Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association.

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach
Update to a Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) This is an update to a previously published Position Statement from the ADA and the EASD in It focuses on new data over the past 3 years that have influence the management of hyperglycemia in patients with T2DM. The reader is referred to the original Position Statement which provides a more comprehensive review of the field (Diabetes Care 2012;35:1364–1379 or Diabetologia 2012;55:1577–1596) Diabetes Care 2015;38:140–149 Diabetologia 2015; /s

Writing Group ADA-EASD Position Statement Update:
American Diabetes Association Richard M. Bergenstal MD Int’l Diabetes Center, Minneapolis, MN John B. Buse MD, PhD University of North Carolina, Chapel Hill, NC Anne L. Peters MD Univ. of Southern California, Los Angeles, CA Richard Wender MD Thomas Jefferson University, Philadelphia, PA Silvio E. Inzucchi MD (co-chair) Yale University, New Haven, CT European Assoc. for the Study of Diabetes Michaela Diamant MD, PhD (posthumous) VU University, Amsterdam, The Netherlands Ele Ferrannini MD University of Pisa, Pisa, Italy Michael Nauck MD Diabeteszentrum, Bad Lauterberg, Germany Apostolos Tsapas MD, PhD Aristotle University, Thessaloniki, Greece David R. Matthews MD, DPhil (co-chair) Oxford University, Oxford, UK Diabetes Care 2015;38: ; Diabetologia 2015; /s ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 The original Writing Group of the 2012 Position Statement is unchanged, except for the passing of Dr. Diamant. The Position Statement Update was peer-reviewed by 16 global experts, and the final draft was approved by the Professional Practice Committee of the ADA and the Panel on Guidelines and Statements of the EASD.

PATIENT-CENTERED CARE 2. BACKGROUND
Epidemiology and health care impact Relationship of glycemic control to outcomes Overview of the pathogenesis of Type 2 diabetes 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets Therapeutic options - Lifestyle - Oral agents & non-insulin injectables - Insulin UPDATED Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38: ; Diabetologia 2015; /s ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 The description of ‘Patient-Centered Care’ and the “Background” section of the 2012 Position Statement did not require any adjustments. Changes were made mainly in the “Anti-Hyperglycemic Therapy” section, specifically under ‘Oral agents & non-insulin injectables” and (next slide) “Dual Combination Therapy”, “Triple Combination Therapy” and “Transitions to and Titrations of Insulin.”

3. ANTIHYPERGLYCEMIC THERAPY
Implementation Strategies - Initial drug therapy - Advancing to dual combination therapy - Advancing to triple combination therapy - Transitions to and titrations of insulin 4. OTHER CONSIDERATIONS Age Weight Sex/racial/ethnic/genetic differences Comorbidities (CAD, HF, CKD, Liver disease, Hypoglycemia-prone) 5. FUTURE DIRECTIONS / RESEARCH NEEDS UPDATED ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38: ; Diabetologia 2015; /s The description of ‘Patient-Centered Care’ and the “Background” section of the 2012 Position Statement did not require any adjustments. Changes were made mainly in the “Anti-Hyperglycemic Therapy” section, specifically under ‘Oral agents & non-insulin injectables” and (next slide) “Dual Combination Therapy”, “Triple Combination Therapy” and “Transitions to and Titrations of Insulin.” The sections describing “Other Considerations” and “Future Directions / Research Needs” also remain largely in place from 2012.

Patient-Centered Approach
“...providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions.” Gauge patient’s preferred level of involvement. Explore, where possible, therapeutic choices. Consider using decision aids. Shared Decision Making – a collaborative process between patient and clinician, using best available evidence and taking into account the patient’s preferences and values Final decisions regarding lifestyle choices ultimately lie with the patient. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 There is increasing emphasis on ‘patient-centeredness’ in chronic disease management. This has been described by the Institute of Medicine as “providing care that is respectful of and responsive to individual patient preferences, needs, and values – ensuring that patient values guide all clinical decisions.” Shared decision making (SDM) is a key component of patient-centered care. This is of particular importance in those conditions, like diabetes, that necessitate patient involvement in lifestyle changes.

