Current Management of Type 1 and Type 2 Diabetes

Thomas Donner, M.D.

Division of Endocrinology & Metabolism

Objectives

After attending this session, the participant should be able to:

• Describe the pathogenesis of type 1 and type 2 diabetes

• Recognize glucose, lipid and blood pressure targets for patients with diabetes

• Understand the actions of insulins, and other injectable and oral anti-hyperglycemic agents

Disclosures

• I have no relevant disclosures

Diabetes

• 8% of the US population affected

• In the US, the leading cause of:– Adult blindness– End stage renal failure– Non-traumatic amputations

• A leading cause of heart attacks and strokes– Risk 2-fold in men and 4-fold in women with DM

• These complications are largely preventable– Aggressive control of glucose, lipids and BP

Pathogenesis of Type 1 Diabetes

• About 5% of all diabetes

• Autoimmune destruction of pancreatic islet cells

• Lifelong requirement of insulin to stay out of ketoacidosis

• Genetic and environmental causes– If an identical twin has type 1 diabetes the other

twin has a 50% chance of developing the disease

Pathogenesis of Type 2 Diabetes

• Strongly correlated with obesity, especially visceral fat• Hormones and cytokines released from fat cells contribute

to both insulin resistance and defective insulin secretion– Insulin resistance

• Decreased uptake of glucose in muscle, fat and liver

• Excessive hepatic glucose output

• Worsened by physical inactivity

– Insulin deficiency• Loss of beta cells appears due to fatty infiltration of the pancreas among

other causes

• If an identical twin has type 2 diabetes the other twin has nearly a 100% chance of developing the disease

Complications DCCT1,2 Kumamoto3 UKPDS4,5

of A1C 9% 7% 9% 7% 7.9% 7%

Retinopathy 63% 69% 17%-21%

Nephropathy 54% 70% 24%-33%

Neuropathy 60% – –

Macrovascular disease 57%* – 15%-33%

Good Glycemic Control Reduces the Incidence of Complications

*After 17 years of follow-up

1DCCT Research Group. N Engl J Med. 1993;329:977; 2 DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653 3Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103; 4UKPDS Group. Lancet. 1998;352:837; Horman R et al. N Engl J Med. 2008;359:1577-1589

Complications DCCT1,2 Kumamoto3 UKPDS4,5

of A1C 9% 7% 9% 7% 7.9% 7%

Retinopathy 63% 69% 17%-21%

Nephropathy 54% 70% 24%-33%

Neuropathy 60% – –

Macrovascular disease 57% – 15%-33%*

Good Glycemic Control Reduces the Incidence of Complications

*Sulfonylurea/Insulin – metformin, after 20 years of follow up

1DCCT Research Group. N Engl J Med. 1993;329:977; 2 DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-2653 3Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:103; 4UKPDS Group. Lancet. 1998;352:837; Horman R et al. N Engl J Med. 2008;359:1577-1589

Adapted with permission from Skyler J. Endocrinol Metab Clin North Am. 1996;25:243DCCT Research Group. N Engl J Med. 1993;329:977

Re

lati

ve

Ris

k

RetinopathyNephropathyNeuropathyMicroalbuminuria

A1C (%)

15

13

11

9

7

5

3

16 7 8 9 10 11 12

A1C and Relative Risk of Microvascular

Complications: DCCT

Goals for Glycemic Control

• Biochemical Index Normal Goal• fasting/preprandial <100 <130 blood

glucose (mg/dl)• postprandial <140 <180• bedtime <100 100-140• HbA1c (%) <5.7 <7*

• American Diabetes Association: Clinical practice Recommendations 2014

* More stringent goals (<6%) can be considered in individual patients, and less stringent goals in older patients, those with advanced complications, or with recurrent hypoglycemia

