Month: September 2013

The Management of Gout (Prophylaxis of Acute Attacks)

September 25, 2013 Pharmacotherapy, Therapeutics 1 comment ,

This post is based on the 2012 clinical guideline from American College of Rheumatology.

The Panel recommended pharmacologic antiinflammatory prophylaxis for all case scenarios of gout where ULT was initiated, given high gout attack rate frequencies in early ULT.

Prophylaxis Regimen

Oral colchicine is a first-line option. Low-dose NSAIDs is also a first-line choice, however if indicated, PPI therapy or other effective suppression therapy for peptic ulcer disease and its complications should be performed.

If these two approaches for prophylaxis are inappropriate due to intolerance or contraindication, or refractoriness to both colchicine and NSAIDs, ACR recommended use of low-dosage prednisone or prednisolone (defined here as ≤10 mg/day). Given the know risks of prolonged use of corticosteroids, the Panel urge clinicians to be particularly attentive in reevaluating the risk/benefit ratio of continued corticosteroid prophylaxis as the tisk of acute gout attack decreases with time in conjunction with effective ULT.

However, ACR Panel had not made consensus for the prophylaxis regimen for more severe forms of chronic tophaceous gouty arthropathy (CTGA).

Duration of Prophylaxis

The ACR Panel recommended to continue pharmacologic gout attack prophylaxis if there is any clinical evidence of continuing gout disease activity (e.g., 1 or more tophi detected on physical examination, recent acute gout attacks, or chronic gouty arthritis), and/or the serum urate target has not yet been achieved.

Three choices where no disease activity and target serum urate level already achieved:

[1].6 months’ duration;

[2].3 months after achieving the target serum urate level for the patient without tophi detected on physical examination;

[3].6 months after achieving the target serum urate level, where there has been resolution of tophi previously detected on physical examination.

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[Update on Sep 23rd 2013] The Management of Gout Part 1 (ULT and CTGA)

September 23, 2013 Pharmacotherapy, Therapeutics 2 comments , ,

In afore blog we had discussed about the management of gout. Today we update the information for the management of gout based on the latest (2012) clinical guidelines for the management of gout from American College of Rheumatology.

In this post we will discuss about the urate-lowering therapy (ULT) and chronic gouty arthritis with tophaceous disease detected on physical examination (CTGA/chronic tophaceous gouty arthropathy). Note CTGA is defined as chronic gouty arthritis with tophaceous disease detected on physical examination.

In this latest clinical guideline, patients with gout have been divided into 9 cohorts, as shown in picture below.

Figure 1. Fundamental case scenarios in ACR 2012 guideline for gout

If the diagnosis of gout is obtained and correct, a list of steps should be considered as the principles of management for all gout case scenarios.Gout Case Scenarios

Step 1. Patient education on the disease,  the diet and the life-sytle recommendations.

These recommendations belong to nonpharmacologic ULT. Generally they include:

1.weight loss for obese patients, to achieve BMI that promotes general health;

2.healthy overall diet;

3.smoking cessation;

4.exercise (achieve physical fitness); and

5.stay well hydrated.

Diet and food are categorized into three groups: diet needed to avoid, diet needed to limit, and diet encouraged.

The food must avoid consists of [1] organ meats high in purine content (e.g., sweetbreads, liver, kidney), [2] high fructose corn syrup-sweetened sodas and other beverages or foods, [3] alcohol overuse (defined as more than 2 servings per day for a male and 1 serving per day for a female), and any alcohol use in gout during periods of frequent gout attacks or advanced gout under poor control.

The food must limit consists of [1] sizes of beef, lamb, pork, seafood with high purine content (e.g., sardines, shellfish), [2] naturally sweet fruit juices, table sugar and sweetened beverages and desserts, and [3] table salt including in sauces and gravies.

The food encouraged are low-fat or non-fat dairy products, vegetables.

