Diabetes Update

03/29/17 Objectives for this talk

• Background and goals of treatment • Drug therapy • Appropriate use of insulin Objectives for this talk

• Background and goals of treatment • Drug therapy • Appropriate use of insulin Pathogenesis of DM: Summary

• Type 1 – Inability to secrete insulin – Presents abruptly, but not always. Can be of slow onset, more often in older patients. • Type 2 – Insulin resistance – Impaired (not absent) ability to secrete insulin – Type 2 diabetes worsens with time. What comes first in type 2 DM?

• Still debated. • Insulin resistance is present early. • Worsening likely due to loss of ability to compensate for insulin resistance by secreting more insulin What do we want to achieve?

Tangible goals Surrogate goals • Prevent worsening of • Low A1c diabetes • Good BP • No long-term complications • Well controlled lipids • CV health • Low inflammatory markers • Good quality of life • Normal creatinine • Minimal highs and lows • Normal liver function tests • Avoid healthcare costs • Normal body mass • Ability to carry out physical activity Some important diabetes treatment trials DCCT/EDIC sites PERCENT OF SUBJECTS IN MEAN HbA1c CATEGORIES 30 Combined Cohort 25 PP Int Con EE 20 RR CC 15 EE NN 10 TT 5

0 <6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.0+ MEAN HbA1cHbA1c Glycemic Intervention and Development of Complications in Type 1 Diabetes DCCT: Intensive vs Conventional Therapy

New-Onset Complication RRR Retinopathy 76% Nephropathy* 54% Neuropathy 60%

*Urinary albumin excretion 300 mg/24 h. DCCT Research Group. N Engl J Med. 1993;329:977. Relationship between Glycemia and Complications DCCT Retinopathy 250

200 43% reduction In risk for every 10% 150 Event decrease in HbA1c Rate per 100 1000 Pt-Y 50

0

5 6 7 8 9 10 11 12 5.5 6.5 7.5 8.5 9.5 10.5 11.5 Current Mean HbA1c (%) DCCT/EDIC data over 31 years

First of any predefined CVD outcome Risk reduction with intensive therapy was 30% (p = 0.016)

Cumulative incidence of cardiovascular outcomes in the conventional treatment and intensive treatment groups during up to 30 years of DCCT/EDIC treatment and follow-up.

Diabetes Care Ahead of Print, published online February 9, 2016

Summary UKPDS results

• Intensive blood-glucose control by either sulfonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. • Metformin monotherapy (obese patients) resulted in greater reduction in risk of any diabetes related event and decreased the risk of MI • BP controlled reduced micro and macrovascular complications Data from DCCT/EDIC and UKPDS

• UKPDS • DCCT – 10 years after UKPDS, – Nine years after DCCT, follow-up showed at 15% incidence of CV events decrease in MI in intense was reduced 57% in treatment group initially on former intensive patients sulfonylurea or insulin; and 33% in more obese treated – Younger age at onset (13- initially with metformin. 39) with no known CVD – Mortality also reduced 13 and 27% respectively

Nathan DM, et. al. NEJM 353:2643, 2005 Holman RR, et. al. NEJM 359, 1577, 2008 Glycemic control and macrovascular disease in ACCORD, ADVANCE, and VADT

Large randomized trials directed at the effect of glycemic control on cardiovascular risk in type 2 diabetes in participants at high risk for vascular events.

ACCORD ADVANCE VADT

# subjects 10,251 11,140 1,791

Average age 62 66 60

A1c control 6.4 vs 7.5 % 6.4 vs 7.0 % 6.9 vs 8.4 %

Primary results No decrease in No decrease in No decrease in cardiovascular events. cardiovascular risk cardiovascular risk Increased cardiovascular Reduced risk of mortality with intensive nephropathy Rx * The excess mortality in the ACCORD study was in subjects in the intensive group who did not achieve targeted control (higher A1c values in spite of efforts to lower glucose. Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial

DIABETES CARE, VOLUME 33, NUMBER 5, MAY 2010

These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD. Implications of major Rx trials

