Medical Care In Diabetes Bijan Iraj,MD Assistant Professor of Internal Medicine and Endocrinology Department of Endocrinology and Metabolism Isfahan Medical School.

Management of Type 2 Diabetes Mellitus DX HIS PE LAB + ECG REFFERAL TARGET HBA1C

Our First Goal Is to Set Appropriate HbA1c

Correlation of A1C with Estimated Average Glucose (eAG) Mean plasma glucose A1C (%) mg/dl mmol/l 6 126 7.0 7 154 8.6 8 183 10.2 9 212 11.8 10 240 13.4 11 269 14.9 12 298 16.5 Table 9, as shown on this slide, contains the correlation between A1C levels and mean plasma glucose (PG) levels based on data from the international A1C-Derived Average Glucose (ADAG) trial using frequent SMBG and continuous glucose monitoring (CGM) in 507 adults (83% Caucasian) with type 1, type 2, and no diabetes1 The ADA and the American Association of Clinical Chemistry have determined that the correlation (r = 0.92) is strong enough to justify reporting both an A1C result and an estimated average glucose (eAG) when a clinician orders the A1C test2 A calculator for converting A1C results into eAG, in either mg/dl or mmol/l, is available at http://professional.diabetes.org/eAG. These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was 0.92. A calculator for converting A1C results into estimated average glucose (eAG), in either mg/dl or mmol/l, is available at http://professional.diabetes.org/GlucoseCalculator.aspx. Reference Nathan DM, Kuenen J, Borg R, et al., for the A1c-Derived Average Glucose Study Group. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31:1473-1478. American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S18, Table 9.

Treat the patient, not the blood sugar.

Lifestyle modification Lipid treatment BP control ASA+/- Cigarette cessation Glucose control

Lifestyle intervention

Lifestyle Therapy medical nutrition therapy regular physical activity sufficient amounts of sleep behavioral support smoking cessation and avoidance of all tobacco products. Lifestyle therapy begins with nutrition counseling and education. All patients should strive to attain and maintain an optimal weight through a primarily plant-based diet high in polyunsaturated and monounsaturated fatty acids, with limited intake of saturated fatty acids and avoidance of trans fats.

Cardiovascular/CNS outcome CKD NAFLD/NASH Cost Pharmacotherapy of DM2 Efficacy: HbA1c Hypoglycemia Weight Side effects Durability Cardiovascular/CNS outcome CKD NAFLD/NASH Cost

ADA Guideline, Diabetes Care 2016 Healthy eating, weight control, increased physical activity Initial monotherapy MET Not at target HbA1c after ~3 months SU TZD DPP-4i SGLT-2i GLP-1 RA Insulin Two-drug combinations Not at target HbA1c after ~3 months SU TZD Insulin SGLT-2i SU TZD GLP-1RA Insulin TZD DPP-4i GLP-1RA Insulin SGLT-2i SU TZD Insulin TZD DPP-4i GLP-1RA SGLT-2i ADA/EASD position statement now recommends GLP-1RAs as second line agents SU DPP-4i GLP-1RA Insulin SGLT-2i Three-drug combinations Not at target HbA1c after 3-6 months combination therapy with insulin Basal Insulin + GLP-1 RA or Prandial Insulin More complex strategies ADA Guideline, Diabetes Care, January 2016

ADA/EASD Position Statement: Antihyperglycemic Therapy in T2DM

Insulin is the most effective glucose-lowering agent Clinical challenge: Selecting the appropriate treatment for your patient 0.5- 0.8 1.5 1.0-1.5 0.5-0.7 ≥2.5 Sulfonylureas Metformin Glinides DPP-IV inhibitors GLP-1RAs Insulin 0.0 0.5 1.0 2.0 2.5 3.0 HbA1c reduction (%) Efficacy as mono therapy Anti diabetic agents TZDs Insulin is the most effective glucose-lowering agent Nathan DM. N Engl J Med. 2007;356:437-40 Nathan et al. Diabetes Care. 2009;32:193-203

Insulin sensitizer with predominant action in the liver: Metformin: Dose Adverse events Titration

Insulin sensitizer with predominant action in Peripheral: TZD Pioglitazon: Dose Advers events

Insulin secretagogues: sulfonylureas Meal plane and Regularity: Dose Potency Age Drug interaction Indications

Hypoglycemia due to SUR Glibenclamid  Glimiprid  Glicloasid  Repaglinid/nateglinid  MR Gliclazid SR Glipizid

Carbohydrate absorption inhibitors α-glucosidose inhibitors Acarbose: Dose Adverse events

GLP-1 Secretion and Inactivation Mixed meal Intestinal GLP-1 release GLP-1 (9-36) inactive (>80% of pool) DPP-4 T1/2 = 1 to 2 min GLP-1 (7-36) active Quickly after it’s release GLP-1 is converted to it’s inactive form by an enzyme dipeptidyl peptidase 4. Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

Inhibition of DPP-4 Increases Active GLP-1 Mixed meal Intestinal GLP-1 release GLP-1 (7-36) active GLP-1 (7-36) active DPP-4 DPP-4 inhibitor GLP-1 (9-36) inactive Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

Incretin – Based therapies DPP-4 Inhibitors: Sitagliptin Linagliptin Saxagliptin Alogliptin

Incretin – Based Therapies GLP1 agonists: Exenetide Liraglutide Exenetide QW

Sodium Glucose Co-Transports 2 inhibitors SGLT2IS

Targeting the Kidney Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

The Kidneys Play an Important Role in Glucose Control Normal Renal Glucose Physiology 180 g of glucose is filtered each day Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation SGLT2 reabsorbs about 90% of the glucose SGLT1 reabsorbs about 10% of the glucose Virtually no glucose excreted in urine Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

SGLT2 Inhibitors in Phase 3 Development Empagliflozin Canagliflozin Dapagliflozin Ipragliflozin

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age Weight Sex / racial / ethnic / genetic differences Comorbidities Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age: Older adults Reduced life expectancy Higher CVD burden Reduced GFR At risk for adverse events from polypharmacy More likely to be compromised from hypoglycemia Less ambitious targets HbA1c <7.5–8.0% if tighter targets not easily achieved Focus on drug safety Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Weight Majority of T2DM patients overweight / obese Intensive lifestyle program Metformin GLP-1 receptor agonists ? Bariatric surgery Consider LADA in lean patients Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone &  CVD events ? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: May use unless condition is unstable or severe Avoid TZDs ? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Increased risk of hypoglycemia Metformin & lactic acidosis US: stop @SCr ≥ 1.5 (1.4 women) UK:  dose @GFR <45 & stop @GFR <30 Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR <30 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Most drugs not tested in advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Emerging concerns regarding association with increased mortality Proper drug selection in the hypoglycemia prone Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

IDF treatment algorithm (2013 update) Sulfonylurea Consider fourth line Basal + mealtime insulin Basal or pre-mix (later basal+mealtime) Lifestyle measures Consider first line Consider second line Consider third line Metformin Basal insulin or pre-mix insulin α-gluc or DPP-4 or TZD or Then, at each step, if not to target (generally HbA1C<7.0%) Metformin (if not first line) GLP-1 agonist Sulfonylurea or α-glucosidase Usual approach Alternative approach IDF 2013 Global Guidelines for Type 2 diabetes

Blood glucose monitoring individualized HbA1C at 3-mo intervals Recommended standards of care for patients with type 2 Diabetes Mellitus Weight at each visit Bp at each visit Blood glucose monitoring individualized HbA1C at 3-mo intervals at diagnosis and then yearly Dilated eye exam Lipid profile Urine micro albumin