Step 2. The causes of hyperuricemia must be clear for all gout patients. To obtain this intention cetain medical evaluations of certain agents and comorbidities should be performed if indicated since that certain agents and comorbidities can promote hyperuricemia (either causing underexcretion or overproduction of uric acid). Note it is important to identify medications that elevate serum urate level, under which nonessential medications should be stopped.

If patients excrete more than 800 mg of uric acid in 24 hours while eating a regular diet, they are overexcretors and thus overproducers of uric acid. If the patient excretes less than 600 mg of uric acid per 24-hour period on a purine-free diet or less than 800 mg per 24-hour period on an unrestricted diet, the patient is considered a hypoexcreter (Note that this sentence has been removed from the latest Medscape reference for the management of gout).

It is controversial that whether to perform 24-hour urine uric acid evaluation in gout patients with former or present urolithiasis. The 2012 ACR guildeline recommended screening for uric acid overproduction in patient subsets with gout clinical disease onset before age 25 yrs or a history of urolithiasis. In contrast, the latest Medscape reference said a 24-hour urine test of uric acid excretion need not be performed since the patient clearly will need allopurinol (overproducer).

If [1] unclear etiology of hyperuricemia; [2] refractory signs or symptoms of gout; [3] difficulty in reaching the target serum urate level, particularly with renal impairment and a trial of XOI treatment; [4] multiple and/or serious adverse events from pharmacologic ULT, referring  the patients to a specialist is recommended.

Step 3. Evaluating for gout disease activity and burden. Evaluate gout patients and categorize them into the nine subgroup as shown in figure above. A history and thorough physical examination for symptoms of arthritis and signs needed to be assessed.

Step 4. Pharmacologic ULT should be started if indicated. Indications for pharmacologic ULT are any patient with established diagnosis of gouty arthritis and with:

  • Tophus or tophi by clinical exam or imaging study;
  • Frequent attack of acute gouty arthritis (≥2 attacks per year);
  • CKD stage 2 or worse; and/or
  • Past urolithiasis.

The serum urate target is <6 mg/dL in all gout patients. In some patients such as patients with palpable and visible tophi, lower target of <5 mg/dL may be needed to improve gout signs and symptoms.

In the afore blog pharmacologic ULT generally is contraindicated until the acute attack is controlled (starting therapy to control hyperuricemia during an acute attack may intensify and prolong the attack), unless kidneys are at risk because of unusual uric acid load. Typically, agents lowering uric acid levels should be started a few weeks after the attack has resolved and with the protection of prophylactic colchicine or NSAIDs to prevent another attack.

Not consistent is that the 2012 ACR guideline said pharmacologic ULT could be started during an acute gout attack, provided that effective antiinflammatory management has been instituted.

Inadequate response of acute gout to pharmacologic therapy are defined as: [1].<20% improvement in pain score within 24 hours, or [2].<50% improvement in pain score >= 24 hours after initiating pharmacologic therapy. The pain score are measured by Likert scale or VAS (visual analog scales) [For more information about VAS please visit Pharmacoeconomic Evaluating Methods].

When pharmacologic ULT is initiated, serum urate should be monitored every 2-5 weeks during ULT titration. Once the serum urate target is achieved and maintaned the frequency could be prolonged to every 6 months.

Same with the former blog about gout management. Pharmacologic ULT are based on three different classes of medicatons: xanthine oxidase inhibitors, uricosuric agents, and pegloticase.

About The Strategy for Pharmacologic ULT

In this post we don’t consider detailly the contraindications, intolerance, serious adverse events, or drug-drug interactions for given agents.

XOI with either allopurinol or febuxostat is the first-line pharmacologic ULT approach. The initial allopurinol dosage should be no greater than 100 mg/day. This should be followed by gradual increase of the maintenance dose, which can safely exceed 300 mg even in patients with CKD.

Also to avoid allopurinol toxicity, the guidelines recommend considering HLA-B*5801 prescreening of patients at particularly high risk for severe adverse reaction to allopurinol (eg, Koreans with stage 3 or worse kidney disease and all patients of Han Chinese and Thai descent).