ADA-EASD Position Statement Update:
Management of Hyperglycemia in T2DM, 2015 2. BACKGROUND Relationship of glycemic control to microvascular and macrovascular outcomes. What do we know about the association of intensive glycemic control to prevention (or delay) in microvascular (retinopathy, nephropathy, neuropathy) and macrovascular complications (myocardial infarction, stroke, peripheral arterial disease)? Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials
Study Microvasc CVD Mortality UKPDS   DCCT / EDIC* ACCORD  ADVANCE VADT This slide presents an overview of the microvascular, macrovascular and mortality outcomes from large T1DM and T2DM randomized clinical trials that have focused on the relationship between glycemic control and complications. From these, it is clear, that more intensive glycemic control in both T1DM and T2DM prevents or delays microvascular complications, specifically retinopathy and albuminuria. In contrast the data concerning glucose control and macrovascular complications are more complex. In the context of relatively short clinical trials, more intensive glucose control has an overall neutral effect on cardiovascular events. In longer term follow-up investigations, however, a statistically significant beneficial effect eventually emerged in both the DCCT (Type 1) and the UKPDS (Type 2.) Some have therefore proposed that there may be a ‘legacy effect’ from previous tight glycemic control on these macrovascular outcomes – something that may not be appreciated for several decades. Notably, however, in ACCORD, an increase in mortality was observed in those patients assigned to the most intensive glucose-lowering therapy. This has raised concerns that overly aggressive glycemic targets in older patients at high cardiovascular risk may be problematic. So, HbA1c targets should be individualized to the patient and disease state. Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359: DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353: Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358: Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow-up * in T1DM

2. BACKGROUND Overview of the pathogenesis of T2DM
ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 2. BACKGROUND Overview of the pathogenesis of T2DM Insulin secretory dysfunction Insulin resistance (muscle, fat, liver) Increased endogenous glucose production Decreased incretin effect Deranged adipocyte biology The pathogenesis of T2DM is complex with multiple defects in multiple organ systems. Insulin resistance appears to be a primary defect, followed by relative beta cell failure with insulin secretory abnormalities, and increased endogenous (hepatic) glucose production. There are also derangements in incretin physiology and in the certain aspects of adipocyte biology. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Multiple, Complex Pathophysiological Abnormalities in T2DM
gut carbohydrate delivery & absorption incretin effect pancreatic insulin secretion ? pancreatic glucagon secretion _ HYPERGLYCEMIA This slide provides a broad overview of the main pathophysiological defects in type 2 diabetes. Insulin resistance is demonstrated in peripheral tissues, such as skeletal muscle and adipocytes. The pancreas develops relative insulin secretory failure and is no longer provide the amount of insulin required for normal glucose. The pancreas also demonstrates a failure of the normal suppression of glucagon after meals. This may be mediated through abnormalities in the incretin axis. Hepatic glucose production is also increased. Renal glucose output is set at a higer threshold than normal. Many of these defects may be influenced by abnormal central control of metabolism. _ + peripheral glucose uptake hepatic glucose production renal glucose excretion Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple, Complex Pathophysiological Abnormalities in T2DM
DA agonists T Z D s Metformin S U s Glinides DPP-4 inhibitors GLP-1R agonists A G I s Amylin mimetics Insulin Bile acid sequestrants gut carbohydrate delivery & absorption incretin effect pancreatic insulin secretion ? pancreatic glucagon secretion _ HYPERGLYCEMIA Anti-hyperglycemic drugs for patients with T2DM are targeted at one or more of the pathophysiological abnormalities of this disease. On this slide, the main sites of action of the currently available 12 individual drug classes is depicted. Combination glucose-lowering therapy has become a standard treatment strategy when patients do not adequately respond to a single agent (often metformin.) _ + peripheral glucose uptake hepatic glucose production renal glucose excretion Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

