CLP 402:

Pharmacotherapy of
Diabetes Mellitus
David Shalkur

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 Objectives: to
• List risk factors of DM
• Recognize current criteria for Diagnosis of DM
• State goals of comprehensive DM treatment including therapeutic
options of meeting each goal
• Identify glyceamic targets in DM treatment for different patient
populations
• Outline options for DM treatment (Non-PCL and PCL)
• State indications for insulin therapy in DM
• Compare efficacy and safety of oral drugs for DM

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 Outline
• Introduction (definition, prevalence, risk factors, impact)
• Diagnosis of DM (Criteria & patient evaluation)
• Treatment Goals & Targets (glyceamic, CV risk reduction, QoL,
Self-care)
• Treatment Options (Lifestyle modifications & Pharmacological)
• Treatment Approach (T1DM & T2DM treatment approaches)
• Monitoring
• For efficacy
• For adverse effects (hypoglycemia/hyperglycemia: risk factors
symptoms and treatment)
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 Introduction
• Definition: DM is a chronic dx of disorder of carbohydrate, protein
and fat metabolism xterised by hyperglycaemia due to insulin lack
and or insensitivity
• Type
• T1DM: auto-immune destruction of β-cells, absolute insulin lack, occurs b4 age 35, 5
– 10%
• T2DM: defect in insulin release, insulin insensitivity, occurs after age 35, ≥ 90% case
of DM,
• GDM: DM diagnosed in a non-DM at 2nd/3rd trimester of pregnancy, due to high
levels of insulin counter-regulatory hormones
• 20DM: DM resulting from other endocrine disorders, and use of some medications
Prevalence:(NIG)? Projected to be 1 - 8%, higher in urban compared
to rural due to differential prevalence in western-life pattern
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 Risk Factors & Impact
• T1DM
• auto-immune diseases
• family history
• T2DM
• aging
• obesity
• genetics
• family history
• dietary habits
• GDM
• obesity
• prior GD
• SDM
• other endocrine disorders
• drugs
• glucocorticoids , thyroid hormone
• thiazide diuretics, beta-adrenoceptor blockers
• interferon,
• diazoxide)
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 Impact of DM
• Morbidity (complications)
• Macrovascular: strokes (11%), PVD (37%), CAD, HF(2.1%)
• Microvascular: neuropathy (diabetic foot), nephropathy (CKD),
retinopathy
• Acute complications: Severe hyperglycaemia, hypoglycaemia
• Others: e.g. diabetic foot, ED
• QoL: complications cause ↓ life enjoyment, ability and
expectancy
• Economic cost: due to chronic care, hours used by caregivers
• Mortality: risk of death due to acute and chronic complications

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Symptoms

Non specific:
• Unexplained weight loss
• Recurrent UTIs
• Classical symptoms: polyuria, polydipsia and polyphagia
• Symptoms of complications: angina pain, peripheral
neuropathy, decline eye sight, kidney disease
• Abnormally large baby weight (at birth)
• Symptoms of acute complications (dehydration, shock)

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 Diagnosis of DM
Table 1: Criteria for DM diagnosis
Parameter Normal Pre-DM DM

FBG (mg%) (at least 8 hr after last ≤ 99 100 – 125 ≥ 126

meal)
OGTT (mg%) (2 hr after 75 g oral ≤ 139 140 -199 ≥ 200
glucose load)
RBG (mg%) (in presence of obvious ≥ 200
DM Symptoms)
Hgb A1C (%) (used for diagnosis only ≤ 5.6 5.7 – 6.4 ≥ 6.5
in standard labs)
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 Screening/Patient Evaluation
Screen
• Individuals with
• risk factors
• GDM: pre-pregnancy wt. > 25 kgM-2, recurrent miscarriage, delivery wt. > 4 Kg
• To guide therapy evaluate DM patients for:
• Co-existing CV risk factors: HTN, dyslipidemia, obesity (i.e. check BP, lipid profile)
• Complications: retinopathy, neuropathy, nephropathy, HF, ulcers, ED,
• Risk factors for DM
• Renal and liver function
• Use age/presentation to classify DM into T1DM, T2DM, GDM
• Beware of LADA and MODY
• LADA: latent auto-immune diabetes of adults
• MODY: Maturity onset diabetes of the young
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 DM Treatment Goals
Table 2: Treatment goals and approaches in DM pharmacotherapy
Goal Approach/option
Glyceamic Use of anti-DM and hypoglyceamia agents
CV risk reduction Identify and treat co-existing CV risk factors (e.g.
HTN, dyslipidemia), and use of antiplatelet

Improves QoL Treats complications, minimize/treat drug side

effects

Enable self-care Provide therapeutic education

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 Glyceamic treatment targets
• Blood glucose (general non pregnant out-patient)
• Pre-prandial 70 – 130 mg%
• Post-prandial < 180 mg%
• FPG < 110 MG%
• 2hr PPG < 140 mg%
• In-patient
• ICU glucose range between 140 – 180 mg%
• Non-ICU in-patients
• Pre-prandial glucose < 140 mg%
• RBG < 180 mg%

• Pregnant
• Pre-meal, bedtime or overnight glucose 60 – 99 mg%
• Peak post-prandial 100 – 129 mg%
• A1C ≤ 6.0%
• To convert mmol/L multiply by 18 and vice versa
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 Glyceamic target (A1C)
Hgb AIC
• Pregnant ≤ 6%
• In-patients: < 6.5% (if achievable without significant
hypoglyceamia (< 70 mg%)
• General out-patients
• Young patients without sig complications: < 6.5%
• General non-pregnant population: < 7%
• Adult populations with sig risk of hypoglyceamia,
complications, limited life expectancy: < 8%

