Transcript Insulin
تجویز منطقی دارو در دیابت نوع 2 ارائه توسط :دکتر نوشین خلیلی فوق تخصص غدد عضو هیئت علمی دانشکده پزشکی اصفهان شعار :WHOغلبه بر دیابت 1. BACKGROUND • Overview of the pathogenesis of Type 2 diabetes 2. ANTI-HYPERGLYCEMIC THERAPY • • Glycemic targets Therapeutic options - Oral agents & non-insulin injectables - Insulin Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Type 2 diabetes is a chronic metabolic condition characterised by insulin resistance that is, the body's inability to effectively use insulin and insufficient pancreatic insulin production, resulting in high blood glucose levels (hyperglycaemia). Criteria for the diagnosis of diabetes FPG≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8h.* OR 2-h PG ≥ 200 mg/dL (11.1mmol/L) during an OGTT. OR A1C ≥ 6.5% (48 mmol/mol). OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1 mmol/L). *In the absence of unequivocal hyperglycemia, results should be confirmed by repeat testing. Overview of the pathogenesis of T2DM - Insulin secretory dysfunction Insulin resistance (muscle, fat, liver) Increased endogenous glucose production Decreased incretin effect Deranged adipocyte biology Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Multiple, Complex Pathophysiological Abnormalities in T2DM pancreatic insulin secretion incretin effect _ gut carbohydrate delivery & absorption pancreatic glucagon secretion ? HYPERGLYCEMIA _ + hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Multiple, Complex Pathophysiological Abnormalities in T2DM GLP-1R agonists Insulin Glinides S U s incretin effect DPP-4 inhibitors Amylin mimetics _ pancreatic insulin secretion pancreatic glucagon secretion DA agonists AGIs gut carbohydrate delivery & absorption ? HYPERGLYCEMIA Metformin _ Bile acid sequestrants + hepatic glucose production SGLT2 I renal glucose excretion TZDs peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 2. ANTI-HYPERGLYCEMIC THERAPY • Glycemic targets - HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 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 (6.0 - 6.5%) - younger, healthier Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia PG = plasma glucose Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 From guidelines to individual My resident called to inform me that we had just received a new admission with a broken hip Mr. O, an 86 -year –old man, He worked all his life and was still able to take on smaller jobs, such as cutting grass, for pay. He and his older brother, aged 92,lived together. brothers never married and his older brother began to develop dementia, Mr. O was his brother's primary caretaker. Mr. O had never had a serious illness and had not seen doctors until he received his Medicare card. Mr. O’s first encounter with a physician was when he was a robust 80-yearold on no medications . Initial blood pressure was 150/96 mmHg, and he had no abnormalities on physical examination . Baseline laboratories showed a blood glucose of 180 mg/dL. Eye grounds were not examined, ECG was normal, and he had no bruits in his neck. He was advised to come back for a fasting glucose test and total lipids . The repeated blood sugar was 170 mg/dl , cholesterol was 220mg/dl,and A1c was 8.5% Initial therapy consisted of an ACE inhibitor and metformin, and he was seen every 3 months to adjust medications. Both the blood pressure and the A1c remained stubbornly elevated, and a calcium-channel blocker was prescribed. A second oral hypoglycemic agent was started in an attempt to further reduce his A1c. When he began to get up every 2 hours to urinate at night, doxazosin was initiated. It was at that time that he became lightheaded on rising from the sitting position. During the next visit, his new physician gave him a brochure and a copy of the first supplement of American Diabetes Association His systolic blood pressure remained in the 150- to 160-mm Hg range, and his A1c was stuck at 8.5%. Long acting insulin was started. Soon afterward, he developed nightmares and noticed unsteadiness when he got up at night to urinate. His A1c was unchanged at 8%, his blood pressure was 154/92 mm