October 16, 2015Mary-Anne Doyle, MD

Endocrinology and Metabolism

Treatment of Diabetes

ObjectivesDiscuss the main principles of therapy for type 1

diabetes including diet, exercise, blood glucose monitoring, oral hypoglycemic agents and insulin administration

Discuss the management of type 2 diabetes including diet, exercise, blood glucose monitoring, oral hypoglycemic agents and insulin

Review steps of insulin administration

Compare the mechanisms of action of the available types of oral hypoglycemic agents.

Case: Type 1 DiabetesJulie is a 17 yo F with type 1 diabetes mellitus.

She was diagnosed at the age of 7 when she developed symptoms of polyuria, polydipsia and polyphagia.

She is currently on: glargine 20u SC q evening and aspart with meals.

Her carbohydrate ratio is 1:10 with all meals and she uses a correction factor of 1:2.

Her most recent HbA1C is 6.9%.

Bolus & Basal InsulinP

las

ma

Insu

lin le

ve

ls

Hours

regular 6-8 hours

NPH 12–18 hours

lispro/aspart 3–5 hours

BASAL INSULIN

detemir ~ 16-24 hours (dose dependant)

glargine ~ 24 hours

Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491 Plank, J. et.al. Diabetes Care, May 2005; 28(5): 1107-12

BOLUS INSULIN

Insulin delivery systems

Recommended injection sites

Insulin RegimensJulie is using multiple daily injections

(MDI).

1.What is this concept?

2.How does using 2 different types of insulin help manage her diabetes?

MDI-Multiple Daily InjectionsMeal Time Insulin : Rapid acting insulin

(Novorapid or Humalog) pre-meals/snacks

Basal Insulin : (Levimir or Lantus) OD or BID

We are trying to replicate a normal pancreatic response

Long acting (BASAL) background insulin (basal) to keep blood sugars between meals in 4-7 range

Rapid (BOLUS) acting insulin to allow for uptake of meal time glucose associatecd with CHO loads

Expected insulin changes during the day Expected insulin changes during the day for individuals with a healthy pancreas.for individuals with a healthy pancreas.

Basal-Bolus ApproachBasal-Bolus Approach

*Insulin effect images are theoretical representations and are not derived from clinical trial data.

therapy addresses:

Bolus needs: Lispro, Aspart Basal needs: Glargine, Detemir , NPH

Meal Meal Meal

Diabetes Control and Complications Trial-DCCT

MDI vs Conventional Diabetes Therapy

Decreased average blood glucose8.6 mmol/L vs 12.8 mmol/L

Decreased HbA1c: 7.1% vs 8.9%

Microvascular complications:76% reduction in retinopathy60% reduction in neuropathy56% reduction in nephropathy

DCCT, New England Journal of Medicine, 1993

Carbohydrate Counting

What is carbohydrate counting and how is it used in the management of diabetes?

What is a correction factor and how is it used?

Carbohydrate Counting

If Julie’s CHO ratio is 1:10, how much rapid-acting insulin should she take with her lunch?

60g CHO / 10 units insulin = 6 units of rapid-acting insulin

Carbohydrate Counting

Correction Factor

In order to calculate the person’s correction factor:= 100/Total Daily Dose (TDD) = # mmol/ unit of insulin

The correction factor represents what 1 unit of insulin is expected to lower the BG by in mmol/L.

Example:TDD is 35 units the correction factor

= 100 ÷ 35 units

= 2.8 mmol/L/per unit of insulin.

Therefore 1 unit of insulin is expected to lower the

BG by 2.8 mmol/L.

Correction Factor-ExampleIf BG is 13 and the target glucose was 6

13 mmol/L-6mmol/L = 7mmol/L

7 mmol/L ÷ 2.8mmol/L/unit (correction factor) = 2.5 units

The use of this formula must always be re-evaluated in the context of how it works. Patients are encouraged to always review the pattern of their glucose levels to determine if correction factors or boluses are working appropriately.

What is Glycemic Index?Not all carbohydrate foods

are created equal

The glycemic index (GI) describes this difference by ranking carbohydrates according to their effect on our blood glucose levels.

Low GI carbs produce only small fluctuations in blood glucose.

Lifestyle ModificationWhat recommendations would

you give Julie in regards to diet and exercise?

Exercise and Type 1 DiabetesModerate to high levels of physical activity is

associated with substantial reduction in morbidity and mortality in both men and women with type 1 and type 2 diabetes.