• Target of 7.0 % HbA1c still considered valid • More aggressive treatment may need to be implemented early with cautious approach with more advanced diabetes and cardiovascular disease • Overly persistent efforts to lower glucose in patients at risk for macrovascular events may not be warranted • Strong evidence for microvascular benefits of glucose control • Type 2 DM worsens with time. Can we prevent this? ADA Treatment Goals for Glycemic Control

General goal for non-pregnant adults HbA1c < 7.0% (normal < 5.7%) Pre-meal 80-130 mg/100 ml Peak post-meal < 180 mg/100 ml (measure 1-2 h after start of meal)

More stringent for selected Individuals • short duration of diabetes As close to normal as • treatment with lifestyle or metformin only possible without significant • long life expectancy hypoglycemia • no significant cardiovascular disease.

Less stringent for some patients • hypoglycemia unawareness HbA1c < 8.0 • limited life expectancy • co-morbidity • long hx DM with minimal complications where control has been historically difficult

American Diabetes Association: Standards of Care (Diabetes Care 40, Suppl. 1, Jan. 2017) Online www.diabetes.org/ Objectives for this talk

• Background and goals of treatment • Drug therapy • Appropriate use of insulin Metformin

• Near universal acceptance as initial drug therapy in absence of contraindication (e.g. renal failure, hypoxia) or intolerance • Decrease hepatic glucose release and increases muscle glucose uptake • Beneficial effects on weight and lipids • Lack of hypoglycemia when used alone • Generic drug with long history of use worldwide (over 50 yr) • Evidence from several studies supports a reduction in CV events, improved carotid IMT • UKPDS showed a significant reduction in MI and cardiac and all cause mortality by 39, 50, and 36% respectively when administered to obese patients (weight > 120% of ideal). Metformin: mechanism of action

• There is clear consensus that metformin reduces hepatic gluconeogenesis • But how it does that is still unclear – evidence for: – Impair (alter) mitochondrial function at complex I – Noncompetitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD), resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose – Activates AMPK leading to reduction of gluconeogenic gene transcription. Increased glucose transport in muscle and β- oxidation of fatty acids. – Other ? Severe hyperglycemia Insulin

Initial Pharmacologic treatment

Contraindication or Metformin intolerance to metformin)

Goal achieved Goal not achieved

Add second drug Another drug

What drug ? Sulfonylureas

• Mechanism of action: ↑ β-cell insulin secretion by activating potassium channels • Glipizide, Glimepiride • Glyburide (glibenclamide) – more hypoglycemia, maybe adverse interactions with cardiac channels • Advantages: – Well tolerated – Low cost • Disadvantages: – Hypoglycemia – Weight gain – Sulfa allergy – May have low durability Sulfonylureas (CV effects)

• UGDP (1970s) – increased CV mortality (controversial) • Retrospective and some prospective analyses of databases support increased risk • UKPDS, ADVANCE, ACCORD do not support increased CV risk Dipeptidyl peptidase -4 (DPP-4) inhibitors

• Several available – Sitagliptin (Januvia) – Alogliptin (Nesina) – Saxagliptin (Onglyza) – Linagliptin (Tradjenta) (no renal adjustment) • Block degradation of endogenous GLP-1 • Not very effective in lowering A1c • Advantages – Little or no hypoglycemia • Disadvantages – Urticaria, angioedema – Pancreatitis risk DPP-4 inhibitors (CV effects)

• Weight neutral • Decrease TG, may reduce hsCRP, may improve endothelial function, and improve reduce ischemia-reperfusion in animals, may decrease IMT (diabetes care Dec 2015 online) • Two large CV outcome trials in high risk patients (SAVOR-TIMI and EXAMINE) showed no difference in outcomes – Slight increase in hospitalization for CHF • TECOS trial – 14,671 patients to add either sitagliptin or placebo, no diff in CV events (839 vs. 851 – No difference in hospitalization for CHF GLP-1 agonists

