Importance of Glycemic Control and Diabetes Management

Importance of Glycemic Control and Diabetes Management
Jaidesh Reddick, PA-C Santa Clara Valley Medical Center October 14, 2019

Objectives Diabetes Management (DM) Overview – Brief
DM Treatment Options in the Out-Patient Setting Combination therapy to achieve target glycemic control Importance of glycemic control to improve outcomes DM Patient Survivor Skills Case Presentations

Diabetes Facts Type 2 diabetes mellitus (T2DM) is a disease that affects more than 415 million people around the world. In 2040, there will be 642 million people with diabetes worldwide. The prevalence of T2DM is expected to double within the next 20 years, due to the increase of the age, obesity and the number of ethnic groups of high risk in the population, with significant increases in cardiovascular disease, end-stage renal disease (ESRD), retinopathy and neuropathy

Diabetes Facts New CDC report mentions more than 100 million US adults are now living with Diabetes or Pre-Diabetes and about 8.1 million are undiagnosed Diabetics 7th leading cause of death in the US Estimated 1.5 million Americans are diagnosed with DM every year $327 Billion – Total cost of Diabetes 2017 in the US

Diabetes Facts Number of visits to Physician Offices with DM as primary diagnosis: million. ED visits with DM as primary diagnosis: million Type 2 Diabetes accounts for 90-95% of all Diabetes Cases About 5% of people with Diabetes are estimated to have Type 1 DM CDC National Diabetes Statistics Report, July, 2017 American Diabetes Association 2017 Report

DIABETES MELLITUS CLINICAL MANIFESTATIONS
Classic Presentation: Polyuria Polydipsia Polyphagia Weight loss. Insidious Onset of lethargy and weakness. Duration of symptoms usually < 1 month.

Microvascular complications
Natural History of DM2 Years from diagnosis -10 -5 5 10 15 Onset Diagnosis Insulin secretion Insulin resistance Postprandial glucose Fasting glucose Microvascular complications Macrovascular complications Pre-diabetes Type 2 diabetes Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. N Engl J Med ;347:

Criteria for the Diagnosis of Diabetes
Fasting Plasma Glucose (FPB) ≥ 126 mg/dl (7.0 mmol/L) OR 2-h Plasma Glucose ≥ 200 mg/dl (11.1 mmol/L) during an OGTT A1C ≥ 6.5% Classic Diabetes Symptoms + Random Plasma Glucose ≥ 200 mg/dl (11.1 mmol/L) ADA Standards of Medical Care in Diabetes. Classification and diagnosis of Diabetes. Diabetes Care 2017; 40 (Suppl. 1): S11-S24

SGLT2 Inhibitor Insulin

9 FDA-Approved Classes of Oral Medications for Type 2 Diabetes
Biguanides - Metformin (first line therapy unless contraindicated) Sulfonylureas, Meglitinides TZDs/ Glitazones (pioglitazone, rosiglitazone) DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin) SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin) Bile acid sequestrant (colesevelam)* Dopamine receptor agonists (bromocriptine meslate)* Alpha glucosidase inhibitors (acarbose, miglitol)* Note: FDA just recently approved ( 9/2019), first pill in class of glucagon-like peptide (GLP-1), called Rybelsus. * not discussed in detail in this presentation

Updates on DM Meds SGLT2 Inhibitors – Alerts issued about the risk of decreased bone mineral density and leg or foot amputations, associated with canagliflozin, as well as risk of ketoacidosis, serious genital infection alert/necrotizing fasciitis of the perineum, Fournier’s Gangrene DPP-4 Inhibitors – Alerts issued about risk of joint pain associated with Sitagliptin, Saxagliptin, Linagliptin and Alogliptin. Risk of Heart Failure with Saxaglipitin and Alogliptin Metformin – Updated Safety profile to indicate use in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function Thiazolidinediones – Alert issued for increased risk of bladder cancer associated with Pioglitazone

Anti-diabetes Medications
Biguanides (metformin) Sulfonylureas Meglitinides Thiazolidinediones Alpha-glucosidase inhibitors DPP-4 inhibitors Incretin mimetic / GLP 1 Receptor Agonist Amylin analogues SGLT-2 inhibitors Bile Acid Sequestrant Dopamine Receptor Agonist D-Phenylalanine Derivatives Insulin: Rapid-acting (Lispro, Aspart, Glulisine, Afrezza* Short-acting (regular) Intermediate-acting (NPH) Long-Acting: Detemir, Glargine, Degludec, Basaglar Pre-mixed * inhaled insulin

Organ Targets of Glucose-lowing drugs

Biguanides metformin (Glucophage)
Effects: primarily decrease glucose production from liver Timing: take with breakfast and dinner, Glucophage XR should be taken with evening meal Common side effects: diarrhea and stomach cramping, metallic taste Adverse effect: lactic acidosis (fatigue, muscle pain, difficulty breathing) can be seen in patients with renal and liver impairments Benefits: weight loss, cardioprotective, safe stable CHF Caution: not recommended if liver, kidney problems or drinking alcohol excessively

Metformin and B12 Deficiency
Long-term use of Metformin may be associated with Biochemical Vitamin B12 deficiency. Periodic measurement of Vitamin B12 levels should be considered for Patients on Metformin, especially in those with anemia or peripheral neuropathy. This complication affects about 30% of patients with diabetes who take metformin. Despite its common occurrence, vitamin B12 deficiency is often unrecognized and untreated. For this reason, patients on metformin should have their B12 level monitored annually. Published in BMJ. 2010;340:c2198 care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S65

Insulin Secretagogues
2nd generation Sulfonylureas Meglitinides glipizide, glyburide, glimepiride (NF) repaglinide Effects: lower BG by stimulating beta cells in the pancreas to release insulin Timing: take 30 minutes before meals Glimepiride – take with 1st meal of the day If missed meal, skip the medication Adverse effects: hypoglycemia, stomach upset, skin rash, weight gain. Avoid glyburide if having kidney impairment.

