptide-1 (GLP-1) receptor agonists and the dipeptidyl peptidase-4 (DPP-4) inhibitors. Both GLP-1 receptor agonists and DPP-4 inhibitors work by potentiating signaling of receptors of incretin; these gut hormones (including GLP-1 and glucose-dependent insulinotropic peptide [GIP]) have the ability to affect both fasting and postprandial serum glucose levels. Different agents have different efficacy on postprandial versus fasting glucose levels.

In brief, endogenous GLP-1 has a short (2- to 4-minute) circulating half-life because of rapid degradation by the DPP-4 enzyme and clearance by the kidneys. The GLP-1 receptor agonists were developed to resist DDP-4 degradation, thereby allowing a longer duration of GLP-1 circulation and glucoregulation. The DDP-4 inhibitors work by preventing degradation of the native incretins--like GLP-1 and GIP--resulting in potentiation of their action.

The antihyperglycemic agents, the incretin-based therapies, appear to offer effective glucose control and a lower incidence of hyperglycemia. Some may have effects that result in weight loss and others have a neutral effect on weight.

AACE Treatment Algorithm

As part of their consensus algorithm for the treatment of diabetic hyperglycemia, the AACE developed a table with a summary list of the key benefits and risks of medications (Table). (12)

Recognizing that individualized therapy requires a complex program--given the number of medications now available and the need, in many cases, for combination therapy--the AACE convened a panel to develop an expert-based treatment algorithm to help clinicians achieve optimum goals safely (Hgure). (12) Unlike some previous algorithms, in which the focus was primarily on older medications and on medication costs (and not on safety and the need for individualizing therapy), the AACE algorithm stratifies patients according to A1 C levels at baseline and recommends medications based on optimum application and safety, with a special focus on reducing the risk of hypoglycemia, weight gain, kidney disease, and other complications.



The availability of a broad range of medications allows individualization of therapy that is tailored to the patient's needs. The newer medications, which are associated with fewer side effects (including hypoglycemia, weight gain, or kidney disease), allow intensive control to be achieved safely in the majority of patients, reducing the risk for both microvascular and macrovascular complications. Even patients with comorbid conditions, such as CVD and kidney disease, can be treated safely to a reasonable goal of glucose control.


(1.) Holman RR, Paul SK, Bethel MA, Matthews DR, Nell HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359: 1577-1589.

(2.) Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2634-2653.

(3.) The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.

(4.) UK Prospective Diabetes Study 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;352:837-853.

(5.) Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545-2549.

(6.) ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.

(7.) Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139.

(8.) Gaude P, Vedel P, Larsen N, Jonson GVH, Parving H, Pedersen O. Multifactorial interventions and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.

(9.) Ray KK, Seshasai SRK, Wijesuriya 8, et al. Effect of intensive glucose control on cardiovascular outcomes and death in patients with diabetes mellitus: A metaanalysis of randomised controlled trials. Lancet. 2009;373:1765-1772.

(10.) Gaede P, Lund-Andersen J, Parring H-H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-591.

(11.) Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A. The prospective pioglitazone clinical trial in macrovascular events (PROactive): Can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care. 2004;27:1647-1653.

(12.) American Association of Clinical Endocrinologists. AACE/ACE diabetes algorithm for glyccmic control. Available at: pdfTGlycemicControlAlgorithmPPT.pdf. Accessed November 20, 2010.

Yehuda Handelsman, MD
Table. Summary of Key Benefits and Risks of Medications

Benefits are classified according to major effects on fasting glucose,
postprandial glucose, and nonalcoholic fatty liver disease. Eight
broad categories of risks are summarized. The intensity of the
background shading of the cells reflects the relative importance of
the benefit or risk.


                            Metformin    DPP-IV       (Incretin
                            (MET)        Inhibitor    Mimetic


Postprandial glucose        Mild         Moderate     Moderate
(PPG) lowering                                        to

Fasting glucose             Moderate     Mild         Mild
(FPG) lowering

Nonalcoholic fatty liver    Mild         Neutral      Mild
disease (NAFLD)


Hypoglycemia                Neutral      Neutral      Neutral

Gastrointestinal            Moderate     Neutral      Moderate

Risk of use with            Severe                    Moderate
renal insufficiency

Contraindicated in liver    Severe       Neutral      Neutral
failure of predisposition
to lactic acidosis

Heart failure/edema         Use with     Neutral      Neutral
                            in CHF

Weight gain                 Benefit      Neutral      Benefit

Fractures                   Neutral      Neutral      Neutral

Drug-drug Interactions      Neutral      Neutral      Neutral


                            (SU)            Glinide *


Postprandial glucose        Moderate        Moderate
(PPG) lowering

Fasting glucose             Moderate        Mild
(FPG) lowering

Nonalcoholic fatty liver    Neutral         Neutral
disease (NAFLD)


Hypoglycemia                Moderate        Mild

Gastrointestinal            Neutral         Neutral

Risk of use with            Moderate        Neutral
renal insufficiency

Contraindicated in liver    Moderate        Moderate
failure of predisposition
to lactic acidosis

Heart failure/edema         Neutral         Neutral

Weight gain                 Mild            Mild

Fractures                   Neutral         Neutral

Drug-drug Interactions      Moderate        Moderate


                            (TZD)               Colosevelam


Postprandial glucose        Mild                Mild
(PPG) lowering

Fasting glucose             Moderate            Mild
(FPG) lowering

Nonalcoholic fatty liver    Moderate            Neutral
disease (NAFLD)


Hypoglycemia                Neutral             Neutral

Gastrointestinal            Neutral             Moderate

Risk of use with            Mild                Neutral
renal insufficiency

Contraindicated in liver    Moderate            Neutral
failure of predisposition
to lactic acidosis

Heart failure/edema         Mild to moderate    Neutral

                            in class 3-4 CHF

Weight gain                 Moderate            Neutral

Fractures                   Moderate            Neutral

Drug-drug Interactions      Neutral             Neutral


                            (AGI)         Insulin      Pramlintide


Postprandial glucose        Moderate      Moderate     Moderate
(PPG) lowering                            to           to
                                          marked       marked

Fasting glucose             Neutral       Moderate     Mild
(FPG) lowering                            to

Nonalcoholic fatty liver    Neutral       Neutral      Neutral
disease (NAFLD)


Hypoglycemia                Neutral       Moderate     Neutral

Gastrointestinal            Moderate      Neutral      Moderate

Risk of use with            Neutral       Moderate     Unknown
renal insufficiency

Contraindicated in liver    Neutral       Neutral      Neutral
failure of predisposition
to lactic acidosis

Heart failure/edema         Neutral       Neutral      Neutral

Weight gain                 Neutral       Mild         Benefit

Fractures                   Neutral       Neutral      Neutral

Drug-drug Interactions      Neutral       Neutral      Neutral

* The term "glinide" includes both repaglinide and nateglinide.
DPP-IV=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1;
CHF=congestive heart failure.

Source: American Association of Clinical Endocrinologists. Available
Accessed November 20, 2010. (12) Reprinted with permission.
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Author:Handelsman, Yehuda
Publication:Family Practice News
Date:Feb 15, 2011
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