• Several drugs differing in duration of action – Exenatide (Byetta) Short-acting BID (needs renal adjustment) – Long acting exenatide (Bydureon) Weekly (needs renal adjustment) – Lixisenatide (Lyxumia) Intermediate-acting Daily – Liraglutide (Victoza) Long-acting Weekly – Dulaglutide (Trulicity) Long-acting Weekly – Albiglutide (Tanzeum) Long-acting Weekly • Activate GLP-1 receptors in pancreatic β -cell and nervous system • ↑ glucose-induced insulin secretion, ↓ glucagon, ↓ gastric emptying,↑ satiety – Decreased hepatic glucose production – Decreased post-prandial glucose • Durable up to at least 3 years, may increase β -cell mass • Mild weight loss • Disadvantages – Nausea, vomiting, or diarrhea – Pancreatitis risk – Medullary thyroid tumors GLP-1 agonists (CV effects) • Many favorable effects on CV risk factors: Decrease weight and visceral fat, decrease BP, increase urinary sodium, improved endothelial function, decrease TG, FFA levels • LEADER trial – Randomized double blind trial, 9340 subjects with type 2 diabetes at high risk for CV disease or with CV disease. – Assessed the effect of liraglutide, a GLP-1 receptor agonist, versus placebo and standard care, on CV outcomes – Mean age 64 years and mean duration of diabetes 13 years. – Composite primary outcome (MI, stroke, or cardiovascular death) occurred in fewer participants in the treatment group (13.0%) when compared with the placebo group (14.9%) after a median follow-up of 3.8 years – Whether this drug class will have similar effects in lower-risk patients with diabetes remains unknown. • SUSTAIN-6 – Studied 2375 patients with type 2 diabetes who were at high CV risk – Primary outcome (MI, stroke, or cardiovascular death) occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, p<0.001)

Sodium-glucose co-transporter-2 (SGLT2) inhibitors (SGLT2)

• Several drugs – Canagliflozin (Invokana) – Dapagliflozin (Farxiga) – Empagliflozin (Jardiance) • Inhibits hSGLT2 (sodium/glucose cotransporter) in renal tubules – Urine glucose 60-100 mg/day – At base HbA1c of 8, will drop by 0.8-1.0 (similar to metformin at that base) Sodium-glucose co-transporter-2 (SGLT2) inhibitors

• Avoid if renal dysfunction • Advantages – Hypoglycemia very unusual – Familial renal glycosuria is a benign disease – Unique action, Can combine with all other agents – CV effects appear beneficial • Disadvantages – UTIs – vulvovaginitis, balanitis – Osmotic diuresis with possible dehydration and hypotension – Increased hepatic glucose output – Risk of DKA Glycated Hemoglobin Levels.

Zinman B et al. N Engl J Med 2015;373:2117-2128 Sodium-glucose co-transporter-2 inhibitors (CV effects)

• By inhibiting salt reabsorption in the proximal tubule vascular volume decreases with BP drop 4-6 mmHg. • Weight loss of 2.5 – 3.0 kg over 6-12 mos persisting for 2 years • Small increase in LDL and HDL cholesterol • Decrease in serum uric acid due to uric acid and glucose co-transport in proximal tubule • Meta-analyses suggests decreased CV risk (HR 0.82) • EMPA-REG NEJM Sept 2015 – 7020 patients were treated (median observation time, 3.1 years). – HR for combined CV event favored drug over placebo at 0.82 (10.5% vs, 12.1%) – Decreased hospitalization for CHF (2.7% VS. 4.1%) DKA induced by SGLT2 inhibition

• May not be recognized as glucose may not be as high as typically seen in DKA • Mechanism not unresolved, several hypotheses: • Increase in glucagon, decrease in insulin • Increased reabsorption of ketone with concomitant delayed clearance of ketone (may not see ketonuria) • Shift in substrate utilization to fatty acid with concomitant increase in ketone body production • Weight loss with concomitant sarcopenia • Associated dehydration, fluid loss (gastroenteritis) or poor fluid intake (vomiting) and infections, in a poor metabolic milieu, might also trigger this event, making the patient ketosis-prone. Cardiovascular Outcomes and Death from Any Cause.