Thiazolidinediones Pioglitazone (Actos), rosiglitazone (Avandia)
Effects: decrease hepatic glucose production, decrease insulin resistance, increase muscle, fat and liver’s sensitivity to insulin. Takes 2-4 weeks for full effects. Timing: once a day, without regards to meal Adverse effects: fluid retention, edema, weight gain, CHF, bone loss in women. Caution: should not take if have HF or liver impairment, requires liver monitoring, increase heart disease and risk of bladder cancer

Alpha-glucosidase inhibitors
Acarbose ( Precose), miglitol (Glyset) Effects: delay absorption and breakdown of carbohydrates Not recommended in patient with Scr>2 mg/ml, cirrhosis, inflammatory bowel disease Timing: take it with 1st bite of a meal Adverse effects: gas, diarrhea, nausea, cramps

DPP – 4 Inhibitors Dipeptidyl Peptidase IV Inhibitors
Sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina) Effects: lowers glucagon secretion, increase insulin secretion. Reduces fasting glucose levels and promote satiety Timing: take without regards to meals Reduce dose in kidney impairment Common adverse effects: headache, runny nose, sore throat, URI Uncommon adverse effects: pancreatitis, angioedema

Incretin Mimetics Exenatide (Byetta), lixisenatide (Adlyxin), liraglutide (Victoza), extended release exenatide (Bydureon), dulaglutide (Trulicity),albiglitude (Tanzeum) Subcutaneous injections Effects: stimulate incretin-based insulin release Not recommended for patient with severe renal impairment, severe GI diseases (e.g. gastroparesis) Adverse effects: nausea (may decrease overtime), diarrhea, headache, may increase INR when used with warfarin; pancreatitis; warning for liraglutide and albiglitude: risk of thyroid C-cell hyperplasia

Amylin Analogues Pramlintide (Symlin)
Effects: regulate gastric emptying, suppress postprandial glucagon secretion and reduces food intake. Proper patient selection is critical to safe and effective use of pramlintide Not recommended for a confirmed diagnosis of gastroparesis; hypoglycemia unawareness. Adverse effects: hypoglycemia, abdominal pain

SGLT-2 inhibitors Canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro) Effects: Block reabsorption of glucose by the kidney, increase excretion of glucose in the urine. Not recommended in moderate to severe kidney disease. Do not use dapaglilozin in bladder cancer. Adverse effects: hypotension, dehydration, UTI, impairment in renal function, genital mycotic infection, increase LDL.

Expected HbA1c Reduction
Comments Class Expected HbA1c Reduction Effects on Weight Hypoglycemia Diet and excise 1-2% loss no metformin 1-1.5% neutral or loss Sulfonylureas weight gain yes Meglitinides % Incretin mimetics % DPP-4 inhibitors 0.5-1% Thiazolidinediones Alpha-glucosidase inhibitors % neutral SGLT2 inhibitors Insulin >1.5% - 2.5%

Glycemic Control Achieving near-normal glycated hemoglobin (HbA1c) significantly decreases risk of macrovascular and microvascular complications[4]. In recent years the number of available agents to treat DM2 has increased. However, only about 50% of diabetic patients reach their HbA1c target. Algorithms for the treatment of diabetes highlight the need for good glycemic control to reduce the development or progression of diabetes complications.

ADA issued important updates to the Standards of Medical Care in DM
Focus on Improving Cardiovascular and Renal Health in People with DM ( Living Standards of Care) ASCVD is the leading cause of morbidity and mortality for individuals with DM and Heart Disease is the cause of 1 in 4 deaths in the US DM is the leading cause of CKD and approximately 1 out of 4 adults with DM has Kidney Disease Recently published research indicates an urgent need to update the 2019 Standards of Care to ensure optimal treatment for those with CVD and / or CKD with DM

The SGLT 2 Inhibitor, Empagliflozin / Jardiance, markedly and rapidly reduced CV death and heart failure hospitalization, likely with hemodynamic / metabolic driven mechanism of action

SGLT2 Inhibitor and CV Benefit
For patients with type 2 diabetes (T2D) and left ventricular hypertrophy, empagliflozin reduced the risk for cardiovascular death vs placebo, according to a post hoc analysis of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME; NCT ) that was published in Diabetes Care. CHICAGO — Patients with type 2 diabetes (T2D) treated with empagliflozin as part of routine clinical care experienced a decrease in risk of heart failure hospitalization, according to research presented at the American Heart Association Scientific Sessions 2018, held November 10-12, in Chicago, Illinois.

GLP-1 Receptor Agonist and Cardiovascular Outcomes in Pt’s with DM2
Patients with DM2 and Cardiovascular Disease (CVD) or high Cardiovascular risk, having subcutaneously administered GLP-1 receptor agonist Liraglutide and Semaglutide, have shown to reduce CVD outcomes Recent Trials demonstrated that subcutaneous Dulaglutide and Oral Semaglutide also provide CVD Benefit In both trials, reductions in A1C, Weight and Systolic Blood Pressure were greater with active drug than placebo

Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes ( see next slide)

Notes Based on Previous Slide
*For agent-specific dosing recommendations, please refer to the manufacturers’ prescribing information. †FDA approved for CVD benefit. CHF, congestive heart failure; CV, cardiovascular; DPP-4, dipeptidyl peptidase 4; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; NASH, nonalcoholic steatohepatitis; SGLT2, sodium– glucose cotransporter 2; SQ, subcutaneous; T2DM, type 2 diabetes.

