Diabetes management (Updated guidelines) Prof. Ashraf Aminorroaya 9 Azar 1396 Isfahan

Tailoring Treatment Diabetes treatment must be individualized, patient-centered, and culturally appropriate. Clinicians need to pay particular attention to populations that may be disproportionately at risk, and treatment must be individualized, patient-centered, and culturally appropriate. [CLICK] For example, some recent studies have recommended lowering the BMI cutpoint for testing in Asian Americans to a BMI of 23, instead of a BMI of 25 as in other adults. [CLICK] To decrease disparities, all providers and groups are encouraged to use the National Quality Forum’s National Voluntary Consensus Standards for Ambulatory Care—Measuring Healthcare Disparities [SLIDE] American Diabetes Association Standards of Medical Care in Diabetes. Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12 2

Diabetes Care Volume 40, April 2017

q N Engl J Med 2015;372:2197-206.

Approach to the Management of Hyperglycemia Patient/Disease Features A1C 7% more stringent less stringent Risks associated with hypoglycemia & other drug adverse effects low high Disease Duration newly diagnosed long-standing Life expectancy long short Important comorbidities absent Few/mild severe Established vascular complications absent Few/mild severe Patient attitude & expected treatment efforts highly motivated, adherent, excellent self-care capabilities less motivated, nonadherent, poor self-care capabilities Resources & support system This slide, “Approach to Management of Hyperglycemia,” depicts the elements of decision making used to determine appropriate efforts to achieve glycemic targets1 (Adapted with permission from Inzucchi et al.) You may have seen this before, but in case not we’ll walk through it briefly. Going down the left side you see a series of patient or disease characteristics with a corresponding A1C impact scale on the right. The small end of the triangle aligns with a more stringent A1C and the fatter end aligns with less stringent A1C. So taking the first one, the red triangle, risks associated with hypoglycemia and other drug adverse effects…. Clearly the risks are lower with a more stringent A1C and higher with a less stringent A1C. These are grouped into two categories, the [CLICK] top set consists of factors that are usually not modifiable and [CLICK] the bottom set may be potentially modifiable. 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 Those with long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty may benefit from less aggressive targets Providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such targets cannot be safely and reasonably achieved Severe or frequent hypoglycemia is an absolute indication for the modification of treatment regimens, including setting higher glycemic goals [SLIDE] readily available limited American Diabetes Association Standards of Medical Care in Diabetes. Glycemic targets. Diabetes Care 2016; 39 (Suppl. 1): S39-S46 References American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014;37(suppl 1):S25; Figure 1 Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi SE, Genuth S. Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials. Ann Intern Med 2011;154:554–559 7

Care Delivery Systems 33-49% of patients still do not meet targets for A1C, blood pressure, or lipids. 14% meet targets for all A1C, BP, lipids, and nonsmoking status. Progress in CVD control is slowing. Substantial system-level improvements are needed. Delivery system is fragmented, lacks clinical information capabilities, duplicates services & is poorly designed. Over the last ten years we’ve seen steady improvement in the proportion of patients with diabetes who are treated with statins and achieving recommended levels for A1C, blood pressure, and LDL, but nevertheless, 33-49% of patients still do not meet targets for glycemic, blood pressure, or cholesterol control, and [CLICK] only 14% meet targets for all three measures plus nonsmoking status. [CLICK] Evidence also suggests that our progress in control of cardiovascular disease is slowing. [CLICK] Even after adjusting for patient factors, the persistent variation in quality of diabetes care across providers and practice settings indicates that there is potential for substantial system-level improvements. [CLICK] A major barrier to optimal care is a delivery system that is often fragmented, lacks clinical information capabilities, duplicates services, and is poorly designed for the coordinated delivery of chronic care. [SLIDE] American Diabetes Association Standards of Medical Care in Diabetes. Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12 10