Hg, and his dose of the calcium-channel blocker was doubled. All of these changes occurred about 3 weeks before admission to our hospital. The night before admission, he got up to urinate, fell, and broke his hip. He was able to reach the telephone to call the local volunteer fire department. When the paramedics arrived, his systolic blood pressure was 80 mm Hg and the diastolic pressure was too low to register. His blood sugar was 40 mg/dL, and he was given 50% glucose solution with immediate improvement of all altered vital signs. He was transferred from the local hospital to my hospital, where on admission he was alert and oriented and in pain from the broken hip. His creatinine level was 1.2 mg/dL (the previous level was 0.9 mg/dL). About 16 hours after the fall and fracture, he was taken to the operating room, where he had a total hip arthroplasty under general anesthesia lasting a little more than 2 hours. While in the recovery room, he was noted to have difficulty using his right hand and was not speaking clearly. Over the next few hours, it became clear that he had a cerebrovascular accident. He had a stormy postoperative course with multiple complications, including C. difficile colitis and an increase of creatinine to 2.0 mg/dL. He was started on physical therapy and eventually transferred to a rehabilitation facility where he remained 3 months after the fall, unlikely to ever live independently. Meanwhile, his brother with dementia had to be admitted to a nursing home with a memory care unit. During this ordeal, Mr. O exhausted his meager savings and required Medicaid funding, which resulted in a lien being placed on his home. In retrospect, he got into a relentless downhill medical care spiral fueled by interventions based on “evidence-based” guidelines to tightly control both the blood sugar and the blood pressure—well-known targets on which physicians' performances are judged. His doctor may have received a bonus for adhering to the guidelines, but Mr. O lost his home and independence. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects Disease duration Life expectancy Important comorbidities Established vascular complications Patient attitude and expected treatment efforts Resources and support system Approach to the management of hyperglycemia HbA1c more stringent 7% low less stringent high newly diagnosed long-standing Usually not modifiable long short absent few / mild severe absent few / mild severe highly motivated, adherent, excellent self-care capacities Readily available less motivated, non-adherent, poor self-care capacities Potentially modifiable limited Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Approach to the Management of Hyperglycemia Risks potentially associated with hypoglycemia, other drug adverse effects more stringent Low Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM HbA1c 7% less stringent High Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Approach to the Management of Hyperglycemia more stringent Disease duration Newly diagnosed Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM HbA1c 7% less stringent Long-standing Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Approach to the Management of Hyperglycemia more stringent Life expectancy Long Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM HbA1c 7% less stringent Short Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Approach to the Management of Hyperglycemia more stringent Important comorbidities Absent Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM HbA1c 7% Few / Mild less stringent Severe Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Approach to the Management of Hyperglycemia more stringent Established vascular complications Absent Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM HbA1c 7% Few / Mild less stringent Severe Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Approach to the Management of Hyperglycemia more stringent Patient attitude & expected treatment efforts HbA1c 7% Highly motivated, adherent, excellent self-care capacities less stringent Less motivated, non-adherent, poor self-care capacities P O T E