HgbA1C Level Not as reliable in patients with advanced chronic kidney disease Factors that may affect A1c Level • Iron supplementation • Erythropoietin administration Dialysis

Credence Trial Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. Credence Trial was designed to evaluate Renal Outcomes in Diabetic Patients with Nephropathy Enrolled over 4400 Diabetic Patients CREDENCE Trial Treatment groups Canagliflozin 100 mg po once daily Placebo po once daily • Primary Endpoints ESRD Doubling of SCr Renal or Cardiovascular Death Patients adults were followed over median duration of ~2.62 years

Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study design Multi-center, Double-blind, randomized placebo-controlled trial Inclusion Criteria Adult at least 30 yo, T2DM, A1c 6.5 – 12%, UACR ≥300 mg/g, and eGFR 30 – 90 mL/min Stable dose of ACEi or ARB for at least 4 weeks prior to randomization Exclusion Criteria T1DM, Non-diabetic kidney disease Kidney disease treated with immunosuppression History of dialysis or kidney transplant Dual-agent treatments (ACEi and ARB, direct renin inhibitor, or mineralocorticoid-receptor antagonist) Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med, 2019; 380:

Credence Trial CONCLUSIONS
In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT opens in new tab.)

Drugs with Beneficial Effects on DKD Progression
• SGLT-2 inhibitors • Consider in patients (T2DM and DKD) with an eGFR ≥30 mL/min and particularly in those with >300 mg/g albuminuria • GLP-1 RA • Consider in patients with CKD who are at increased risk for CV events

ADA Diabetes Care 2018, Dec; 41(12)

Glucose-lowering medication in type 2 diabetes: overall approach.
Glucose-lowering medication in type 2 diabetes: overall approach. For appropriate context, see Fig ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase 4 inhibitor; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; SGLT2i, sodium–glucose cotransporter 2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. Adapted from Davies et al. (39). American Diabetes Association Dia Care 2019;42:S90-S102 ©2019 by American Diabetes Association

Choosing glucose-lowering medication if cost is a major issue
Choosing glucose-lowering medication if cost is a major issue. DPP-4i, dipeptidyl peptidase 4 inhibitor; SGLT2i, SGLT2 inhibitor; SU, sulfonylurea.

Intensifying to injectable therapies
Intensifying to injectable therapies. FRC, fixed-ratio combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; FBG, fasting blood glucose; FPG, fasting plasma glucose; max, maximum; PPG, postprandial glucose.

Considering oral therapy in combination with injectable therapies
Considering oral therapy in combination with injectable therapies. DKA, diabetic ketoacidosis; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1 RA, glucagon-like peptide 1 receptor agonist; SGLT2i, SGLT2 inhibitor; SU, sulfonylurea.

ADA 2015 General Recommendations For The Treatment of Type 2 Diabetes
Dual Therapy Consider starting at this stage when A1C is ≥ 9% Combination Injectable Therapy Consider starting at this stage when FSBG is ≥ mg/dl and/or A1C is ≥10-12%, especially if symptomatic or catabolic features are present, in which case basal insulin Plus 1 mealtime insulin is the preferred initial regimen. Triple Therapy Usually basal insulin. DPP4-I, DPP4 inhibitor; fxs, fractures; GI, Gastrointestinal; GLP-1RA, GLE-1 receptor Agonist; Gu, Genitoruinary; HF, Heart Failure; Hypo, Hypoglycemia, SGLT2-i, SGLT2 inhibitory; SFU sulfonylurea; TZD, Thiazolidinedione. Adapted from: ADA. Diabetes Care (sup 1): S1-S93

Glycemic Target Goals for Patients with Type 2 Diabetes Treatment Goal ADA / AACE
HbA1C (%) < 7 ≤ 6.5 FPG (mg/dL) 80-130 <110 Preprandial glucose (mg/dL) Postprandial glucose (mg/dL) <180 <140** ** 2 Hr PPG American Diabetes Association. Diabetes Care. 2015; 38(suppl 1):S33-S40. Handelsman, Y., et al. (2015). Endocr Pract 21(0): 1-87.

Initiation and Adjustment of Basal Insulin
Start 10 U if BMI<25 or 15 U if BMI>25 Dose QAM or QHS Adjust 10-15% or 2-4 units once or twice weekly to reach FBG Target For Hypoglycemia: Determine and address cause; reduce dose by 3-4 units or 10-20%

Efficacy of Adding Insulin to Oral Medications in DM2
Met + NPH SU + Premix A1C % 1 or 2 Oral Agents + Glargine 9.7 9.7 9 8.6 8 7.6 7.2 7.0 Other studies show similar results with varying combinations of orals + single injection insulin regimens. 7 Met + NPH at bedtime Met Glim Glim + 70/30 at dinner Oral + Glargine at bedtime Oral Yki-Järvinen H et al. Ann Intern Med. 1999;130: ; Riddle MC et al. Diabetes Care. 1998;21: ; Riddle MC et al. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P.