Zinman B et al. N Engl J Med 2015;373:2117-2128 DCCT Retinopathy Results: > 3 Step Change

Primary Prevention Secondary Intervention

DCCT Research Group NEJM 1993;342:381 Drugs for type 2 diabetes beyond metformin (less often used)

Drug Actions Mechanism Advantages Disadvantages Meglitinides ↑ β-cell Potassium Action focused Not very effective repaglinide insulin channels on time of Other concerns shared nateglinide secretion food with sulfonylureas intake Thiazolidine- ↑ Insulin Activate PPAR-γ Pioglit ↑ HDL, Any use is questionable diones (TZDs) sensitivity ↓ TG Wt gain, edema, CHF, pioglitazone mainly in No ↑ LDL, bone fractures, rosiglitazone muscle hypoglycemia bladder CA Rosiglit ↑ CV events α-glucosidase ↓ Inhibit α- Nonsystemic Not very effective Inhibitors intestinal glucosidase No GI gas, diarrhea acarbose glucose hypoglycemia miglitol absorption Colesevelam Unclear Bile acid No Constipation, ↑ TGS sequestrant hypoglycemia ↓ absorption of meds Bromocriptine ↑ Insulin Hypothalamic No Dizziness, syncope, sensitivity dopaminergic hypoglycemia nausea, fatigue, rhinitis, effect Long term safety? Objectives for this talk

• Background and goals of treatment • Drug therapy • Appropriate use of insulin Insulin

Advantages Disadvantages

• Most effective • Weight gain • “Natural” • Injections • Least expensive • Once daily for many patients • Less weight gain than TZD • Essentially no side effects apart from hypoglycemia Does insulin impose CV risk or mortality?

• UK cohort study of 165,308 adults with type 2 DM. After applying structural models, insulin dose was not associated with mortality in any group. Study provides reassurance. • In the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) cohort, there were fewer CV events in the intensive arm, where subjects received higher insulin doses, than in the conventional arm. • In the UKPDS no increase in CV events was found among in individuals assigned to treatment with insulin • After adjustment for baseline covariates, no significant association of insulin dose with CV risk in ACCORD.

Diabetes Care 2015;38:2000–2008 Gamble et. al. Lancet Diabetes Endocrinol (1):43-52;2017 Insulin effects to keep in mind

• Insulin can increase sodium retention and stimulate the sympathetic nervous system. • Insulin has been shown to be anti-inflammatory, antioxidant, and profibrinolytic and cardioprotective in patients with acute myocardial infarction. • Overall, insulin does not induce ASCVD when administered properly for diabetes control in humans and lowering glucose to target range is desirable in many ways.

Mirza SA Comment, Arch Intern Med 167;858 2007 Sun et. al. World J Diabetes 5(2):89-96 2014

Degludec

42 h Insulin regimens

• Simple: once or twice daily • Complex: basal and bolus Rx using multiple doses • Choice depends on severity of diabetes

JAMA 289:2254-2264, 2003 Med Clin N Am 88, 865–895, 2004

Basal Insulin Bolus

Basal Insulin dosing in type 2 DM

• Weight based (may not be the best approach) – Start with 10-20 units depending on A1c or 0.2 units/kg • With lower A1c and relatively stable glucose, control may require only basal insulin • Can often start with a low dose, but very large amounts may eventually be needed due to resistance requiring vigorous titration. • May need large amounts in sick patients due to stress, steroids, tube feeds, etc • Severely insulin deficient: needs may approach like that in type 1 diabetes requiring basal/bolus regimen or insulin pump therapy 756 subjects with type 2 DM age 55-56 Followed algorithm