3. ANTI-HYPERGLYCEMIC THERAPY
ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets HbA1c < 7.0% (mean PG  mg/dl [ mmol/l]) Pre-prandial PG <130 mg/dl (7.2 mmol/l) Post-prandial PG <180 mg/dl (10.0 mmol/l) Individualization is key: Tighter targets ( %) - younger, healthier Looser targets ( %+) - older, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia In general, the goal in diabetes is to reduce glucose so that the glycated hemoglobin (HbA1c) concentration is reduced to 7% or less. Individualization of treatment targets is important, however. Young patients may benefit from tighter control, below 6.5%, since they are apt to have more years of life and exposure to hyperglycemia which can lead to long-term vascular complications. In contrast, in older individuals, especially those with multiple comorbidities, established vascular complications, or with a predisposition to hypoglycemia, more conservative targets are necessary, such as 7.5 – 8.0% or even higher, depending on the patient’s condition. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 PG = plasma glucose

This is a depiction of the elements of decision-making used to determine the intensivenss of efforts to achieve glycemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. In general, most patients should be targeted to <7%, but as previously discussed, tighter targets may benefit younger patients whereas in older individuals, a more conservative approach is necessary. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

Here is on element of decision-making used to determine appropriate efforts to achieve glycemic targets – the risks potentially associated with drug side effects, especially hypoglycemia. Again, greater concerns about this domain is represented by increasing height of the ramp. Less risk justifies more stringent efforts to lower HbA1c, whereas higher risk compels less stringent efforts. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

Here is another element of decision-making used to determine appropriate efforts to achieve glycemic targets – diabetes duration. Less years of diabetes justifies more stringent efforts to lower HbA1c, whereas longer disease duration suggests the need for less stringent efforts. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

Another element to consider is life expectancy
Another element to consider is life expectancy. Longer life expectancy justifies more stringent efforts to lower HbA1c, whereas more conservative efforts are acceptable when life expectancy is shorter. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

Important comorbidities (i. e
Important comorbidities (i.e. significant medical conditions other than diabetes) are another patient characteristic that drives decision making re A1c targets. Being in otherwise good health justifies more stringent efforts to lower HbA1c, whereas extensive comorbid conditions may compel the need for less stringent efforts. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

Similarly, the clinician should weigh the presence of established vascular complications. Having no vascular complications justifies more stringent efforts to lower HbA1c, whereas advanced complications mandates a more conservative approach. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

Here represented is the patient’s attitude and expected treatment efforts, an important element to consider when determining A1c targets. More stringent efforts are possible in highly motivated, adherent patients with excellent self-care capacities. Such efforts are not possible when the patient is not motivated, non-adherent, and has poor self-care capacities. This is particularly the case when the treatment program requires substantial patient engagement. Of course, it is the clinician’s obligation to help motivate the patient and improve their adherence and self-care efforts. So, this element is potentially modifiable. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

Another potentially modifiable patient feature involves his or her resources and support systems. When these are not available, more stringent efforts will be more challenging. If readily available, more aggressive approaches are possible. As in the previous slide, the care team can help in certain aspects of this domain, such as assisting the patient in pursuing drug discounts, more advantageous insurance coverage, etc. A reminder that, where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. Note that this ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. (Adapted with permission from Ismail-Beigi et al, Ann Intern Med 2011;154: )

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle Weight optimization Healthy diet Increased activity level Non-pharmacological options are critically important – they are cost effective and have no side effects, per se. Patients with T2DM should become more physically active, eat a healthy diet and try to optimize body weight. These efforts will result in less insulin resistance, with better blood glucose control the result. There are also additional health benefits from such interventions. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non-insulin injectables Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors SGLT-2 inhibitors GLP-1 receptor agonists Meglitinides a-glucosidase inhibitors Colesevelam Dopamine-2 agonists Amylin mimetics Here are the currently available non-insulin anti-hyperglycemic drug classes. Those on the left are the most popular in the U.S. and Europe. Those on the right are less commonly used and may be considered in certain circumstances. Clinicians should become facile with at least the major glucose-lowering drug classes, including insulin, to optimally manage patients with T2DM. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38: ; Diabetologia 2015; /s