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Pharmacological approaches to Glycemic treatment This section has been renamed to highlight that this section focuses on Pharmacotherapy and includes updates on injectable insulin therapy, addition of cardiovascular risk reduction evidence and newly available biosimilar insulins Recommendations on Pharmacotherapy of type 2 diabetes Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy The algorithm for combination injectable therapy has been changed to reflect studies demonstrating The non-inferiority of basal + GLP-1 receptor agonist vs basal insulin plus rapid acting insulin vs two daily injections of premixed insulin The non-inferiority of multiple dose premixed insulin regimen vs basal bolus therapy T2DM, Type 2 diabetes mellitus; GLP-1 Glucagon like peptide 1 Diabetes Care 2017;40(Suppl. 1):S1–S138

Pharmacological approaches to Glycemic treatment (contd.) Recommendations on Pharmacotherapy of type 2 diabetes Consider initiating insulin therapy (with or without additional agents) in patients with newly diagnosed type 2 diabetes who are symptomatic and/or have A1C ≥10% (86 mmol/mol) and/or blood glucose levels ≥300 mg/dL (16.7 mmol/L) If noninsulin monotherapy at maximum tolerated dose does not achieve or maintain the A1C target after 3 months, add a second oral agent, a glucagon-like peptide 1 receptor agonist, or basal insulin A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include efficacy, hypoglycemia risk, impact on weight, potential side effects, cost, and patient preferences FDA approved once-daily combination products containing basal insulin plus a GLP-1 receptor agonist have been included: Insulin glargine plus lixisenatide - Insulin degludec plus liraglutide A1C, glycated hemoglobin; GLP-1 Glucagon like peptide 1 Diabetes Care 2017;40(Suppl. 1):S1–S138

Start with monotherapy unless: A1c is greater than or equal to 9%, consider dual therapy A1c is greater than or equal to 10 %, blood glucose is greater than or equal to 300 mg/dL or patient is markedly symptomatic, consider combination injectable therapy Monotherapy Metformin Lifestyle Management EFFICACY* high HYPO RISK low risk WEIGHT neutral/loss SIDE EFFECTS GI/lactic acidosis COSTS* low If A1c is not achieved approximately after 3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference- choice dependent on variety of patient- & disease-specific factors) Dual Therapy Metformin + Lifestyle Management Sulfonylurea Thiazolidinedione DPP-4 inhibitor SGLT2 inhibitor GLP-1 receptor agonist Insulin (Basal) EFFICACY* high intermediate highest HYPO RISK moderate risk low risk high risk WEIGHT gain neutral loss SIDE EFFECTS hypoglycemia Edema, HF, fxs rare GU, dehydration, fxs GI COSTS* low If A1c is not achieved approximately after 3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference- choice dependent on variety of patient- & disease-specific factors) Diabetes Care 2017;40(Suppl. 1):S1–S138

Contd. Dual Therapy Triple Therapy Metformin + Lifestyle Management Sulfonylurea + Thiazolidinedione + DPP-4 inhibitor + SGLT2 inhibitor + GLP-1 receptor agonist + Insulin (Basal) + or If A1c is not achieved approximately after 3 months of triple therapy, and patient (1) on oral combination, move to basal insulin or GLP-1 RA, (2) on GLP-1 RA, add basal insulin or (3) on optimally titrated basal insulin, addaGLP-1 RA or meal time insulin. Metformin therapy should be maintained, while other oral agents may be discontinued on an individual basis to avoid unnecessary complex or costly regimens. (i.e. adding fourth antihyperglycemic agent). TZD SU SU SU SU TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i SGLT2-i GLP-1-RA GLP-1-RA Insulin $ GLP-1-RA Insulin $ GLP-1-RA Insulin $ Insulin $ Insulin $ Combination Injectable Therapy Fig.8.1: Antihyperglycemic therapy in type 2 diabetes: general recommendations. The order in the chart is determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1 RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. $ Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al 2015 *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 Studyof Diabetes. Diabetes Care 2015;38:140–149 Diabetes Care 2017;40(Suppl. 1):S1–S138