For all 9 cohorts when the serum urate target has not been met and/or with continuing disease activity, ACR recommended upward dose titration of the XOI to the respective maximum appropriate dose for the individual patient. If upward titration of the initial XOI agent was not tolerated or did not achieve the serum urate target, substitution of another XOI was an appropriate first-line option. However, if XOIs were contraindicated or not tolerated, consider uricosuric medications as alternative. Note that the unachieved target and/or continuing disease activity is with the presupposition that [1] nonpharmacologic ULT have been applied; [2] appropriate treatment and antiinflammatory prophylaxis are employed for attacks of acute gouty arthritis.

The TFP recommends single XOI therapy with either allopurinol or febuxostat as the first-line pharmacologic approach (evidence A). If XOI is contraindicated or not tolerated, probenecid is recommended as an alternative first-line pharmacologic ULT option. But FTP did not recommend probenecid as a first-line ULT monotherapy in those with a creatinine clearance below 50 ml/minute.

Pharmacologic ULT could be started during an acute gout attack, provided that effective antiinflammatory management has been instituted. Regular monitoring of serum urate (every 2-5 weeks) during ULT titration is recommended. Once the serum urate target is achieved and maintained the frequency of monitor could be prolonged to every 6 months.

If with the approach above, the serum urate target remained unachieved or continuing disease activity remained, we should titrate the dosage of the first-line single drug to the maximum tolerable dose. If issue remains despite maximum or maximum dosage is not tolerated, approach two is to add uricosuric agent to XOI. Note that the unachieved target and/or continuing disease activity is with the presupposition that [1] nonpharmacologic ULT have been applied; [2] appropriate treatment and antiinflammatory prophylaxis are employed for attacks of acute gouty arthritis.

If with approach two, the serum urate target remained unachieved or continuing disease activity remained, pegloticase might be considered as the last approach. However, pegloticase treatment shoud be limited to gout patients with severe gout disease burden and refractoriness to, or intolerance of, appropriately dosed oral ULT options.

After palpable tophi and all acute and chronic gouty arthritis gout symptoms have resolved, ULT should be continued in order to maintain serum urate <6mg/dL indefinitely.

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The Management of Multiple Myeloma in Younger Patients

September 19, 2013 Chemotherapy, Cytogenetics, Hematology, Therapeutics, Transplantation No comments , , , , , , , , , ,

Therapy for multiple myeloma (MM) has advanced with gratifying speed over the past 5 to 7 years and with this progress, a degree of uncertainty has arisen about optimal approaches to therapy, particularly in the newly diagnosed patients. Indeed, using mordern therapeutic strategies, living with MM for a decade or longer has now become a reality for a significant proportion of patients.

Pathophysiology

MM is characterized by neoplastic proliferation of plasma cells involving more than 10% of the bone marrow. Increasing evidence suggests that the bone marrow microenvironment of tumor cells plays a pivotal role in the pathogenesis of myelomas.

The malignant cells of MM, plasma cells, and plasmacytoid lymphocytes are the most mature cells of B-lymphocytes. B-cell maturation is associated with a programmed rearrangement of DNA sequences in the process of encoding the structure of mature immunoglobulins. It is characterized by overproduction of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains, which may be identified with serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP).

The role of cytokines in the pathogenesis of MM is an important area of research. Interleukin (IL)–6 is also an important factor promoting the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic basis for the clinical sequelae of MM involves the skeletal, hematologic, renal, and nervous systems, as well as general processes.

Development Progresses

Skeletal processes

Plasma-cell proliferation causes extensive skeletal destruction with osteolytic lesions, anemia, and hypercalcemia. Mechanisms for hypercalcemia include bony involvement and, possibly, humoral mechanisms. Isolated plasmacytomas (which affect 2-10% of patients) lead to hypercalcemia through production of the osteoclast-activating factor.