Diabetes Care, Nov. 2003

Insulin dosing in type 1 DM Bolus

Basal Insulin dosing in type 1 DM

• Weight based, Start with roughly 0.4-0.5 units/kg • More important to monitor carefully and adjust • New onset diabetes commonly associated with residual insulin, so initial needs may be small compared to eventual requirements • Typical adult with established type 1 diabetes needs about 40-50 units (total insulin) daily • Needs may vary greatly with activity, eating patterns • Overweight/obese type 1 diabetes may require much larger dosing. Basal/bolus (MDI or pump)

• Approximately one-half of the total dose should be given as a basal insulin, either as once or twice per day long-acting insulin (glargine or detemir) or as twice per day intermediate-acting insulin (NPH). • Glargine or detemir can be given either at bedtime or in the morning. May need to change to BID • Bolus insulin is given as short or rapid-acting insulin, divided before meals. The pre-meal dosing is determined by the pre-meal glucose level, meal size and content, as well as activity and exercise pattern. Dosing bolus insulin

• Option 1: Fixed scheduled dose – keep meal CHO constant • Option 2: Estimate CHO intake and determine bolus dose – example: one unit for each 12 grams CHO. • Ask patients about their eating habits and accommodate to the extent reasonable Correction Insulin:

• Correction = (BG-X)/Y where X = target glucose and Y = 1800 / total daily insulin (“rule of 1800”).

Example: Total insulin = 36 units/day. Y = 50 High Target = 150. X = 150 If glucose = 220 then (220-100) / 50 = + 2 Units If usual dose = 7, then inject 7 + 2 = 9 Units. OR • Use a table 150-200 1 Unit 301-350 4 201-250 2 351-400 6 251-300 3 > 400 call Pattern Adjustments

• Adjust based on prior recorded glucose values • Many patients can perform on their own • Algorithms or Common sense • Flow sheets or computer logs help.

EXAMPLE:

AM 7 AM noon glucose LisPro glucose

126 7 244 259 10 189 186 8 212 96 8 171 Pattern Adjustments

• Adjust based on prior recorded glucose values • Many patients can perform on their own • Algorithms or Common sense • Flow sheets or computer logs help. Best to record usual insulin dosing apart from adjustments.

EXAMPLE:

AM 7 AM noon glucose LisPro glucose

126 7 244 259 7 + 3 189 186 7 + 1 212 96 7 + 1 171 Pattern Adjustments

• Adjust based on prior recorded glucose values • Many patients can perform on their own • Algorithms or Common sense • Flow sheets or computer logs help. Best to record usual insulin dosing apart from adjustments

EXAMPLE:

AM 7 AM 9 AM noon glucose LisPro glucose glucose

126 7 285 244 259 7 + 3 223 189 186 7 + 1 240 212 96 7 + 1 195 171 Pattern Adjustments

• Adjust based on prior recorded glucose values • Many patients can perform on their own • Algorithms or Common sense • Flow sheets or computer logs help. Best to record usual insulin dosing apart from adjustments

EXAMPLE:

AM 7 AM 9 AM noon glucose LisPro glucose glucose

126 7 146 244 259 7 + 3 150 189 186 7 + 1 102 212 96 7 + 1 133 171 Adjust for exercise

• Match food to activity - Take enough extra food to balance out activity • Take additional food during and/or after activity • Reduce insulin if the goal is weight loss Types of insulin

• Non-analog (biosynthetic human insulin) sold as Humulin N or Humulin R, Novolin N or Novolin R – N = NPH, R = regular • Commonly used analogs – Long acting: glargine, detemir – Fast acting: lispro, aspart, glulisine • Newer insulin preparations – U-500 vial or pen form – U-300 glargine (sold as Toujeo) – U-200 lispro – Degludec: extra long acting (sold as Tresiba) – Inhaled (sold as Afrezza) • Pre-mixed long acting/short acting, 50-75/25-50 Degludec (Tresiba)

• Duration 42h, onset 30-90 • Administered daily • Modified insulin that has one single amino acid deleted in comparison to human insulin, and is conjugated to hexadecanedioic acid via gamma-L- glutamyl spacer at the amino acid lysine at position B29. • BEGIN Basal-Bolus Type 2 trial (755 pts on degludec, 251 on glargine), less hypoglycemia and less nocturnal hypoglycemia, otherwise non-inferior to glargine U-500 insulin