FBG, Fasting blood glucose; SMBG, Self monitored blood glucose Fig. 8.2 Combination injectable therapy for type 2 diabetes Adapted with permission from Inzucchi et al. Initiate basal Insulin Usually with metformin +/- other noninsulin agent Start: 10U/day or 0.1-0.2 U/Kg/day Adjust: 10-15% or 2-4 units once or twice weekly to reach FBG target For Hypo: Determine & address cause; if no clear reason for hypo, dose by 4 units or 10-20% If A1c not controlled, consider combination injectable therapy Add 1 rapid-acting insulin injection before largest meal Start: 4 units, 0.1 U/Kg/day or 10% basal dose. If A1c <8%,consider basal by same amount Adjust: dose by 1-2 units or 10-15% once or twice weekly until SMBG target reached For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% Change to premixed insulin twice daily (before breakfast and supper) Add GLP-1 RA If not tolerated or A1C target not reached, change to 2 insulin injection regimen If goals are not met, consider changing to alternative insulin regimen If A1c is not controlled, advance to basal bolus If A1c is not controlled, advance to 3rd injection Add ≥ 2 rapid-acting insulin injection before meals (‘basal-bolus’) Start: 4 units, 0.1 U/Kg/day or 10% basal dose. If A1c <8%, consider basal by same amount Adjust: dose(s) by 1-2 units or 10-15% once or twice weekly to achieve SMBG target. For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% Change to premixed analog insulin 3 times daily (breakfast, lunch, supper) Start: Add additional injection before lunch Adjust: dose(s) by 1-2 units or 10-15% once or twice weekly to achieve SMBG target. For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% If goals are not met, consider changing to alternative insulin regimen FBG, Fasting blood glucose; SMBG, Self monitored blood glucose Diabetes Care 2017;40(Suppl. 1):S1–S138

Pharmacological approaches to Glycemic treatment (contd.) Recommendations for combination injectable therapy Recommendations at the level of 2 injections per day Either 1 rapid acting insulin, or GLP-1RA can be added to basal insulin Dotted line removed  and Premix BID is an option for intensification from basal insulin If one regimen is not effective, switching to the alternative insulin regimen may be considered (Premix BID, Basal+ Prandial, Basal+GLP-1 RA) Recommendations at the level of 3 injections per day Premix TID is included as an intensification option when patients fail to achieve targets on Premix BID regimens Patients can be considered to switch from one regimen to another (i.e., premixed analog insulin three times daily to basal bolus regimen or vice-versa) if A1C targets are not being met and/or depending on other patient considerations Recommendations for combination injectable therapy BID, twice daily; TID, thrice daily; GLP-1 RA, Glucagon like peptide 1 receptor agonist; A1C, glycated hemoglobin Diabetes Care 2017;40(Suppl. 1):S1–S138

FBG, Fasting blood glucose; SMBG, Self monitored blood glucose. Fig. 8.2 Combination injectable therapy for type 2 diabetes Adapted with permission from Inzucchi et al. Initiate basal Insulin Usually with metformin +/- other noninsulin agent Start: 10U/day or 0.1-0.2 U/Kg/day Adjust: 10-15% or 2-4 units once or twice weekly to reach FBG target For Hypo: Determine & address cause; if no clear reason for hypo, dose by 4 units or 10-20% If A1c not controlled, consider combination injectable therapy Add 1 rapid-acting insulin injection before largest meal Start: 4 units, 0.1U/Kg/day or 10% basal dose. If A1c <8%,consider basal by same amount Adjust: dose by 1-2 units or 10-15% once or twice weekly until SMBG target reached For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% Change to premixed insulin twice daily (before breakfast and supper) Add GLP-1 RA If not tolerated or A1C target not reached, change to 2 insulin injection regimen If goals are not met, consider changing to alternative insulin regimen If A1c is not controlled, advance to basal bolus If A1c is not controlled, advance to 3rd injection Add ≥ 2 rapid-acting insulin injection before meals (‘basal-bolus’) Start: 4 units, 0.1 U/Kg/day or 10% basal dose. If A1c <8%, consider basal by same amount Adjust: dose(s) by 1-2 units or 10-15% once or twice weekly to achieve SMBG target. For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% Change to premixed analog insulin 3 times daily (breakfast, lunch, supper) Start: Add additional injection before lunch Adjust: dose(s) by 1-2 units or 10-15% once or twice weekly to achieve SMBG target. For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% If goals are not met, consider changing to alternative insulin regimen FBG, Fasting blood glucose; SMBG, Self monitored blood glucose. Diabetes Care 2017;40(Suppl. 1):S1–S138