Destruction of bone and its replacement by tumor may lead to pain, spinal cord compression, and pathologic fracture. The mechanism of spinal cord compression symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. With pathologic fracture, bony involvement is typically lytic in nature.

Hematologic processes

Bone marrow infiltration by plasma cells results in neutropeniaanemia, andthrombocytopenia. In terms of bleeding, M components may interact specifically with clotting factors, leading to defective aggregation.

Renal processes

The most common mechanisms of renal injury in MM are direct tubular injury, amyloidosis, or involvement by plasmacytoma.[14, 15] Renal conditions that may be observed include hypercalcemic nephropathy, hyperuricemia due to renal infiltration of plasma cells resulting in myeloma, light-chain nephropathy,amyloidosis, and glomerulosclerosis.

Neurologic processes

The nervous system may be involved as a result of radiculopathy and/or cord compression due to nerve compression and skeletal destruction (amyloid infiltration of nerves).

General processes

General pathophysiologic processes include hyperviscosity syndrome. This syndrome is infrequent in MM and occurs with IgG1, IgG3, or IgA. MM may involve sludging in the capillaries, which results in purpura, retinal hemorrhage, papilledema, coronary ischemia, or central nervous system (CNS) symptoms (eg, confusion, vertigo, seizure). Cryoglobulinemia causes Raynaud phenomenon, thrombosis, and gangrene in the extremities.

Workup

Some tests can afford important prognostic information and the subtypes of myeloma. These tests include classic CRAB measurements (calcium level, renal function, amemia, bone damage) , β2-microglobulin, albumin, lactate dehydrogenase (LDH), serum and urine monoclonal protein (24-hour) such as serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE), 24 h urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE), and so on, serum-free light chain assay.

Bone marrow examinations such as morphology, FISH (fluorescent in situ hybridization) analysis of key genetic events, metaphase cytogenetics are also mandatory at present.

Table 1. Genetic Tests to Be Performed in Myeloma Patients at Diagnosis.

With these tests, multiple myeloma can be divided into three subtypes, which are solitary plasmacytoma, smoldering myeloma (asymptomatic myeloma) and active myeloma (symptomatic myeloma).

Subtypes of Multiple Myeloma

According to the latest NCCN guideline MM can be categorized into three subgroups including solitary plasmacytoma, smoldering myeloma (asymptomatic), and active myeloma (symptomatic).

Solitary plasmacytoma

Solitary plasmacytoma is a large solitary focus of plasma cell proliferation. To simplify, solitary plasmacytomas can be divided into 2 groups according to location: Plasmacytoma of the skeletal system (SBP) or Extramedullary plasmacytoma (EMP). Similarly, the latest NCCN guideline for MM categorizes solitary plasmacytoma into solitary osseous or solitary extraosseous.

Criteria for identifying solitary bone plasmacytoma (SBP) vary among authors. Some include patients with more than one lesion and elevated levels of myeloma protein and exclude patients whose disease progressed within 2 years or whose abnormal protein persisted after radiotherapy. With the use of magnetic resonance imaging (MRI), flow cytometry, and polymerase chain reaction (PCR), the currently accepted criteria are as follows:

  • Single area of bone destruction due to clonal plasma cells
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of anemia, hypercalcemia, or renal impairment attributable to myeloma
  • Low, if present, concentrations of serum or urine monoclonal protein
  • Preserved levels of uninvolved immunoglobulins

Diagnostic criteria for extramedullary plasmacytoma (EMP) are as follows:

  • Tissue biopsy showing monoclonal plasma cell histology
  • Bone marrow plasma cell infiltration not exceeding 5% of all nucleated cells
  • Absence of osteolytic bone lesions or other tissue involvement (no evidence of myeloma)
  • Absence of hypercalcemia or renal failure
  • Low serum M protein concentration, if present

Smoldering myeloma

Smoldering myeloma describes a stage of disease of MM with no symptoms and no related organ or tissue impairment. According to the latest version of NCCN guideline for MM, criteria for the definition of smoldering myeloma are as follows:

  • M-protein in serum ≥30 g/L and/or
  • Bone marrow clonal plasma cells ≥10%
  • No related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms.