• 500 units/ml (as opposed to 100 units/ml for U-100 insulin • There are no U-500 syringes so, e.g. 25 units drawn in a U-100 syringe will deliver 125 units of insulin. • Formulated as regular insulin but duration longer than regular • Generally used in multiple doses pre-meals and sometimes HS – but does not match well to meal glucose absorption • Can be used in pumps Prescribing information, Eli Lilly Co, Indianapolis, IN U-500 regular insulin

• Sold as Humulin R U-500 • Now approved in pen form – Do not convert dosing – Pen can deliver up to 300 units in a single injection Other concentrated insulins

• U-300 glargine (Toujeo) • U-200 lispro • Degludec available as U-100 or U-200 Medtronic MiniMed 670G S.C. Insulin Pumps (CSII)

• Use estimated as about 40% of patients with type 1 diabetes in the USA • Can be used with a real-time S.C. sensor but (currently) does not act on monitored blood glucose except in limited fashion. • It does require calibration using fingerstick recordings. • Requires pump needle insertion recommended every three days. • Advantages: Convenient, better control of basal insulin, can use a square wave, can be linked to sensors • Indications: Type 1 or Type 2 with substantial insulin deficiency. Educated patient able to use pump effectively. Original Insulin Pump

1963 First insulin pump Basal and bolus infusions used. Continuous subcutaneous insulin infusion Real-Time Glucose Sensing

• Glucose levels are measured every 5 minutes in the interstitial fluid • Glucose levels are transmitted to a receiver using radio frequency waves • Receiver displays real-time glucose values, interval trend graphs, and directional arrows • Alarms provide alerts for hypo-hyperglycemia • Glucose data can be analyzed and summarized using computer programs Smart Pumps

Medtronic Minimed Guardian REAL-time Continuous Glucose Monitoring System (Paradigm) Last five years

MiniMed® 530G System

SmartGuard™ technology that takes action to reduce the risk of lows*. CareLink Software Output CareLink Software Output Mini Med 670G/Enlite 3 Hybrid Closed loop system

• The MiniMed 670G is FDA approved for people with type 1 diabetes ages 14 and over, though a pediatric study (7- 13 year olds) is currently underway to investigate an expansion in how it can be prescribed.

• The device cannot be used in children less than seven years old and those on less than eight units of insulin per day. The Artificial Pancreas

For the future Mean (SD) of venous PG (A), CGMG (B), insulin and glucagon doses (C), plasma insulin levels (D), and glucagon levels (E) for all experiments. 6 subjects, followed 48h q 15 min venous blood measurement.

Russell et.al. Diabetes Care, 35:2148-55,2012 Sick Day Management • Goals: Maintain hydration, prevent ketosis, control glucose • Obtain information: Is pt alert? Are you alone?, Can you get to a hospital if needed? Can you check ketones? Are you able to hold liquids down? Can you be reached by phone (what number)? • Take 4-6 ounces liquids per hour (non-caloric if able to eat calories). If unable to hold liquids down then go to ER • Try to take your normal calories by eating easy-on-the-stomach foods like regular (non-diet) gelatin, crackers, soups and applesauce. If these are too hard to eat, stick to drinking liquids that contain carbohydrates. Aim for 50 grams of carbohydrate every three to four hours. • Take basal insulin. Take pre-meal and correction insulin if eating (1.5 to 2 times more correction if ketones present). If unable to eat, measure glucose every 3-4 hours and cover with correction insulin (1.5 to 2 times more correction if ketones present). • Go to ER if impaired mentation, unable to hold liquids, glucose and ketones do not improve with Rx. Lower threshold if – Patient alone – Cannot easily be transported due to distance, weather, etc – Ketones large – Significant nausea, vomiting – High fever or issues related to illness underlying worsening glucose control and ketones END