Pharmacological approaches to Glycemic treatment Recommendations for combination injectable therapy: Level of 2 injections per day Previous version Considered intensification with premix insulin twice daily as a less preferred alternative when intensifying insulin therapy from basal insulin compared to adding a mealtime insulin and the option to switch to premix insulin twice daily was presented as a dotted line The algorithm also did not include an option to switch to an alternative insulin regimen ( Basal+ prandial to Premix/ Premix to Basal + Prandial) when treatment goals were not met Changes in the current guidelines Dotted line removed and Premix BID is an option for intensification from basal insulin If one regimen is not effective, switching to the alternative insulin regimen may be considered (Basal+prandial ,Premix BID, Basal + GLP 1 RA) Each approach has its advantages and disadvantages and health care providers may choose the most appropriate regimen for their patients Recommendations for combination injectable therapy BID, twice daily; GLP-1 RA, Glucagon like peptide 1 receptor agonist Diabetes Care 2017;40(Suppl. 1):S1–S138

FBG, Fasting blood glucose; SMBG, Self monitored blood glucose. Fig. 8.2 Combination injectable therapy for type 2 diabetes Adapted with permission from Inzucchi et al. Initiate basal Insulin Usually with metformin +/- other noninsulin agent Start: 10U/day or 0.1-0.2 U/Kg/day Adjust: 10-15% or 2-4 units once or twice weekly to reach FBG target For Hypo: Determine & address cause; if no clear reason for hypo, dose by 4 units or 10-20% If A1c not controlled, consider combination injectable therapy Add 1 rapid-acting insulin injection before largest meal Start: 4 units, 0.1U/Kg/day or 10% basal dose. If A1c <8%,consider basal by same amount Adjust: dose by 1-2 units or 10-15% once or twice weekly until SMBG target reached For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% Change to premixed insulin twice daily (before breakfast and supper) Add GLP-1 RA If not tolerated or A1C target not reached, change to 2 insulin injection regimen If goals are not met, consider changing to alternative insulin regimen If A1c is not controlled, advance to basal bolus If A1c is not controlled, advance to 3rd injection new inclusion Add ≥ 2 rapid-acting insulin injection before meals (‘basal-bolus’) Start: 4 units, 0.1 U/Kg/day or 10% basal dose. If A1c <8%, consider basal by same amount Adjust: dose(s) by 1-2 units or 10-15% once or twice weekly to achieve SMBG target. For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% Change to premixed analog insulin 3 times daily (breakfast, lunch, supper) Start: Add additional injection before lunch Adjust: dose(s) by 1-2 units or 10-15% once or twice weekly to achieve SMBG target. For Hypo: Determine & address cause; if no clear reason for hypo, dose by 2-4 units or 10-20% If goals are not met, consider changing to alternative insulin regimen FBG, Fasting blood glucose; SMBG, Self monitored blood glucose. Diabetes Care 2017;40(Suppl. 1):S1–S138

TRIAD: Barriers to Adherence Patient factors: Remembering to get or take medicines Fear Depression Health beliefs Medication factors: Complexity Multiple daily dosing Cost Side effects System factors: Inadequate follow up or support These barriers to adherence include patient factors, such as remembering to get or take medicines, fear, depression, or health beliefs; [CLICK] medication factors such as complexity, multiple daily dosing, cost, side effects), and [CLICK] system factors, such as inadequate follow up or support. [SLIDE] American Diabetes Association Standards of Medical Care in Diabetes. Strategies for improving diabetes care. Diabetes Care 2016; 39 (Suppl. 1): S6-S12 26