Pearls on combination therapy once on insulin in DM2:
Continue insulin secretogogues when basal insulin added Discontinue insulin secretogogues if bolus insulin is added unless benefits are seen Continue metformin to minimize wt gain and for CV benefits OK to continue TZD for glycemic stability but 15% develop edema and 3% CHF

Action Profiles of Insulins
Aspart, lispro, glulisine 4–5 hours Regular 6–8 hours NPH 12–16 hours Detemir ~14 hours Plasma Insulin Levels Glargine ~24 hours Hours 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Burge MR, Schade DS. Endocrinol Metab Clin North Am. 1997;26: ; Barlocco D. Curr Opin Invest Drugs. 2003;4: ; Danne T et al. Diabetes Care. 2003;26:

Type of Insulin by Pharmacokinetics
Insulin Type Onset Peak Duration Considerations Rapid Acting: Aspart/Lispro 15 min 1-2 hrs 3-4 hrs Can be administered 0-15 min before a meal Less risk of postprandial hypoglycemia compared to regular insulin Short Acting: Regular 30-60 min 2-3 hrs 6-8 hrs Must be injected min before a meal Injection with or after a meal could increase risk for hypoglycemia Intermediate Acting: NPH 2-4 hrs 4-8 hrs 10-16 hrs Greater risk of nocturnal hypoglycemia compared to insulin analogs Long Acting: Glargine No peak 24 hrs Less nocturnal hypoglycemia compared to NPH Long Acting: Detemir 14-16 hrs Regular U-500 ≤0.5 ~2-3 12-24 Inject 30 min before a meal Indicated for highly insulin resistant individuals Use caution when measuring dosage to avoid inadvertent overdose

Basal-bolus insulin to mimic pancreatic insulin secretion
Breakfast Lunch Dinner Aspart or Lispro Plasma insulin NPH, glargine or detemir 4:00 8:00 12:00 16:00 20:00 24:00 4:00 Time

MIMICKING NATURE WITH INSULIN THERAPY The Basal/Bolus Insulin Concept : Multiple Daily Injection Program Basal Insulin—Glargine Suppresses glucose production between meals and overnight Nearly constant levels ~50% of daily needs Bolus Insulin (Mealtime or Prandial)—Lispro Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour ~10% - 20% of total daily insulin requirement at each meal Slide 6-20 MIMICKING NATURE WITH INSULIN THERAPY The Basal/Bolus Insulin Concept Insulin is capable of restoring glycemia to nearly normal in most patients with type 2 diabetes. The basal/bolus insulin concept attempts to mimic, with insulin therapy, the patterns that normally control glucose in persons without diabetes. Basal insulin suppresses glucose production so that the levels remain nearly constant between meals and overnight. Basal insulin meets about half of the patient’s daily need for insulin and may be sufficient when considerable endogenous insulin remains. Bolus insulin (10% to 20% of the total daily insulin requirement given at each meal) limits hyperglycemia after meals. This tends to smooth the peaks of glucose that occur in response to these meals. Frequent glucose monitoring aids in determining the candidates for basal or mealtime regimens. Ideally, each component of insulin replacement therapy should come from a different type of insulin with a specific profile to fit the patient’s needs. Practical methods to accomplish this basal/bolus strategy will be illustrated later in this module. Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3: ; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.

Example of initial basal-bolus regimen
Patient’s weight = 100 kg TDD = 0.5 units x 100 kg = 50 units per day Use 50% of TDD for basal insulin: 50 units/2 = 25 units basal (as glargine or units BID of NPH) Divide remaining 50% by 3 to determine prandial insulin dose 50 units/2 = 25 units prandial/3 = 8 units TID AC

Which sliding scale do I choose?
Sliding scale is determined by the patient’s insulin sensitivity (or correction factor) Insulin sensitivity = how many mg/dl will 1 unit of insulin reduce blood sugar? “Rule of 1500”: 1500 divided by TDD = insulin sensitivity In our pt: 1500/50 units = 30 mg/dl  give 1 unit of insulin for every 30 points above target

Mixed Insulin Dosing When using mixed insulin, ie 70/30, Give 60% of TDD of Insulin in the Morning before Breakfast and give 40% of TDD Insulin in the Evening before Dinner Titrate as needed every 3 days until glycemic goal achieved

Insulin Pumps Closely mimics a normally functionally pancreas
Most often used with Lispro (Humalog®) Pts manage basal rates and boluses of insulin with the pump unless they are cognitively impaired

Goals—”GLUCOSE is BAD” or “ABCDEFG”
Glycemic control Lipids Urine microalbumin Cigarettes Ophthalmologic Sex-related topics Extremities Blood pressure Aspirin Dental A1c Blood pressure Cholesterol Diet Eye exam Foot exam GFR--microalbumin 3 to 5 fold greater propensity for UTIs in DM woman ADA: Aspirin (75 to 162 mg/day) is recommended for secondary prevention in diabetics with a history of myocardial infarction, vascular bypass, stroke or transient ischemic attack, peripheral vascular disease, claudication, or angina. Aspirin (75 to 162 mg/day) is recommended for primary prevention in any diabetic patient with an additional cardiovascular risk factor (eg, age >40 years, cigarette smoking, hypertension, obesity, albuminuria, hyperlipidemia, or a family history of coronary heart disease). Aspirin is not recommended for diabetic patients under the age of 30 years due to a lack of evidence of benefit, and aspirin is contraindicated under the age of 21 years because of an increased risk of Reye's syndrome. Increased risk of periodontal disease—annual exam at least Yale Diabetes Center 2005 ACP Diabetes Care Guide 2007