Note that the M-protein refers to the monoclonal protein produced by MM cells.

Active/symptomatic myeloma

Criteria for the definition of active/symptomatic myeloma requires one or more of the following:

  • Calcium elevation (>11.5 mg/dL) [>2.65 mmol/L]
  • Renal insufficiency (creatinine >2 mg/dL) [177 µmol/L or more]
  • Anemia (hemoglobin <10 g/dL or 2 g/dL < normal)
  • Bone disease (lytic or osteopenic)

In the section of management of MM we will discuss the specific therapeutic approaches for these three subtypes of MM.

Prognosis and Genetics

Several factors can afford important prognostic information for multiple myeloma. They are β2-microglobulin, lactate dehydrogenase (LDH), cytogenetics, and plasma cell-specific FISH analysis (hyperdiploidy, t(4;14)(p16;q32), t(14;16)(q32;q23), 17p13, t (11;14)(q13;q32), 1q amplifications, 1p deletions, loss of 12p, gains of Cr5).

Table 2. Risk Classification Based on Baseline Testing

Of note that in the latest NCCN guideline about multiple myeloma several high-risk chromosomal aberrations in MM locates at 14q32, including three main ones that are t(11;14)(q13;q32), t(4;14)(p16;q32) and t(14;16)(q32;q23). Thus the risk incidence of t(11;14) is inconsistent with what was decribed in Table 2.

For this inconsistent two view I have sent an inquiry to NCCN and their answer was “We have reviewed your inquiry with the NCCN Guidelines Panel Chair, Dr. Kenneth Anderson. NCCN does not classify t(11;14) as high risk, it is only listed as a major group containing the 14q32 translocation. ”

And pay attention that patients with t(4;14), β2 microglobulin <4 mg/L and hemoglobin ≥10 g/dL may have intermediate risk disease.

Although the genetics can afford the prognosis of multiple myeloma, this approach still needs more evidence. At present the method is still the Durie-Salmon criteria or ISS criteria.

Table 3. Stage of Multiple Myeloma

As shown in the table 2 at left, the stage of multiple myeloma can be divided into three periods: stage I, stage II, and stage III.

The Management of Solitary Plasmacytoma

For those patients with osseous plasmacytoma, primary radiation therapy (45 Gy or more) to the involved field is the initial treatment and is potentially curative. Extraosseous plasmacytomas are treated initially with radiation therapy (45 Gy or more) to the involved field followed by surgery if necessary.

After radiation thearpy, patients with solitary plasmacytoma need follow-up. Blood and urine tests performed every 4 weeks initially to monitor response to the primary radiation therapy. If the patient achieves complete disappearance of the paraprotein then the frequency could be reduced to every 3-6 months or as indicated clinically. If the protein persists, then the monitoring should continue every 4 weeks. These tests include CBC, serum chemistry and those listed in the section of workup.

If progressive disease emerges, then the patient should be re-evaluated for recurrent plasmacytoma or myeloma, and systemic therapy administered as indicated.

The Management of Smoldering Myeloma

Although the activity of novel agents has advanced to the point that early interventions are now being explored in clinical trials for smoldering myeloma, there is still no evidence that early treatment will improve survival in asymptomatic and biochemically stable patients. A critical point is that up to 25% of smoldering myeloma patients will not require active treatment for 10 to 15 years. However, the majority will indeed progress during that time.

Once diagnosed, smoldering myeloma patients require frequent monitoring to allow treatment to begin before end-organ damage is evident. These tests are similar with solitary plasmacytoma, which are listed in the section of workup. If the disease progresses to symptomatic myeloma, these patients should be managed as active/symptomatic myeloma. We will discuss the management of active/symptomatic myeloma below.