Diabetes Prevention Program: Treatment Protocol

• Overweight patients with impaired glucose tolerance• Metformin

– 850 mg QD for 1 month– 850 mg BID after 1 month

• Lifestyle Intervention– Moderate exercise for at least 150 minutes/week– Weight loss of > 7%– 16 lesson curriculum taught on one-to-one basis

• Placebo• Follow-up

– Average 2.8 years (range 1.8-4.6)

Diabetes Prevention Program Research Group. N Engl J Med 2002;346:393-403

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cum

ulat

ive

inci

denc

e (%

)

Placebo (n=1082)

Metformin (n=1073, p<0.001 vs. Placebo)

Lifestyle (n=1079, p<0.001 vs. Metformin ,p<0.001 vs. Placebo)

Incidence of Diabetes Incidence of Diabetes

Risk reductionRisk reduction31% by metformin31% by metformin58% by lifestyle58% by lifestyle

The DPP Research Group, NEJM 346:393-403, 2002

Lifestyle

Metformin

Treatment of Type 2 Diabetes

Meal Planning

• Decrease fat content and total calories– weight reduction in obese patients– decrease saturated fat– increase fiber

• induces satiety, lowers postprandial glucose

• Reduce foods high in simple sugars to reduce postprandial hyperglycemia

• For patients on prandial insulin– try to keep carbohydrate calories constant for the same meal

if on set insulin dosages or:– adjust pre-meal insulin for alterations in carbohydrate

calories (insulin:carb ratios)

Benefits of Exercise

• Decreases insulin resistance which lowers blood glucose

• Improves weight, blood pressure, LDL and HDL cholesterol

• May increase risk of hypoglycemia in patients on insulin or insulin secretogogues

• Patients at risk should be pre-screened for coronary artery disease

Benefits of Modest Weight loss

Glucose and insulin levels Blood pressure LDL and triglycerides, increase HDL CRP and IL-6 Cardiovascular risk Severity of sleep apnea

Oral Pharmacologic therapy

• Monotherapy– Insulin secretogogues: sulfonylureas, nateglinide

and repaglinide– Biguanides: metformin– Alpha-glucosidase inhibitors– Thiazolidinediones– DPP-4 inhibitors– SGLT-2 inhibitors

• Combination therapy

↓ GLUCOSE PRODUCTIONInsulin

MetforminDPP-4 inhibitors

(Thiazolidinediones)

MUSCLE

↑ PERIPHERAL GLUCOSE UPTAKE

InsulinThiazolidinediones

(Metformin)

Sites of Action of Antihyperglycemic Agents

PANCREAS

↑ INSULIN SECRETION Sulfonylureas

MeglitinidesNateglinide

DDP-4 inhibitors

ADIPOSE TISSUE

LIVER

SLOW GLUCOSE ABSORPTION Alpha-glucosidase inhibitors

Modified from: Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

INTESTINE

RENAL TUBULES

SGLT-2 Inhibitors

MUSCLE

Sites of Action of Antihyperglycemic Agents

PANCREASADIPOSE TISSUE

LIVER

Modified from: Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

INTESTINE

↑ INSULIN SECRETION Sulfonylureas

MeglitinidesNateglinide

DDP-4 inhibitors

↑ PERIPHERAL GLUCOSE UPTAKE

InsulinThiazolidinediones

(Metformin)

GLUCOSE PRODUCTION

InsulinMetformin

DPP-4 inhibitors(Thiazolidinediones)

SLOW GLUCOSE ABSORPTION

Alpha-glucosidase inhibitors

Relative HbA1c-Lowering Efficacy of Established Oral Diabetes Medications

Agent No.Studie

s

No. Patients Studied

HbA1c Reduction Range (%)

Median (%)