In type 1 diabetes, there is little or no endogenous insulin secretion and no physiological regulation of insulin levels.

If exogenous insulin and/or carbohydrate ingestion is not adjusted, hypoglycemia often occurs .

Fear of hypoglycemia may be a barrier to exercise in people with type 1 diabetes

Exercise and Type 1 DiabetesHypoglycemia may be prevented by

Increasing CHO intake Reducing meal time insulin prior to exerciseAltering basal insulin for insulin pump usersPerforming resistance exercise immediately prior to

aerobic exercise

Exercise performed late in the day or in the evening can be associated with increased risk of overnight hypoglycemia.

Hyperglycemia can occur after very intense exercise and usually associated with high intensity sports/activities/resistance training.

Diet1. Counseling by a registered dietitian : Eating Well with

Canada’s Food Guide in order

2. Type 1 diabetes:- teach how to match insulin to CHO intake- maintain regularity in timing and spacing of meals-low glycemic index foods

3. Sucrose and sucrose-containing foods can be substituted for other CHOs as part of mixed meals up to a maximum of 10% of total daily energy, provided adequate control of BG and lipids is maintained.

5. Adults: no more than 7% of total daily energy from saturated fats and should limit intake of trans fatty acid.

6. T1DM: informed of delayed hypoglycemia resulting from alcohol consumed with or after the previous evening’s meal.

Driving GuidelinesJulie is beginning to drive.

What advice should be given to people with diabetes in regards to glucose monitoring and driving?

Driving GuidelinesMeasure BG level immediately before and at

least every 4 hours (more often in cases of hypoglycemia unawareness) during long drives.

Always carry BG monitoring equipment and supplies of rapidly absorbable carbohydrate within easy reach (e.g. attached to the visor).

Should not drive when their BG level is below <4 mmol/L; treat and only drive if BG >5 mmol/L.FIVE TO DRIVE

Stop and treat as soon as hypoglycemia and/or impaired driving is suspected.

TYPE 2 DIABETES MELLITUS

Case:

Marie, is a 58-year-old t woman with a BMI 34 kg/m2

woman who has had type 2 diabetes mellitus for the last 8

years presented saying: “My blood sugars are constantly high.”

At diagnosis 8 year ago:polyuria, polydipsia, and weight lossA1c 8.4%prescribed metformin 500 mg BID

Clinical Course. . .Gradually rising hemoglobin A1c values – now

11.2%

Tried to increase the dose of Metformin, limited by diarrhea and upset stomach

Tried sitagliptin → nausea, headache and GI upset, discontinued

Gliclazide MR 30 OD started and then gradually increased to 120 mg OD

Compliant with her medications, trying to exercise (walking) and watching her diet

Pharmacologic Management of

Type 2 diabetes

Acarbose-Mechanism of ActionInhibits intestinal enzyme alpha-glucosidase and pancreatic enzyme alpha-amylase reduces digestion of carbohydrates and less glucose absorption

Alpha-Glucosidase inhibitorsEg Acarbose (Glucobay)

A1c lowering 0.6%

Not recommended as initial therapy in patients with marked hyperglycemia (i.e. A1c > 8.5% )

Hypoglycemia rarely occurs

Weight neutral

GI side effects –flatulence, diarrhea, bloating

Metformin-Mechanism of Action

BiguanidesBenefitsA1c lowering 1.0-1.5%

Low risk of hypoglycemia

Weight neutral as monotherapy and less weight gain in combination therapy

Improved cardiovascular risk factors

Risks:Contraindicated in renal failure (eGFR<30 ml/min) and hepatic failure (increases risk of lactic acidosis)

May be associated with B12 deficiency

GI side effects- cramping, bloating, diarrhea*

TZD-Mechanism of Action

Enhances insulin sensitivity in peripheral tissues and liver by activation of ppar-gamma receptors

Eg. Pioglitazone or Rosiglitazone

ThiazolidinedionesBenefits:Longer duration of monotherapy compared with metformin or glyburide Mild BP loweringA1c lowering 0.8%Low risk of hypoglycemia

Risks:Weight gainIncreased peripheral edema/heart failure (contraindicated in CHF)Increased risk of macular edema (rare)Increased risk of fracturesPossible increased risk of MI with Rosiglitazone.Possible increased risk of bladder cancer with pioglitazone

Secretagogues-Mechanism of Action

• Sulfonylureas bind to SU receptor inhibiting an efflux of K.• This leads to depolarization and opening of Ca channels.• Influx of Ca triggers exocytosis and release of insulin