N T I A L LY MODIFIABLE Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Approach to the Management of Hyperglycemia more stringent Resources and support systems HbA1c 7% Readily available less stringent Limited P O T E N T I A L LY MODIFIABLE Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 2. ANTI-HYPERGLYCEMIC THERAPY • Therapeutic options: Lifestyle - Weight optimization - Healthy diet - Increased activity level Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 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 Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Oral Class Biguanides Mechanism • Activates AMPkinase (?other) • Hepatic glucose production Advantages • Extensive experience • No hypoglycemia • Weight neutral • ? CVD Sulfonylureas • Closes KATP channels • Extensive experience • Insulin secretion • Microvascular risk Disadvantages • Gastrointestinal Low • Lactic acidosis (rare) • B-12 deficiency • Contraindications • Hypoglycemia • Weight • Low durability • ? Blunts ischemic preconditioning Meglitinides • Closes KATP channels • Postprandial glucose • Hypoglycemia • Dosing flexibility • Insulin secretion • Weight • ? Blunts ischemic preconditioning • Dosing frequency TZDs • PPAR-g activator • Insulin sensitivity • No hypoglycemia • Durability • TGs (pio) • HDL-C • ? CVD events (pio) Table 1. Properties of anti-hyperglycemic agents Cost • Weight • Edema/heart failure • Bone fractures • LDL-C (rosi) • ? MI (rosi) Low Mod. Low Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Oral Class Mechanism a-Glucosidase • Inhibits a-glucosidase inhibitors • Slows carbohydrate digestion / absorption Advantages Disadvantages Cost • 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 • No hypoglycemia • Well tolerated • Angioedema / urticaria • ? Pancreatitis • ? Heart failure High Bile acid sequestrants • Bind bile acids • ? Hepatic glucose production • No hypoglycemia • LDL-C • Gastrointestinal • Modest A1c • Dosing frequency High Dopamine-2 agonists • Activates DA receptor • Alters hypothalamic control of metabolism • insulin sensitivity • No hypoglyemia • ? CVD events • Modest A1c • Dizziness, fatigue • Nausea • Rhinitis High SGLT2 inhibitors • Inhibits SGLT2 in proximal nephron • Increases glucosuria • Weight • No hypoglycemia • BP • Effective at all stages • GU infections High • Polyuria • Volume depletion • LDL-C • Cr (transient) Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Injectabl e Class Mechanism Advantages Disadvantages Cost Amylin mimetics • Activates amylin receptor • glucagon • gastric emptying • satiety • Gastrointestinal • Weight • Postprandial glucose • Modest A1c • Injectable • Hypo if insulin dose not reduced • Dosing frequency • Training requirements GLP-1 receptor agonists • Activates GLP-1 R • Insulin, glucagon • gastric emptying • satiety • Weight • No hypoglycemia • Postprandial glucose • Some CV risk factors • Gastrointestinal High • ? Pancreatitis • Heart rate • Medullary ca (rodents) • Injectable • Training requirements Insulin • Activates insulin receptor • Myriad • Universally effective • Unlimited efficacy • Microvascular risk • Hypoglycemia • Weight gain • ? Mitogenicity • Injectable • Patient reluctance • Training requirements Table 1. Properties of anti-hyperglycemic agents High Variable Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Noninsulin Agents Available for T2D Class a-Glucosidase inhibitors Primary Mechanism of Action Delay carbohydrate absorption from intestine Decrease glucagon secretion Slow gastric emptying Increase satiety Decrease HGP Increase glucose uptake in muscle Decrease HGP? Increase incretin levels? Agent(s) Acarbose Miglitol Available as Precose or generic Glyset Pramlintide Symlin Metformin Glucophage or generic Colesevelam WelChol Increase glucose-dependent insulin secretion Decrease glucagon secretion Alogliptin Linagliptin Saxagliptin Sitagliptin Nesina Tradjenta Onglyza Januvia Dopamine-2 agonist Activates dopaminergic receptors Bromocriptine Cycloset Glinides Increase insulin secretion Nateglinide Repaglinide Starlix or generic Prandin Amylin analogue Biguanide Bile acid sequestrant DPP-4 inhibitors DPP-4 = dipeptidyl peptidase; HGP = hepatic glucose production. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Continued on next slide Noninsulin Agents Available for T2D Class Primary Mechanism of Action GLP-1 receptor agonists SGLT2 inhibitors Sulfonylureas Agent(s) Available as Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety Albiglutide Dulaglutide Exenatide Exenatide XR Liraglutide Tanzeum Trulicity Byetta Bydureon Victoza Increase urinary excretion of glucose Canagliflozin Dapagliflozin Empagliflozin Invokana Farxiga Jardiance Glimepiride Glipizide Glyburide Amaryl or generic Glucotrol or generic Diaeta, Glynase, Micronase, or generic Pioglitazone Rosiglitazone Actos Avandia Increase insulin secretion Increase glucose uptake in muscle and fat Decrease HGP Thiazolidinediones GLP-1 = glucagon-like peptide; HGP = hepatic glucose production; SGLT2 = sodium glucose cotransporter 2. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Continued from previous slide Effects of Agents Available for T2D Met FPG lowering PPG lowering Mod Mild GLP1RA Mild to mod* Mod to marked SGLT2I Mod Mild DPP4I Mild Mod TZD Mod Mild AGI Neutral Mod Coles Mild Mild BCR-QR SU/ Glinide Insulin Pram Neutral SU: mod Glinide: mild Mod to marked (basal insulin or premixed) Mild Mod Mod to marked (short/ rapidacting insulin or premixed) Mod to marked Mild AGI = a-glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; FPG = fasting plasma glucose; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; Mod = moderate; PPG = postprandial glucose; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Mild: albiglutide and exenatide; moderate: dulaglutide, exenatide extended release, and liraglutide. Continued on next slide Effects of Agents Available for T2D NAFLD benefit Hypoglycemia Weight Met GLP1RA SGLT2I DPP4I TZD AGI Coles BCR-QR SU/ Glinide Insulin Pram Mild Mild Neutral Neutral Mod Neutral Neutral Neutral Neutral Neutral Neutral Mod to severe* Neutral Gain Loss Neutral Neutral Neutral Neutral Neutral Neutral Neutral Neutral SU: mod to severe Glinide: mild to mod Slight loss Loss Loss Neutral Gain Neutral Neutral Neutral Gain AGI = a-glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; Mod = moderate; NAFLD, nonalcoholic fatty liver disease; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Especially with short/ rapid-acting or premixed. Continued from previous slide Effects of Agents Available for T2D Met Renal impairment/ GU GI adverse effects GLP1RA SGLT2I Contra- Exenatide indicated contraGU in stage indicated infection 3B, 4, 5 CrCl <30 risk CKD mg/mL DPP4I TZD AGI Coles BCR-QR Dose adjustment (except linagliptin) May worsen fluid retention Neutral Neutral Neutral SU/ Glinide Insulin Increased Increased risks of hypohypoglycemia glycemia risk and fluid retention Pram Neutral Mod Mod* Neutral Neutral* Neutral Mod Mild Mod Neutral Neutral Mod CHF Neutral Neutral Neutral Neutral† Mod Neutral Neutral Neutral Neutral Neutral Neutral CVD Possible benefit Neutral Neutral Neutral Neutral Neutral Neutral Safe ? Neutral Neutral Bone Neutral Neutral Bone loss Neutral Mod bone Neutral loss Neutral Neutral Neutral Neutral Neutral AGI = a-glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; CHF = congestive heart failure; CVD = cardiovascular disease; DPP4I = dipeptidyl peptidase 4 inhibitors; GI = gastrointestinal; GLP1RA = glucagon-like peptide 1 receptor agonists; GU = genitourinary; Met = metformin; Mod = moderate; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Caution in labeling about pancreatitis. †Caution: possibly increased CHF hospitalization risk seen in CV safety trial. Continued from previous slide Q4. How are glycemic targets achieved for T2D? Monotherapy, Dual Therapy, and Triple Therapy for T2D Monotherapy* Dual therapy* Triple therapy* Metformin (or other firstline agent) plus First- and second-line agent plus Metformin GLP1RA GLP1RA GLP1RA SGLT2I SGLT2I SGLT2I DPP4I TZD† DPP4I TZD† Basal insulin† AGI Basal insulin† DPP4I TZD† Colesevelam Colesevelam SU/glinide† BCR-QR BCR-QR AGI AGI SU/glinide† SU/glinide† AGI = a-glucosidase inhibitors; BCR-QR = bromocriptine quick release; Coles = colesevelam; DPP4I = dipeptidyl peptidase 4 inhibitors; GLP1RA = glucagon-like peptide 1 receptor agonists; Met = metformin; SGLT2I = sodium-glucose cotransporter 2 inhibitors; SU = sulfonylureas; TZD = thiazolidinediones. *Intensify therapy whenever A1C exceeds individualized target. Boldface denotes little or no risk of hypoglycemia or weight gain, few adverse events, and/or the possibility of benefits beyond glucose-lowering. † Use with caution. 