Metformin 9 2,876 0.8-3.0 1.3

Sulfonylureas 7 5,683 0.9-2.5 1.8

Meglitinides 6 2,456 0.4-1.9 1.0-1.1

TZD’s 7 2,663 0.9-2.9 1.3-1.4

DPP-4 inhibitors 6 11,267 0.4-1.2 0.6-0.7

-Glucosidase inhibitors

16 3,230 0.6-1.3 0.7-0.8

SGLT-2 inhibitors

13 4,063 0.5-0.7 0.5-0.6

Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.Richter B, et al. Vasc Health Risk Manag. 2008;4: 753–768.Musso G, et al. Ann Med. 2012 Jun;44(4):375-93

Kimmel B, Inzucchi SE. Clin Diabetes. 2005;23:64-76. DeFronzo R, et al. Presented at: ADA 2004 Scien Sess.Buse JB, et al. Diabetes Care. 2004;27:2628-2635.

Sulfonylureas: Available agents

• First Generation– Tolbutamide– Chlorpropamide– Tolazamide

• Second Generation– Glyburide– Glipizide– Glimepiride

Sulfonylureas

• Inexpensive

• Risk for significant hypoglycemia is 1-3%/year– glyburide carries the highest risk

• Small weight gain

• Long-term failure with monotherapy is a common problem

Nateglinide and Repaglinide

• Shorter-acting insulin secretogogues

• Given just before meals

• Lesser risk of hypoglycemia with prolonged fasting

Metformin

• Often leads to a modest weight loss• Lowers total and LDL cholesterol, and triglycerides• Lowers clotting factors: plasminogen activating

inhibitor-1 (PAI-1), fibrinogen• Reduced risk of myocardial infarction, stroke and

diabetes-related deaths in overweight patients more than sulfonylureas or insulin in the UKPDS

Metformin and Cancer Mortality

• Cancer mortality is increased in those with diabetes (HR 1.09)

• Metformin reduces the risk of colon and pancreas cancer• Mortality is increased relative to nondiabetes in those on

monotherapy with sulfonylureas (HR 1.13) or insulin (HR 1.13) but reduced in those on metformin monotherapy (HR 0.85)

• Metformin carries a 0.75 HR for breast cancer c/w other diabetes medications

Currie et. al. Diabetes Care. 2012;35(2):299-304Chlebowski RT at al. J Clin Oncol. 2012

Metformin• GI side effects most common

– Diarrhea is most common but typically mild to moderate and self-limited

– Nausea, vomiting, bloating, flatulence and anorexia are less common

– Minimize by slow titration, dosing with meals, extended release formulation

• Lactic acidosis– Very rare complication– Typically occurs in at risk patients in whom it should be

avoided:• Kidney failure (decreased drug clearance)• Liver failure (decreased lactate clearance)• Other conditions associated with lactic acidosis

-Glucosidase Inhibitors: Acarbose and Miglitol

• Slow carbohydrate digestion• Lower postprandial glucose• GI side effects

– Flatulence and diarrhea are common– Nausea and vomiting uncommon – Start with low dosages (25 mg with meals) and titrate up

slowly to max dose of 100 mg with meals– Acarbose in combination with a sulfonyurea or insulin

may lead to hypoglycemia; if hypoglycemia occurs, treat with glucose PO or IV, not sucrose, the digestion of which is blocked by these agents

Thiazolidinediones: Pioglitazone (Actos) and Rosiglitazone (Avandia)

• Effective as monotherapy, or in combination with all other oral agents

• Do not cause hypoglycemia when used as monotherapy

• Increase HDL • Change dense LDL cholesterol into a less

atherogenic “fluffy” LDL particle

Thiazolidinediones

• Cardiovascular effects appear to be agent-specific– Pioglitazone has more favorable lipid effects – Long-term treatment with pioglitazone has been shown to

reduce cardiovascular events– Studies of rosiglitazone show either no CV benefit or an

small increased risk of myocardial infarction• Adverse effects

– Weight gain– Peripheral edema– CHF exacerbation in those with more advanced heart