Oral Class Mechanism Advantages Disadvantages Cost
Biguanides Activates AMP-kinase (?other)  Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ?  CVD Gastrointestinal Lactic acidosis (rare) B-12 deficiency Contraindications Low Sulfonylureas Closes KATP channels  Insulin secretion  Microvascular risk Hypoglycemia  Weight Low durability ? Blunts ischemic preconditioning Meglitinides  Postprandial glucose Dosing flexibility Dosing frequency Mod. TZDs PPAR-g activator  Insulin sensitivity Durability  TGs (pio)  HDL-C ?  CVD events (pio) Edema/heart failure Bone fractures  LDL-C (rosi) ?  MI (rosi) Here are some of the older oral drug classes used in T2DM. The table describes the mechanism of action of each class, its advantages, disadvantages and cost. Less commonly used classes are denoted in grey font. Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015; /s

Oral Class Mechanism Advantages Disadvantages Cost
a-Glucosidase inhibitors Inhibits a-glucosidase Slows carbohydrate digestion / absorption No hypoglycemia Nonsystemic  Postprandial glucose ?  CVD events Gastrointestinal Dosing frequency Modest  A1c Mod. DPP-4 inhibitors Inhibits DPP-4 Increases incretin (GLP-1, GIP) levels Well tolerated Angioedema / urticaria ? Pancreatitis ?  Heart failure High Bile acid sequestrants Bind bile acids ?  Hepatic glucose production  LDL-C Dopamine-2 agonists Activates DA receptor Alters hypothalamic control of metabolism  insulin sensitivity No hypoglyemia Dizziness, fatigue Nausea Rhinitis SGLT2 inhibitors Inhibits SGLT2 in proximal nephron Increases glucosuria  Weight  BP Effective at all stages GU infections Polyuria Volume depletion  LDL-C Cr (transient) Additional oral agent classes used in T2DM are included on this slide. The table describes the mechanism of action of each class, its advantages, disadvantages and cost. Less commonly used classes are denoted in grey font. Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015; /s

Injectable Class Mechanism Advantages Disadvantages Cost
Amylin mimetics Activates amylin receptor  glucagon  gastric emptying  satiety  Weight  Postprandial glucose Gastrointestinal Modest  A1c Hypo if insulin dose not reduced Dosing frequency Training requirements High GLP-1 receptor agonists Activates GLP-1 R  Insulin,  glucagon No hypoglycemia  Some CV risk factors ? Pancreatitis  Heart rate Medullary ca (rodents) Insulin Activates insulin receptor Myriad Universally effective Unlimited efficacy  Microvascular risk Hypoglycemia Weight gain ? Mitogenicity Patient reluctance Variable Here now are the injectable drugs used in T2DM. The table describes the mechanism of action of each class, its advantages, disadvantages and cost. Less commonly used classes are denoted in grey font. Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38: ; Diabetologia 2015; /s

Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, the usual transition being vertical, from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). The figure denotes relative glucose lowering efficacy, risk of hypoglycemia, effect on body weight, other side effects and approximate relative cost for each drug class. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis, unless there are contraindications.

If the A1c target is not achieved after ~3 months, there is no clearly preferred second agent after metformin. Each drug has its advantages and disadvantages, and what might be best for one patient may not be so for the next. In general, the clinician should consider one of 6 treatment options combined with metformin (i.e., dual combination): a sulfonylurea, TZD, DPP-4 inhibitor, SLGT2 inhibitor, GLP-1 receptor agonist or basal insulin. The major update to this figure from 2012 is the inclusion of the SGLT2 inhibitors. Note that the order in the chart is determined by historical introduction and route of administration and is not meant to imply any specific preference. Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects, especially hypoglycemia. Shared decision-making with the patient may help in the selection of therapeutic options. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider these in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects.

If the A1c target is still not achieved after ~3 months and appropriate drug dosage titration, add a third agent (i.e., triple combination therapy), with mechanisms of action should complement each other. Options obviously become more limited as one progresses down the figure. When glucose levels are especially high, a regimen that incorporates basal insulin should be strongly considered, especially if the patient is symptomatic. One important benefit of insulin is its near universal effectiveness when dosed properly. Drug choice is based on patient preferences as well as various patient, disease, and drug characteristics, with the goal being to reduce glucose concentrations while minimizing side effects, especially hypoglycemia. Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider in patients with irregular meal schedules or who develop late postprandial hypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects.