Comprehensive DM2 Management Algorithm
Lifestyle Therapy, including weight loss is key to managing DM2 Individualize A1C Targets Glycemic Control Targets Therapy choices must be individualized based on Pt’s characteristics, formulary restrictions, costs, patient preferences, etc. Minimizing risk of Hypoglycemia and Weight gain Algorithm stratifies choice of therapies based on initial A1C Combination therapy is usually required and should involve agents with complimentary actions

Comprehensive DM2 Management Algorithm cont.
Comprehensive management include BP, Lipid therapies, Proteinuria and related comorbidities Patient should be evaluated every 3 months until stable and then less often, ie every 6 months or once / year Therapy regimen should be simple to optimize adherence Algorithm includes every FDA approved class of medication for DM

Take home messages: Good glycemic control is essential to reduction of microvascular and possibly macrovascular outcomes Combination therapy is often necessary and starting insulin early on is safe and effective Consider choosing Diabetes Treatments that will enhance Patient compliance Avoid Diabetes medications that could potentially cause medical complications for certain patients

THANK YOU

CASE PRESENTATIONS

CASE 1 Case 1: Failure of Metformin Monotherapy
A 68-year-old male patient with T2DM has received optimal metformin monotherapy for the last 2 years (current dose of 2000 mg/day) and tolerates the treatment well. Hypoglycemia has not been an issue to date. (BMI) is 28 kg/m2, which he has worked hard to reduce from 35 kg/m2 over the last 2 years. He has mild hypertension, which is well- controlled on a thiazide plus an angiotensin-converting enzyme inhibitor. His blood lipids are well-controlled on atorvastatin 10 mg daily. He now presents at the clinic with an HbA1c of 7.6%. During consultation, the patient mentions that he has seen advertisements for canagliflozin (Invokana) and questioned its efficacy.

CASE 1 (cont.) After reviewing the available therapeutic choices and using a shared decision-making model, a dipeptidyl peptidase-4 (DPP-4) inhibitor is selected as add-on therapy based upon simplicity of use, tolerability, and the patient’s wish to avoid anything that might cause weight gain. Because he is an uncircumcised male, he decided against canagliflozin once informed of the potential side effect of balanitis.

CASE 1 (cont.) In this case, the patient has already done very well in terms of weight reduction and maintenance. At this point, add-on therapy may be needed to improve glycemic control. Where the patient was only modestly above his ADA- recommended HbA1c goal of 7.0%, aggressive therapy which may be associated with adverse effects was not warranted. Although not obese, this patient was concerned about body weight; therefore, treatments associated with weight gain; sulfonylureas (SUs) and insulin may not be suitable.

CASE 1 (cont.) The patient and doctor opted for a DPP-4 inhibitor as add-on treatment. Other reasonable options might include a 3-month trial of lifestyle modification, a glucagon-like peptide-1 receptor agonist (GLP-1RA), a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or an alpha-glucosidase inhibitor. Because the patient was disinclined to use an injectable agent, GLP-1RAs were not the best choice. SGLT-2 inhibitors would be a consideration and the patient specifically mentioned that class, because he is uncircumcised, he may be at increased risk to incur one of the genital mycotic infections seen with this class of agents. Such infections are less common in men than in women, but the risk in men may be increased in uncircumcised individuals. Tolerability of alpha-glucosidase inhibitors is substantially less than DPP-4 inhibitors, hence the shared decision to use this class of agents.

Case 2: Julia Julia is a 40 year old female with a 4 year history of type 2 diabetes Julia is on max doses of Metformin, SFU and DPP-4 Inhibitor She states she does not want to take insulin PMH: Dyslipidemia, HTN, OSA and Overweight (BMI=30) eGFR 75 ml/min HgbA1C for the past year has been 8.5% FBS (mg/dl) PPG (mg/dl) Mean 191 Mean 265

What would you recommend now for Julia?
Start a SGLT2 inhibitor Try to convince her to start basal insulin Start a GLP-1 receptor agonist and discontinue the DPP-4 inhibitor Start a fixed combination of a basal insulin and a GLP-RA

Case 2: Julia (continued)
Julia agreed to start a GLP1-RA If prescribing Exenatide, it is important to tell the patient that it takes 6 weeks to reach equilibration Julia experienced no nausea or hypoglycemia over the next 3 months Julia lost 14 pounds and her HgbA1C fell from 8.5% to 7.3%. Before GLP -1 FBS mean 191 mg/dl and PPG mean 265 mg/dl After GLP-1 FBS mean 131 mg/dl and PPG mean 167 mg/dl

Case 3: Shirley

Shirley

Case 3: Shirley

Case 3 Shirley Shirley

Case 4: Deteriorating Kidney Function
A 70-year-old obese female presents with stage 3 chronic kidney disease (CKD) and treatment-naïve T2DM (HbA1c of 7.6%). Her current eGFR is 45 mL/min/1.73 m2 (ie, “moderate” renal impairment). She is normotensive. Insulin and GLP-1RAs are considered; she elects to try a GLP-1RA.

Discussion CKD is a common condition in patients with T2DM that complicates the management of these patients. Drug clearance is often impaired, leading to prolonged exposure to increased drug levels.19 As such, kidney function should be assessed before starting glucose- lowering therapy, and the patient should be carefully monitored for hypoglycemia (which may indicate increased drug levels) during treatment.20 Many available glucose-lowering drugs are contraindicated, or should be used with caution, in patients with T2DM and CKD.19,20 For example, the standard first-line glucose-lowering therapy (metformin) is contraindicated in patients with an eGFR <60 mL/min/1.73 m2.