failure– Increased osteoporotic fractures in post-menopausal

women– Bladder cancer

Glucagon-like Peptide-1 (GLP-1) Actions

Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169

Stomach:Stomach: Helps regulate Helps regulate

gastric emptyinggastric emptying

Promotes satiety and Promotes satiety and reduces appetitereduces appetite

Liver:Liver: Glucagon Glucagon reduces reduces

hepatic glucose outputhepatic glucose outputBeta cells:Beta cells:EnhancesEnhances glucose- glucose-

dependent dependent insulin secretioninsulin secretion

Alpha cells:Alpha cells: PostprandialPostprandial

glucagon secretionglucagon secretion

GLP-1: Secreted upon the ingestion of food -

diminished in type 2 diabetes

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

GLP-1 Secretion and Inactivation

GLP-1inactive

(>80% of pool)

ActiveGLP-1

Meal

DPP-4

IntestinalGLP-1 release

GLP-1 t½ = 1 to 2 min

GLP-1 = glucagon-like peptide–1; DPP-4= dipeptidyl-peptidase–4

IntestinalGLP-1release

Mixed Meal

Drucker DJ. Diabetes Care. 2003;26:2929-2940. DPP-4 – dipeptidyl peptidase-4

Inhibition of DPP-4 to Increase Active GLP-1

Sitagliptin/Saxagliptin/ Linagliptin:

DPP-4 Inhibitors

DPP-4 inhibitors - oral

DPP-4

DPP-4 Inhibitors

• Very low risk of hypoglycemia due to glucose-dependent insulin secretion

• Neutral effect on body weight

• Most agents need to be renally dosed as most are renally cleared

GLP-1 Agonists

• Exenatide (Byetta, Bydureon) and liraglutide (Victoza)• Resistant to DPP-IV inactivation

– overcome the 1-2 minute half life of GLP-1

• Given as subcutaneous injections • Mimic the actions of endogenous GLP-1

– Glucose-responsive insulin secretion – no hypoglycemia

– Suppress hepatic glucose production

– Suppress appetite• Weight loss of 4-12 lbs commonly seen

20 10 0 10 20 30

Natural History of Type 2 Diabetes

Adapted from International Diabetes Center (IDC). Minneapolis, Minnesota.

Years of Diabetes

Relative -Cell Function

PlasmaGlucose

Insulin resistance

Insulin secretion

126 mg/dL Fasting glucose

Postmeal glucose

6-6

Insulin Therapy in Type 2 Diabetes

• Compensates for decreased endogenous insulin• Improves B-cell function by reducing

glucotoxicity• A bedtime intermediate or long-acting insulin may

be added to oral agents to suppress nocturnal hepatic glucose production and improve fasting glucose levels

• Multiple insulin injections may be required with progressive B-cell failure to optimize control

Insulin Therapy: Indications in Type 2 Diabetes

• Very symptomatic: weight loss, polyuria, polydipsia

• Marked hyperglycemia (glucose >300 mg/dl)

• Pregnancy

• Inadequate glycemic control with combination oral agent therapy

Intensive Insulin Therapyin Type 1 and Type 2 Diabetes

Insulin and Glucose Patterns in Normals

and in Type 2 Diabetes

Polonsky, et al. N Engl J Med. 1988;318:1231-1239.

100

200

300

400

Glucose Insulin

0600 1000 18001400 02002200 0600

Time of Day

0600 1000 18001400 02002200 0600

Time of Day

20

40

60

80

100

120

B L SB L S

NormalType 2 Diabetes

mg/

dL

U/m

L

6-17

Insulin Pharmacology

• “Basal” insulins (long-acting glargine, detemir and intermediate-acting NPH ) suppress hepatic glucose production in the post-absorptive state

• “Bolus” insulins (short-acting regular, ultra short-acting lispro, aspart and glulisine) promote uptake of ingested carbohydrates by peripheral cells

Comparison of Human Insulins and Analogs

Insulin Onset of Duration ofPreparations Action Peak (h) Action (h)