The Management of Active/Symptomatic Myeloma

If the patients with MM progresse to active/symptomatic myeloma. Treatment should be initiated. Generally, we divide the treatment strategy into initial drug therapy, hematopoietic cell transplantation, and consolidation and maintenance thearpy after transplantation.

Therapeutic goal

There is a growing body of evidence showing an association between depth of response to therapy and improved long-term outcomes, including progressive-free survival (PFS) and overall survival (OS), in MM patients. Using conventional chemotherapy, it has been shown that there is a correlation between response before and after transplantation and that the quality of response after transplantation has a marked impact on outcome.

Importantly, studies suggest that if a patient achieves a complete response (CR), this must be durable and that the duration of CR is the best predictor of OS. However, some special cases makes the view that initially obtaining a CR in predicting long-term outcome questionable, for instance, group of rapidly responding but early relapsing patients, group of more indolent myelomas that revert to an “monoclonal gammopathy of uncertain significance like” profile after therapy, and group of myeloma patients with stable nonprogressive disease after induction therapy.

Initial drug therapy

Although success and long-term remission have been achieved in many transplantation-eligible patients using limited treatment regimens, such as thalidomide/dexamethasone, bortezomib/dexamethasone, and lenalidomide/dexamethasone, complete and very good partial response (VGPR) rates can be substantially increased by combining these various drugs in triplets or even using 4 drugs together.

On the right is the data of several clinical trials. I list all the detail of regimens below:

VAD: vincristine, adriamycin, and dexamethasone;

TD: thalidomide and dexamethasone;

RD: lenalidomide and dexamethasone;

PAD: bortezomib, doxorubicin, and dexamethasone;

VTD: bortezomib, thalidomide, and dexamethasone;

CVD: cyclophosphamide, bortezomib, and dexamethasone;

RVD: lenalidomide, bortezomib, and dexamethasone;

CVRD: cyclosphamide, bortezomib, lenalidomide, and dexamethasone.

A note of caution is that many of these studies are based on relatively small numbers of patients at single, or limited numbers, of centers, but cumulatively the message is consistent, with frequent, rapid, and deep responses seen.

Althought response rates are clearly improved with new drug cocktails, proving a consequent OS advantage is difficult and especially challenging given the large numbers of patients and the long duration of follow-up required. However, based upon response rates, depth of response achieved, and PFS as surrogates, 3-drug cocktails are currently the modality of choice in clinical practice, with use of RVD, CVD, or VTD as the most commonly chosen regimens outside of clinical trials.

Transplantation

Transplantation is a useful modality helping achieve or consolidating CR. But is it necessary to provide any consolidation chemotherapy before transplantation? If the patient is going to proceed to  transplantation, when do we implement the transplantation. However, because the goal of therapy is to maximize the depth and duration of remission, induction therapy can be continued in some patients for as long as the patient is responding and tolerating therapy, which might be instead of transplantation.

Generally ASCT is the primarily way of transplantation. Allo-SCT should infrequently be performed outside of clinical trials, as the risk of morbidity and early mortality of even nonmyeloablative transplantations is considerable.

Question one is whether to offer any consolidation chemotherapy before transplantation.

After initial induction thrapy, the subsequent approach is to provide further 4 to 6 cycles of induction threapy, then proceed eligible patients to ASCT. The reason to use stem cell transplantation is to provide a consolidation of remission after obtaining the best possible response to frontline treatment.

But a controversial area is what to do if the patient has already achieved a CR before transplantation. In this decision, the role of continued chemotherapy treatment versus proceeding to transplantation is less clear and an are of active research. Generally, in practice we prefer to proceed patients to transplantation without any further induction chemotherapy.

The reason to proceed to transplantation even achieving CR before transplantation is that current measures of CR are insufficiently sensitive and residual disease is in many, if not all, patients present but below the level of detection.