Discussion (cont.) GLP-1RAs can be used with caution in patients with CKD as long as the eGFR is >30 mL/min/1.73 m2, and DPP-4 inhibitors can be used at reduced doses.20 SGLT-2 inhibitors act by inhibiting reabsorption of glucose from the renal tubules into the bloodstream, thereby increasing urinary glucose excretion. Thus, as eGFR decreases, the ability of SGLT-2 inhibitors to lower blood glucose by this mechanism will also decrease. SGLT-2 inhibitors are not indicated in patients with an eGFR <45 mL/min/1.73 m2.21,22 All forms of insulin are safe to use in mild to severe renal failure including dialysis, although healthcare providers and patients should be aware that dosage adjustments may be needed as renal function changes.

Case 5: Fear of Injections
A female patient presents with an HbA1c of 9.5% and has received metformin plus SU for the last 2 years. During a discussion of therapeutic options, the patient expresses anxiety about using injectable therapy, but her target HbA1c goal has not been attained with any of the multiple oral regimens she has tried. Once the patient actually experiences an injection in the office, she is much less apprehensive. The idea of a once-weekly GLP-1RA appeals to her more than daily basal insulin.

Discussion In this case, it was important to help the patient overcome her fear of injections because adding a third oral agent had not been successful. Although it can sometimes be a challenge, there is value in determining the reasons why patients are anxious about injectable therapy and if there are any potential trade-offs that would make it more attractive (eg, weight loss or the need for only once-weekly administration An injection trial, even with saline, in the office can sometimes help patients overcome their fear and become more willing to try injectable therapies. Where insulin is required, a strategy to assist patients in overcoming their fear of injections is to start with very low-dose basal insulin. Many patients can accept basal insulin but fear multiple mealtime injections. In such cases, taking a stepwise approach may be helpful, such as starting with just evening mealtime insulin.

Simplifying Treatment Decision-Making
Choosing the right therapy for the right patient is important to create a positive cycle of change for patients, enabling them to improve their glycemic control while increasing exercise, eating healthier, and losing weight. The requirement for additional medication is an unwanted burden for patients, and the way in which the clinician presents further treatment to the patient is of utmost importance. It is critical that patients are aware that diabetes is typically a progressive disorder and that the requirement to augment treatment is an anticipated part of the process, despite a patient’s best efforts. Factors that should be considered when deciding on therapy options include efficacy, side effect profile, cost, contraindications, previous therapy/adverse events, therapy delivery route/regimen, and patient preferences and perceptions. A positive patient–clinician relationship, which incorporates shared decision-making, can increase the likelihood of successful treatment. Clinician awareness of these factors should lead to better treatment choice, improved adherence, and improved outcomes for patients.

Case 6: Steven

Steven

Case 6: Steven Steven

Case 7: New Onset DM 50 y/o male presents to ED with c/o polyuria, polydipsia, blurry vision, fatigue and about a 17 pound unexplained weight loss Patients blood glucose level = 455 mg/dl UA Glucose = 500 HgbA1C = 12.2 Weight = 190 pounds BMI = 30.27 Creatinine = 1.4

Case 7: Medical Nutritional Therapy (MNT)
Tacos with deep fried shells Hotdogs Cheesy Fries Chinese Food Skips Breakfast/Lunch-makes up for it by sipping on soda and sweetened tea beverages throughout the day

Case 7: Discharge Home DM Meds
Since Patients HgbA1C is over 10% what insulin should be considered? What oral medication/s would be considered, if any

Case 7: Treatment 1. Lantus 15 units QHS and Lispro 5 units QAC with a Mild Correction Scale; 1:50 > 150 mg/dl Would not consider Metformin since current Creatinine Level slightly elevated Basal Insulin and GLP-1-RA could also be used; however for tighter glycemic control, Multiple Daily Injections (MDI) would be more beneficial

Case 8: Patient is a 63 year old lady who was diagnosed with DM 2 years ago. Patient was started on Metformin 500mg twice daily. Patient reports nausea with Metformin. Her blood glucose is usually in 300s. She sometimes takes up to 5 tabs of Metformin to get her blood glucose to improve. She complains of incontinence and has seen a urologist. She has lost 32 lbs in the last year and has a HbA1c of 12.5%

Case 8: Treatment Options
Since patient is having nausea with Metformin and her HgbA1C indicates poorly controlled DM possible considerations for tighter glycemic control would be Basal Insulin, Low dose sulfonylurea or possibly GLP-1-RA. Would not consider SGLT2-Inhibitor since she already has issues with incontinence and may be at risk for developing GU infection

Case 9: Patient is a 40-year-old African-American man, married with 4 children, who works as a foreman of a loading dock. He was diagnosed with T2DM 3 months ago. He weighs lb and has a body mass index (BMI) of 31.6 kg/m2. He is a current smoker. He is on no prescription medications. His current A1C level is 7.8%. He complains of sleep disturbance

Case 9: Biometrics: • Height: 70 in. • Weight: 220.5 lb (100 kg) •
BMI: 31.6 kg/m2 Vital signs: Pulse: 55 bpm • Respirations: 22/minute Blood pressure (BP): 148/92 mm Hg Smoker (½ pack a day x 15 years) Social alcohol use (beer on weekends) Denies illicit drug use

Case 9: Patient started on Metformin 500 mg PO BID which was increased to 1000 mg PO BID after one week. To achieve tighter glycemic control, what other treatment options should be considered? Since patient is overweight, consider medication that is weight neutral; ie, DPP-4 Inhibitor or Incretin Mimetic Januvia would be a good choice since Patient could take the combination medication, Janumet