37 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin Combination Figure 2. Anti-hyperglycemic Basal Insulin + injectable therapy‡ in T2DM: General therapy + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin Combination Figure 2. Anti-hyperglycemic Basal Insulin + injectable therapy‡ in T2DM: General therapy + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin Combination Figure 2. Anti-hyperglycemic Basal Insulin + injectable therapy‡ in T2DM: General therapy + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin Combination injectable therapy‡ + Basal Insulin + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs Metformin intolerance or contraindicati on Dual therapy† HbA1c ≥9% Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Uncontrolled hyperglycemia (catabolic features, BG ≥300-350 mg/dl, HbA1c ≥1012%) Combination injectable therapy‡ Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Basal Insulin + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Figure 2A. Antihyperglycemic therapy in T2DM: Avoidance of hypoglycemia Combination injectable therapy‡ Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Basal Insulin + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Figure 2B. Antihyperglycemic therapy in T2DM: Avoidance of weight gain Combination injectable therapy‡ Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Basal Insulin + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Healthy eating, weight control, increased physical activity & diabetes education Monotherapy Metformin Efficacy* Hypo risk Weight Side effects Costs high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Dual therapy† Efficacy* Hypo risk Weight Side effects Costs Metformin Metformin Sulfonylurea Thiazolidinedione DPP-4 inhibitor high moderate risk gain hypoglycemia low high low risk gain edema, HF, fxs low intermediate low risk neutral rare high + + Metformin Metformin + Metformin + + Metformin + SGLT2 inhibitor GLP-1 receptor agonist Insulin (basal) intermediate low risk loss GU, dehydration high high low risk loss GI high highest high risk gain hypoglycemia variable If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific factors): Metformin + Triple therapy Sulfonylurea + TZD Figure 2C. Antihyperglycemic therapy in T2DM: Minimization of costs Combination injectable therapy‡ Metformin + Thiazolidinedione + Metformin Metformin + + DPP-4 Inhibitor + SU SGLT-2 Inhibitor + SU SU Metformin + GLP-1 receptor agonist + Metformin + Insulin (basal) + TZD SU or DPP-4-i or DPP-4-i or TZD or TZD or TZD or DPP-4-i or SGLT2-i or SGLT2-i or SGLT2-i or DPP-4-i or Insulin§ or SGLT2-i or Insulin§ or Insulin§ or GLP-1-RA or GLP-1-RA or or Insulin§ or GLP-1-RA Insulin§ If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i: Metformin + Basal Insulin + Mealtime Insulin or GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 • 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) - Pre-mixed formulations Diabetes Care 2012;35:1364–1379; Diabetologia 2012;55:1577–1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 3. ANTI-HYPERGLYCEMIC THERAPY • Therapeutic options: Insulins Insulin level Rapid (Lispro, Aspart, Glulisine) Short (Regular) Long (Detemir) (Degludec) Long (Glargine) 0 22 2 4 24 6 Hours 8 10 12 14 16 Hours after injection 18 20 Rapid analogues (lispro, aspart, glulisine) Basal analogues (glargine, detemir, degludec) Dipeptidyl peptidase 4 (DPP-4) inhibitors Glucagon-like peptide-1 (GLP-1) is produced from the proglucagon gene in L-cells of the small intestine and is secreted in response to nutrients. GLP-1 exerts its main effect by stimulating glucose-dependent insulin