Question two is when do we offer stem cell transplantation to our patients who are eligible to this procedure. The timing of ASCT is also an area of active research. Patients are usually more fit for intensive therapy early in the course of the disease, but prior studies using conventional chemotherapy as induction demonstrated this a delayed ASCT had no adverse impact on OS and is feasible as part of salvage therapy in first relapse.

Maintenance therapy

Clinical studies found thalidomide maintenance to improve overall survival. Lenalidomide may offer the same advantages with less toxicity. Generally, it has become our practice to use maintenance routinely when patients have not achieved a CR after stem cell transplantation or when genetic risk markers suggest a very high risk of early relapse.

Figure 1. Respond Criteria for Multiple Myeloma

Glycemic Goals in Adult with Diabetes

September 3, 2013 Diabetes No comments , , ,

Generally there are two primary techniques for health providers and patients to evaluate the effectiveness of the management plan on glycemic control: patient self-monitoring of blood glucose or interstitial glucose, and A1C. What should be emphasized is that A1C has a strong predictive value for diabetes complications.

Hyperglycemia defines diabetes, and glycemic control is fundamental to the management of diabetes. Poor controlled hyperglycemia is correlation with diabetes complications such as microvascular complications and cardiovascular diseases (CVD).

Microvascular Complications

Many studies and trials proved that the greatest number of microvascular complications would be averted by taking patients from very poor control to fair or good control. Compared with standard glycemic control (e.g., target A1C <7%), intensive glycemic control (e.g., target A1C <6.5%) seems to have more benefit on the onset or progression of microvascular complications, with further reduction in the risk of microvascular complications.

Despite these confirmed benefit of intensive glycemic control, the risks of lower glycemic targets may outweigh the potential benefits on microvascular complications on a population level when given the substantially increased risk of hypoglycemia. Thus, lower glycemic target is appropriate in selected individuals such as those with short duration of diabetes, little comorbidity, and long life expectancy, as long as significant hypoglycemia dose not become a barrier.

Cardiovascular Diseases

CVD, a more common cause of death in population with diabetes than microbascular complications, is less clearly impacted by levels of hyperglycemia or intensity of glycemic control. Studies about this topic are inconsistent.

In the DCCT, there was a trend toward lower risk of CVD events with intensive control, and in 9-year post-DCCT follow-up of the EDIC cohort participants previously randomized to the intensive arm had a significant 42% reduction in CVD outcomes and a significant 57% reduction in the risk of nonfatal myocardial infarction, stroke, or CVD death compared with those previously in the standard arm.

During the UKPDS trial, there was a 16% reduction in cardiovascular events in the intensive glycemic control arm, although this difference was not statistically significant, and there was no suggestion of benefit on other CVD outcomes such as stroke.

Conversely, results of three more-recent large trials (ACCORD, ADVANCE, and VADT) suggest no significant reduction in CVD outcomes with intensive glycemic control in these populations, who had more advanced diabetes than UKPDS participants. All three of these trials were conducted in participants with more-long-standing diabetes (mean duration 8-11 years) and either know CVD or multiple cardiovascular risk factors.

However, the benefits of intensive glycemic control on CVD primarily rests on long-term follow-up of study cohorts treated early in the course of type 1 and type 2 diabetes and subset analyses of ACCORD, ADVANCE, and VADT.

Summary

Lowering A1C to below or around 7% has been shown to reduce microvascular complications of diabetes, and if implemented soon after diagnosis of diabetes is associated with long-term reduction in microvascular disease.

Providers might reasonably suggest more stringent A1C goals (such as <6.5%) for selected individual patients, if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, long life expectancy, and no significant CVD.

Severe hypoglycemia should be avoid with efforts. Providers should not aggressively attempt to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably easily and safely achieved (with history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, and those with longstanding diabetes in whom the general goal is difficult to attain despite DSME, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin), where a less-stringent A1C goals (e.g., <8%) might be appropriate.

Table 1 Summary of Glycemic Recommendation for Many Nonpregnant Adults With Diabetes.