Case 10: Patient with DM Type1
Patient is a 54 y/o female Weight: 65 kg, BMI = 25.3 HbA1c 8.5% FSBG in office = 220 mg/dl + chronic pancreatitis, T1D diagnosed in 2005, hypertension without treatment, after amputation of the thumb and the second toe of the left foot, stopped smoking 2002 Current diseases: BP 135/85, long-term not-healed defect on left leg – fifth toe, hyperkalemia (6,1 mmol/l), microalbuminuria Patient currently on Lantus 10 units QHS and Lispro 3 units AC Breakfast, 2 units AC Lunch and 3 units AC Dinner

Case 10: Patient morning FSBG levels are always above 180 mg/dl
Patient also states that all her meal time FSBG levels are usually in the mg/dl range Patient also admits she snacks often at bedtime and sometimes during the day

Case 10: Treatment To improve glycemic control, especially since patient has h/o amputation and long-term unhealed defect of left leg, what percentage of dose changes would need to be made to patient’s current insulin regimen? Patients’ Lantus dose should at least be increased by % and mealtime insulin doses should also be increase by 1-2 units Patient should be encouraged to snack on carb free snacks before bedtime.

Case Study References Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract ; 87(1):4-14. American Diabetes Association. Statistics about diabetes. Published June 10, Accessed March 5, 2015. Centers for Disease Control and Prevention. Prevalence of overweight and obesity among adults with diagnosed diabetes– United States, and MMWR. 2004;53(45): Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes Care. 2012;35(6): Diabetic Connect. CDC: 1 in 10 primary-care visits involve diabetes. articles/general/1070-cdc Accessed March 5, 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 Study of Diabetes. Diabetes Care. 2015;38(1): American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care. 2014;37(Suppl 1):S14-S80. Fonseca V. Diabetes mellitus in the next decade: novel pipeline medications to treat hyperglycemia. Clin Ther. 2013;35(5): Graffigna G, Barello S, Libreri C, Bosio CA. How to engage type-2 diabetic patients in their own health management: implications for clinical practice. BMC Public Health.2014;14:648. Munshi MN, Segal AR, Suhl E, et al. Assessment of barriers to improve diabetes management in older adults: a randomized controlled study. Diabetes Care.2013;36(3): Schmittdiel JA, Uratsu CS, Karter AJ, et al. Why don't diabetes patients achieve recommended risk factor targets? Poor adherence versus lack of treatment intensification. J Gen Intern Med. 2008;23(5):

Case Study References Shah ND, Mullan RJ, Breslin M, et al. Translating comparative effectiveness into practice: the case of diabetes medications. Med Care. 2010; 48(Suppl 6):S153-S158. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358(6): Lee YK, Ng CJ, Lee PY, et al. What are the barriers faced by patients using insulin? A qualitative study of Malaysian health care professionals' views. Patient Prefer Adherence.2013;7: Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus.CMAJ. 2005;172(2): Defronzo RA. Banting lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4): Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009. 32(1): Violante R, Oliveira JH, Yoon KH, et al. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. Diabet Med. 2012;29(11):e417-e424. Cavanaugh KL. Diabetes management issues for patients with chronic kidney disease.Clinical Diabetes. 2007;25(3):90-97. Abe M, Okada K, Soma M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr Drug Metab. 2011;12(1):57-69. European Medicines Agency. Forxiga: Summary of product characteristics. Accessed March 10, 2015 Europeans Medicines Agency. Summary of product characteristics: Invokana (canagliflozin). Accessed March 10,

References References:
Arnouts P et al. glucose-lowing drugs in patients with chronic kidney disease: a narrative review on pharmacokinetic properties. Nephro Dial Transplant, 0:1-18, 2013 UpToDate: accessed April 2015 Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287:360-72,2002 Joslin Diabetes Center & Joslin Clinic. Clinical Guideline for pharmacological Management of Adults with type 2 Diabetes. Sep 2014 TCOYD Acknowledgement: Laurie Cheung, RN, CDE for her contribution to slides

REFERENCES ADA Website CDC National Diabetes Statistics Report
Diabetes Education Services Website American Association of Clinical Endocrinologist and American College of Endocrinology Ominus Octect – DeFronzo, Ralph A, MD Consultant 360; Volume 55- Issue 8- August 2015 Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. N Engl J Med ;347: American Diabetes Association. Diabetes Care. 2015; 38(suppl 1):S33-S40. Handelsman, Y., et al. (2015). Endocr Pract 21(0): 1-87.

Pocket Cards For DM Medications ADA Algorithm Medication cost

“American Diabetes Association, Standards of Medical Care in Diabetes ”, The Journal of Clinical and Applied Research and Education, Vol 40 Supplement 1, Jan 2017

Patient Education Diabetes Survival Skills
This template can be used as a starter file for presenting training materials in a group setting. Sections Sections can help to organize your slides or facilitate collaboration between multiple authors. On the Home tab under Slides, click Section, and then click Add Section. Notes Use the Notes pane for delivery notes or to provide additional details for the audience. You can see these notes in Presenter View during your presentation. Keep in mind the font size (important for accessibility, visibility, videotaping, and online production) Coordinated colors Pay particular attention to the graphs, charts, and text boxes. Consider that attendees will print in black and white or grayscale. Run a test print to make sure your colors work when printed in pure black and white and grayscale. Graphics, tables, and graphs Keep it simple: If possible, use consistent, non-distracting styles and colors. Label all graphs and tables.