release from the pancreatic islets It has also been shown to slow gastric emptying inhibit inappropriate post-meal glucagon release and reduce food intake . GLP-1 Has a Short Duration of Effect Due to Degradation by Dipeptidyl Peptidase IV (DPP-IV) DPP-IV His Ala 7 Glu Gly Thr Phe Thr Ser Asp Val 9 Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu 37 Phe Ile Ala Trp Adapted from Mentlein R. Eur. J. Biochem 1993;214:829-835. Leu Val Lys Gly Arg Gly GLP-1-based therapies, including the dipeptidyl peptidase 4 (DPP-4) inhibitors, do not usually cause hypoglycemia unless combined with therapies that can cause hypoglycemia. DPP-4 inhibitors have a modest effect on GLP-1 levels, compared with giving GLP-1 agonists GLP-1 Short half-life (2 minutes) Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) DPP-IV inhibition Extends endogenous GLP-1 half-life Approved in US: Sitagliptin (Merck) GLP-1 receptor agonists Mimic many of the glucoregulatory effects of GLP-1 Resistant to DPP-IV Approved in US: Exenatide Liraglutide Renal Glucose Reabsorption in Type 2 Diabetes Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule Renal glucose reabsorption is increased in type 2 diabetes Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose Wright EM, et al. J Intern Med. 2007;261:32-43. Sglt2 i SGLT2 I Canagliflozin is taken orally before the first meal of the day. The initial dose is 100 mg once daily, and it can be increased to 300 mg daily Dapagliflozin (10 mg once daily) can be taken any time of day, with or without food. Empagliflozin is taken orally once daily in the morning, with or without food .The initial dose is 10 mg daily, and it can be increased to 25 mg once daily to achieve glycemic goals. Amylin: The Other β Cell Hormone Pramlintide is a stable, soluble amylin analog that is administered by mealtime subcutaneous injection. It is available for use for both type 1 and insulin-treated type 2 diabetes. Pramlintide reproduces the actions of amylin and controls glucose without causing weight gain. Pramlintide HYPERTENSION/BLOOD PRESSURE CONTROL Screening and Diagnosis Blood pressure should be measured at every routine visit. Patients found to have elevated blood pressure should have blood pressure confirmed on a separate day. Goals Systolic Targets People with diabetes and hypertension should be treated to a systolic blood pressure goal of less than140 mmHg. Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals with diabetes, younger patients, albuminuria, one or more additional atherosclerotic cardiovascular disease risk factors. Diastolic Targets Individuals with diabetes should be treated to a diastolic blood pressure goal of<90 mmHg Lower diastolic targets, such as<80 mmHg, may be appropriate for certain individuals with diabetes Treatment Patients with blood pressure >120/80 mmHg should be advised on lifestyle changes to reduce blood pressure. Patients with confirmed office-based blood pressure >140/90 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely subsequent titration of pharmacological therapy to achieve blood pressure goals. Pharmacological therapy for patients with diabetes and hypertension should comprise a regimen that includes either an ACE inhibitor or an angiotensin receptor blocker but not both. Multiple-drug therapy (including a thiazide diuretic and ACE inhibitor/ angiotensin receptor blocker, at maximal doses) is generally required to achieve blood pressure targets. LIPID MANAGEMENT In adults, a screening lipid profile is reasonable At first diagnosis At the initial medical evaluation And/or at age 40 years and periodically Treatment recommendations and goals Intensify lifestyle therapy and optimize glycemic control for patients with Triglyceride levels >150 mg/dL and/or HDL cholesterol >40 mg/dL in men and >50 mg/dL in women For patients with fasting triglyceride levels > 500 mg/dL, evaluate for secondary causes and consider medical therapy to reduce the risk of pancreatitis For patients of all ages with diabetes and atherosclerotic cardiovascular disease, high-intensity statin therapy should be added to lifestyle therapy. Questions? 77 78