Lispro/Aspart/Glulisine 5-15 min 1-2 3-6

Human Regular 30-60 min 2-4 6-10

Human NPH 1-2 h 4-8 10-20

Glargine 1-2 h flat ~24

Detemir 1-2 h flat 18-24

Time course of action of any insulin can vary in different people or at different times in the same person; thus, time periods indicated here should be considered general guidelines only.Adapted from Mudaliar S et al. Endocrinol Metab Clin North Am. 2001;30:935-982. J Plank et al. Diabetes Care 2005;28(5):1107-12

Rapid-acting Analogs: Insulin aspart, lispro and glulisine

• Rapidly absorbed and can be taken shortly before the meal– better postprandial glucose control than regular

insulin– injection15-20 minutes before the meal is optimal to

time insulin action with food absorption

• More rapidly cleared than regular insulin– less late, postprandial hypoglycemia

Insu

lin E

ffe

ct

B DL HS

Bolus insulin

Basal insulin

Physiologic Insulin Replacement: Basal-Bolus Insulin Therapy

Endogenous insulin

Adapted with permission from McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002:193

0600 0800 18001200 2400 0600

Time of day

20

40

60

80

100 B L D

Basal-Bolus Insulin Treatmentwith Insulin Analogues

B=breakfast; L=lunch; D=dinner

Glargine or detemir

Lispro, glulisine, or aspart

Normal pattern

U/mL

• Adjust insulin based on:– Meal content

• Insulin:Carb ratio, usually 1:10 to 1:15 • 500/Total daily insulin dose; ie 500/50 = 1ns:carb 1:10

– Glucose level• correction factor: usually 1 unit to reduce BG 30-50 mg/dl to a

target of 100-120 mg/dl• 1800/Total daily dose; ie 1800/60 = CF of 1:30

– Physical activity (downwardly adjust pump basal rate, long-acting insulin, or meal bolus)

• To achieve target glucose ranges– 80-130 mg/dl pre-meal, 100-160 after meals, 100-140 at

bedtime

Diabetes Self Management

Insulin pump therapy

Most physiologic insulin replacement modality. Continuous subcutaneous infusion catheter delivers aspart, lispro or glulisine insulin

- Basal insulin - pre-programmed - can be varied hourly - temporary basal rates can be programmed for inactivity, exercise or illness- Bolus insulin - pump is commanded to give bolus insulin before meals or to correct elevated glucose levels - can give 0.1 unit bolus increments

Home Glucose Monitoring

• Critical for intensive diabetes control with insulin

• Frequency of testing correlates with better control

• Should be performed:– before meals, at bedtime, before and after

exercise, and periodically 2 hours after meals and at 3am

Subcutaneous Continuous Glucose Monitors

• MiniMed and DexCom • Alarms for high and low glucose readings• Useful for catching periods of hypoglycemia

(especially overnight) of which patients are unaware

• Useful to observe BG trends to assist with basal and bolus insulin dosage adjustments

• Shown in adults with type 1 DM to reduce the incidence of severe hypoglycemia and reduce HbA1c levels

Continuous Glucose Monitoring

Combined Insulin Pump and Glucose Sensor Use

A - Paradigm PumpB - Infusion SetC - Continuous Glucose MonitorD - Transmitter

Most Patients with Diabetes Die of Cardiovascular Disease

• 2- to 4-fold more likely to have heart disease

• 2- to 4-fold more likely to have a stroke

• 2- to 8-fold more likely to have heart failure

• ~ 70% of all diabetes-related deaths are associated with vascular disease

Cardiovascular Risk Factor Goals

• Blood Pressure – < 130/80

• Lipids– LDL: <100 mg/dl, < 70 in those with CAD– HDL: > 40 mg/dl in men and > 50 mg/dl in women– Triglycerides: < 150 mg/dl

• Stop smoking

• Aspirin 81 mg daily in those with known CV disease or men > age 50, women > age 60

Thank you