Secretagogues

SulfonylureasGlyburideGlimeperideGliclazide

MeglitinidesRepaglinide

SulfonylureasBenefitsA1c lowering 0.8%

Rapid glucose lowering

RisksMay cause hypoglycemia

(Glyburide>Glimeperide>Gliclazide)

Associated with weight gain

MeglitinidesBenefits:A1c lowering 0.7%

Rapid glucose lowering

Shorter half-life leading to less hypoglycemia (can be held if not eating)

Targets post-prandial hypoglycemia better than sulfonylureas

Safe to use in renal impairment

Risks:Weight gain

Risk of hypoglycemia (mild to moderate and less than Gliclazide)

Moderate Cost (more than Gliclazide less than DPP-IV inhibitor)

Recent concerns regarding possible interactions with clopidrogrel (Plavix)

Incretins Incretins  hormones are secreted

in the gut but lead to increase insulin secretion from the pancreas

The incretin concept was developed when it was observed that there is substantially more insulin secreted in response to oral glucose versus intravenous glucose.

Two main incretin hormones: GLP-1 (glucagon like peptide-1) GIP (glucose-dependent

insulinotropic peptide)

GLP-1 Agonist Mechanism of Action

Activates incretin pathway through a DPP-IV resistant GLP-1 analogue

GLP-1 Agonists (liraglutide, exenatide)

Benefits:A1c lowering 1.0%

Significant weight loss

Low risk of hypoglycemia

Risks:GI side effects-nausea, cramping, bloating (usually resolve within 2-3 weeks)

Subcutaneous injection

Rare cases of pancreatitis

Increased risk of parafollicular hyperplasia (contra-indicated in patients with a family history of MTC/MEN2)

Costly

DPP-IV Inhibitors

Amplifies Incretin pathway activation by inhibiting breakdown of endogenous GLP-1 and GIP

DPP-IV Inhibitors A1c lowering 0.7%

Low risk of hypoglycemia as monotherapy

Weight neutral

Improves post-prandial control

Rare cases of pancreatitis

GI Side effects-nausea, bloating, decreased appetite

Costly

SGLT-2 Inhibitors Mechanism of Action

SGLT2 inhibitors block glucose transport in the proximal renal tubule leading to urinary excretion of glucose

SGLT2-inhibitorsEg Canagliflozin, DapagliflozinA1c lowering 0.7-1.0%Hypoglycemia negligibleAssociated with weight lossIncreased glycosuria may lead to increased risk of

urinary tract infections and yeast infectionsOsmotic diuresis may cause hypotensionCases of ketoacidosis in patients with normal blood

glucoseNeeds further investigation

Effect on CV outcomes? Increased HDL/LDL/Costly

Renal Impairment and diabetes therapy

Things to consider when deciding best treatmentEvidence to support the use of this

treatment in this population?

Can they afford it?

Is it covered?

Are there any contraindications?

Medication interactions?

Desired effect comparable to research?

Management of Type 2 Diabetes

Back to case: What is the current situation?

What is the next step in management of this patient’s diabetes?

Why insulin?Diabetes is a progressive disease characterized

by decreasing beta-cell function over time.

Studies have shown that glycemic control steadily deteriorates over time, and most patients eventually require insulin therapy for the control of their hyperglycemia.

Some studies indicate that loss of beta-cell function occurs early in the disease and early intervention with insulin may not only stabilize but also even spare beta-cell function.

When should you consider insulin?

Suboptimal control with max doses of oral agents

At diagnosis if marked hyperglycemia (A1c >9.0)

Temporarily - during illness, pregnancy, stress, procedure/surgery, glucocorticoids

*No evidence that exogenous insulin accelerates the risk of complications of diabetes, and its appropriate use should be encouraged

What insulin regimen is appropriate?

A common initial approach:for patients on maximized doses of oral agents

add bedtime basal insulin.

Patients presenting with extreme hyperglycemia need a more intensive insulin:Basal-bolus regimen (Multiple Daily injections-

MDI)To be maximally effective carbohydrate

counting and frequent blood glucose monitoring

Premixed insulinFewer injections and glucose monitoring but less flexible Should eat consistent amounts of CHOs at consistent times

of the day

Diet and Physical Activity

Benefits of activityIncluding increased

cardiorespiratory fitnessIncreased vigourImproved glycemic controlDecreased insulin

resistanceImproved lipid profileBlood pressure reduction Weight loss

Exercise Definitions

CDA Guidelines exercise

Diet

Questions ?