Previously, when combinations of multiple oral agents (i. e
Previously, when combinations of multiple oral agents (i.e., up to triple combination therapy) were no longer effective at controlling blood glucose, insulin was typically added, initially as a single injection of basal insulin. If this was or became ineffective in controlling HbA1c, post-prandial hyperglycemia was usually to blame. Adding several injections of rapid-acting insulin analogues (‘basal-bolus’ insulin therapy) would be the next step to control meal time glycemic excursions. Over the past several years, there has been increasing evidence that the combination of basal insulin with a GLP-1 receptor agonist may provide equal glucose lowering effect as up to 3 injections of meal time insulin, yet with weight loss instead of weight gain, and with less hypoglycemia. This updated figure therefore underscores the potential value of this specific combination. It should be considered in patients who appear to need more than basal insulin, with or without oral agents. In those patients who do not respond adequately to the addition of a GLP-1 receptor agonist to basal insulin, the “basal–bolus” insulin strategy should be used instead (or twice daily premixed insulin.) In selected patients at this stage of disease, the addition of an SGLT2 inhibitor may further improve control and reduce the amount of insulin required. This is particularly an issue when large doses of insulin are required in obese, highly insulin-resistant patients. Another, older, option, the addition of a TZD (usually pioglitazone), also has an insulin-sparing effect and may also reduce HbA1c, albeit at the expense of weight gain, edema, and increased heart failure risk.

In patients intolerant of, or with contraindications to metformin, consider initial drug from other classes depicted under “Dual therapy” and proceed accordingly. In this circumstance, while published trials are generally lacking, it is reasonable to consider three-drug combinations that do not include metformin. Consider starting with 2-drug combinations in patients with very high HbA1c (e.g. ≥9%) to achieve control more rapidly (although a step-wise approach will eventually the patient to target as well.) Insulin has the advantage of being effective where other agents may not be and should be considered a part of any combination regimen when hyperglycemia is severe, especially if the patient is symptomatic or if any catabolic features (weight loss, any ketosis) are evident. Consider initiating combination injectable therapy with insulin when blood glucose is >300–350 mg/dL (>16.7–19.4 mmol/L) and/or HbA1c >10–12%. Potentially, as the patient’s glucose toxicity resolves, the regimen can be subsequently simplified.

What follows are variations of the main treatment recommendations (Figure 2), to help guide the clinician in choosing agents which may be most appropriate under certain common clinical scenarios: to avoid weight gain to avoid hypoglycemia, and to minimize costs. Here is the variation when a major goal is to avoid hypoglycemia. Options are limited to TZDs, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. (Of course, other drugs can be used, but cautiously if the over-riding goal is to avoid hypoglycemia.)

Here is the variation of Figure 2 when a major goal is to avoid weight gain. Options are limited to DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. (Of course, other drugs can be used, but cautiously if the over-riding goal is to avoid weight gain.)

Here is the variation of Figure 2 when a major goal is to minimize cost. Treatment is limited to metformin, sulfonylureas, TZD (mainly pioglitazone) and certain insulins (human insulins.)

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulins Human Insulins - Neutral protamine Hagedorn (NPH) - Regular human insulin - Pre-mixed formulations Insulin Analogues - Basal analogues (glargine, detemir, degludec) - Rapid analogues (lispro, aspart, glulisine) Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38: ; Diabetologia 2015; /s Several insulin options are available, from older human insulins to newer analogues. Each category also includes premixed formulations which combine intermediate-acting and either short- or rapid-acting insulins.