Basic Survival Skills Glucose Monitoring Home glucometer
Blood Glucose testing times Patient Blood Glucose Targets Call if blood glucose <70 or >250 Meal Plan Activity Oral Diabetes Medications Insulin S/Sx/Tx Hypoglycemia and Hyperglycemia Follow-up appointment for Diabetes Management Target Range for blood glucose How and when to monitor blood glucose Effects of Carbohydrates and basic meal plan How and when to take Diabetes medications and insulin Symptom and treatment of Hypoglycemia and Hyperglycemia When to call their healthcare provider Date and time of follow-up appointment

Target Blood Glucose Range
Home blood glucose Before Meals mg/dL 2 hours after meals 180 mg/dL or less Bedtime mg /dL AIC - Past 3 month average of BG Target <7 % = 154 mg /dL

Factors that lower blood glucose
Not enough carbohydrate – skipped or delayed meals, miscalculated carb content Medication administration issues – incorrect dosing, taking medication or insulin twice, taking rapid-acting insulin instead of long-acting insulin Alcohol intake without eating Increased insulin sensitivity – weight loss, during or after increased physical activity Decrease insulin clearance – declining renal function

What is Hypoglycemia? Blood glucose less than or equal to 70 mg/dl with or without symptoms Also referred to as “low blood sugar” Shaking, rapid heartbeat, sweating, dizziness, headaches, confusion, hunger, irritability, pale skin, weakness, fatigue, anxiety, calmmy skin, sleepiness, lack of coordination, seizures, unconsciousness, nightmares or crying out during sleep, nausea, tingling or numbness in the lips or tongue, blurred impaired vision

Treatment of mild hypoglycemia
Other food sources containing 15g rapid-acting carbohydrates Glucose tablets tablets Fruit Juice oz Regular soft drinks oz Lifesavers Raisins tbsp Sugar or jelly tbsp

15 Grams of Carbohydrate 3-4 glucose tablets*
1 tube oral glucose gel 3-4 glucose tablets* ½ cup juice or regular soda 4 teaspoons of sugar 1 Tablespoon of honey or jelly 1 cup non-fat milk *some glucose tablets are 4 grams each, some glucose tablets are 5 grams each

Blood Glucose Guidelines for Outpatient Non-Pregnant Adults, 1/2
Target blood glucose goals Before meals: mg/dL 2 hours after meal: less than 190 mg/dL Bedtime: mg/dL For blood glucose levels less than 70 mg/dL Take 15 gm of Carbohydrate, examples (4 glucose tablets, ½ cup juice or soda, 4 teaspoons sugar). Wait 15 minutes. Recheck blood sugar. Repeat treatment if blood sugar < 70 mg/dL or you still have symptoms of low blood sugar (shakiness, sweatiness or fast heart beat). If blood sugar > 70 mg/dL or you have no more symptoms of low blood sugar, eat one carbohydrate/protein snack if next meal is more than one hour away. Call your provider for persistent unexplained blood sugar < 70 mg/dL

Blood Glucose Guidelines for Outpatient Non-Pregnant Adults, 2/2
For blood glucose between mg/dL and no signs of illness or infection Choose food and portion sizes carefully. Drink more water. Eating non-starchy vegetables can help you to feel full and does not raise your blood sugar as high. Take a walk before or after eating. Talk with your provider on next visit. For blood glucose greater than 250 mg/dL with no signs of illness Increase water intake – 1 cup every hour. Check blood sugar every 2-4 hours. For Diabetes Type 1 – check urine for ketones. Do not exercise, best to rest. Call provider if blood glucose is persistently above 250 mg/dL.

Sick Day Care Plan If able to eat meals and /or BG > 250 mg/dl, drink 1 cup of fluids that are caffeine free and sugar free If unable to eat or BG < 250 mg/dl, alternate 1 cup of sugar-free fluids one hour and 1 cup with fluids containing sugar the next hour Check your blood glucose every 2-4 hours Check your urine for ketones if your BG > 250 mg/dl ( Type 1 DM) Take your Diabetes Medications and/or insulin, unless otherwise instructed by your Provider Rest ( Do Not Exercise) Call your provider if BG is persistently > 250 mg/dl

When to Call for Help Go to Emergency Department if your blood glucose is persistently greater than 250 mg/dl and if you…….. can’t keep any food or fluid down have nausea, vomiting or diarrhea have fever, abdominal pain or signs of worsening infection

What to eat? Basic Meal Plan
Carbohydrate affects blood sugar more than other nutrients Carbohydrate is found in sugar, sweets, grains, fruits, starchy vegetables, milk, yogurt and beans Eat at least 3 meals each day Eat the same amount of carbohydrates each meal Eat meals at the same time each day and don’t skip meals Include healthy fats such as nuts, olive or canola oil

Wonderful teaching handout developed by our own Dietitian Shannon
½ of your plate with non-starchy vegetable(broccoli, greens beans, carrot) ¼ plate with carb food (bread, potato, rice, pasta or starchy vegetables) ¼ with protein foods Add a small piece of fruit or 8 ounces of skim/low fat milk

Exercise Lowers Blood Sugar
Regular exercise helps control glucose, fats, improves blood pressure and help weight loss. Walking is a perfect “getting started exercise”. Start with 15 minutes 3 days a week and gradually build up. Carry glucose tablets, snacks (on medications) and water.

Diabetes Medication/Insulin
Name and dose How does the medication/insulin work When should the medication/insulin should be taken Common side effects Prescriptions for insulin vials/syringes, insulin pen/pen needles

Risk of Progression of Complications by HgbA1C

Importance of Glycemic Control and Diabetes Management

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Importance of Glycemic Control and Diabetes Management

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