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulins Rapid (Lispro, Aspart, Glulisine) Short (Regular) Insulin level Here is a diagrammatic representation of the approximate pharmacokinetic properties of various insulin formulations. Understanding the onset, peak and duration of action of insulin products is key for successful management of patients with diabetes. Long (Detemir) (Degludec) Long (Glargine) Hours Hours after injection

Basal insulin alone is usually the optimal initial regimen, beginning at U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. In patients still not at target after basal insulin has been adequately titrated, and the patient is willing to take >1 injections, there are several options. First, consider GLP-1 receptor agonists (see Fig. 2). The combination of basal insulin + GLP-1RA is becoming well established after several studies confirmed its efficacy on par with more complex multi-dose insulin regimens, but with less hypoglycemia and with weight loss instead of weight gain. If such an approach is not possible or has been tried and proven unsuccessful, there are 3 possible advanced insulin regimens: Adding 1 injection of a rapid acting insulin analogue before the largest meal, Adding 2-3 injections of a rapid acting insulin analogue before 2-3 meals, or Using premixed insulin BID Each approach has its advantages and disadvantages. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient. Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy.

4. OTHER CONSIDERATIONS Age Weight
ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 4. OTHER CONSIDERATIONS Age Weight Sex / racial / ethnic / genetic differences Comorbidities Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia-prone Here are some other considerations in designing an optimal glucose lowering drug regimen for patients. Age of the patient may influence drug choice mainly through the avoidance of certain adverse effects, such as hypoglycemia. The patient’s current weight (and attitude toward their weight) may also lead one towards or away from certain drug classes. Patient sex is likely more of a consideration in discussing certain side effects (e.g., bone loss from TZDs.) We know relatively little about which racial groups or ethnicities respond best to which agents. Those from East Asia tend to demonstrate more insulin deficiency, whereas people from South Asia and parts of Latin America, as well as Native Americans, exhibit higher degrees of insulin resistance. How this translates to drug choice is arguable, in the absence of specific clinical trials testing these questions. Of course, there are certain monogenic forms of daibetes (e.g., MODY’s) that may respond best to specific agents, such as sulfonylureas. However, since typical T2DM is a polygenic disease, a targeted approach based on genomic information is unlikely to be more successful than simple therapeutic trials in the vast majority of patients. For now, to a large degree, drug side effects or concerns thereof guide drug choice. This is particularly so in the context of various comorbid conditions such as: CAD (? no sulfonylureas due to concerns about increased CV mortality and theoretical effects on ischemic preconditioning) Heart failure (no TZDs due to fluid retention; new possible cautions re DPP-4 inhibitors) CKD (if advanced, no metformin because of lactic acidosis risk, especially if GFR <30; no SGLT2 inhibitors because not effective when eGFR <45-60) Liver disease (pioglitazone may be favored in steatosis, if liver disease is mild. Otherwise, insulin may be safest choice since other medicines have not been extensively tested in liver disease patients), and Propensity to hypoglcyemia especially if hypoglycemia unawareness has become established (avoid sulfonylureas and insulin if possible) Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

4. FUTURE DIRECTIONS / RESEARCH NEEDS
ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 4. FUTURE DIRECTIONS / RESEARCH NEEDS Comparative effectiveness research Focus on important clinical outcomes Contributions of genomic research Perpetual need for clinical judgment! More data are needed to optimally manage our patients with T2DM. Not enough comparative effectiveness research is available. These studies are underway (e.g., GRADE trial, sponsored by NIH.) In the future, through genomic research, clinicians may have more information about which patients respond to a greater or lesser degree to individual drug types (or risk of side effects.) Good clinical judgment by seasoned clinicians, however, will always be important. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596

Diet, exercise, & education: foundation of any T2DM therapy program
ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 KEY POINTS Glycemic targets & BG-lowering therapies must be individualized, based on a variety of patient and disease characteristics. Diet, exercise, & education: foundation of any T2DM therapy program Unless contraindicated, metformin remains the optimal first-line drug. After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable. Try to minimize side effects. Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain BG control. All treatment decisions should be made in conjunction with the patient (focusing on his or her preferences, needs & values.) Comprehensive CV risk reduction - a major focus of therapy Summary points of the 2012 ADA-EASD Position Statement and its 2015 update. Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38: ; Diabetologia 2015; /s

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association.

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Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association.

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