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 Treatment Options
• Lifestyle modifications (non-PCL)
• Weight reduction
• Physical exercise
• Alcohol moderation
• Cessation of cigarette smoking
• Medical nutrition therapy (MNT)
• Pharmacological options
• Insulin
• hypoglyceamia agents: sulphonylureas, meglitinides
• Anti-DM: Biguanides, thiazolidinediones, alpha-glucose inhibitors,
Incretin mimetics, amylin analogue, SGLT2 inhibitor and dopamine
receptor agonist
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 Lifestyle modifications
• Weight reduction
• In over weight or obese patients
• Target normal wt (NBMI 18.5 – 24.9 KgM-2) for over-wt and 5 – 7% wt loss for obese
• Use exercise, diet and drugs
• Benefit glyceamic, BP, lipid levels/ improves CV risk
• Exercise
• Dynamic exercise 150 mins/week
• Fixed pattern for those on insulin improves therapy effectiveness & reduces risk of hypoglyceamia
• Improves glyceamic, lipid, body weight goals and improves CV risk
• Cessation of cigarette
• Improves CV risk
• Moderation of alcohol
• Alcohol contributes to both hyperglyceamia and hypoglyceamia
• Contributes to hypoglyceamic unawareness
• Improves glyceamic control, CV risk
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 Dietary approach
• Carbohydrate
• Direct effect on post-prandial hyperglyceamia
• Generally eat as those without DM based on age, development and activity but
• Reduce high calorie diet
• Choose food with low glyceamic index ( < 65%)
• Choose carbohydrates from fruits/vegetable over simple sugars
• Sugar cane contains sucrose (fructose/ glucose) noted to improve glyceamic control compared to meal sources
containing glucose (fruits also contain fructose)
• Protein
• Generally use as those without DM
• Caution in those with nephrotic syndrome
• More protein needed in patients undergoing dialysis
• Fats
• Choose low fat or fat-free diary products over higher fat contents
• Unsaturated fats are better compared to saturated fats
• Omega-3 reduces LDL, TG, but increase HDL (as from olive oil)
• Polyunsaturated fats reduces all cholesterol types (as from soya bean oil)
• Good choice improves body weight, lipid and CV risk goals
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 Pharmacological Treatment
Insulin
• Pathophysiological basis: absolute/relative insulin deficiency
• MOA: binds to insulin receptors at target cells to facilitate glucose
uptake and utilization causing drop in blood glucose level
• Indication
• T1DM
• T2DM: Pregnancy, surgery, severe infections, oral medications tolerance & DM
clinical presentation: (e.g. AIC ≥ 9.5%, FBG > 250 mg%, RBG > 300 mg%,
presence of urine ketone, poly-triad, wt.)
• Route of administration
• upper outer arm, abdomen, buttocks, upper outer thigh
• Rotate injection sites to minimize risk of injection site local effects
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 Insulin
• Table 3:Types of insulin
Category Example Onset of action Effect
Rapid acting Lispro, aspart, glulisine 10 – 20 mins Prandial

Short acting Insulin regular, insulin Zn susp 20 -60 min Prandial

semilente
Intermediate NPH (isophane), insulin Zn lente 2 – 6 hours Basal

Long-acting Glargine, insulin Zn susp 1 -24 hrs Basal

ultralente
Premixed Lispro 75/25, 50/50, aspart 20 -60 mins Prandial +
(with NPH) 70/30, NPH/regular 70/30, 50/50 Basal

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 Insulin regimen
Table 4: Insulin regimen
Regimen Daily frequency Complexity Flexibility
Basal only 1 Low low

Basal + 1 meal time rapid 2 Moderate High

acting
Basal + ≥ 2 rapid acting ≥3 High High

Premixed insulin 2 Moderate Low

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 Table 5: Other agents use in DM pharmacotherapy
Class Pathophysiologi Mechanism of action Examples
cal base
Sulfonylureas Defects in insulin Close KATP channels to ↑ insulin release Glipizide, glyburide,
release glimepiride
Biguanides ↑ in hepatic Inhibits mitochondrion glycerophosphatase to Glucophage
glucose output ↓HGP, gluconeogenesis
Meglitinides Defects in insulin Close KATP channels to ↑ insulin release Nateglinide,
release repaglinide
Thiazolidinediones Insulin Activates PPAR-Y to ↑ tissue insulin sensitivity at Pioglitazone,
insensitivity target cells rosiglitazone
Dipeptyldyl Increase Inhibits DD-4 to increase GLP-1, GIP, ↓ glucagon Linagliptin,
peptidase 4 (DD-4) glucagon secretion, ↑ insulin secretion saxagliptin,
inhibitor secretion sitagliptin
SGLT2 inhibitor Increase in renal Inhibits SGL co-transporter 2 to ↓ glucose Canafliflozin,
glucose reuptake reabsorption, ↑ glucose clearance, ↓ plasma dapagliflozin
glucose
PPAR-Y= Peroxisome proliferator-activated
receptor- Y; SGLT2= Na-glucose transporter

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 Others (cont’d)
• GLP-1 receptor agonist
• Pathophysiology: increase in glucagon secretion
• MOA: decrease glucagon secretion, increase insulin secretion
• Examples: Exanatide, liraglutide, albiglutide
• Amylin mimetics
• Pathophysiology: defects in amylin influence glucagon release
inhibition
• MOA: Inhibits glucagon release, decrease gastric emptying time,
increase satiety
• Examples: Pramlintide
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 Table 6: Effects of anti-DM drugs on BG, hypoglyceamia and weight
Class A1C effect (%) Hypoglyceamia Weight effect
Sulfonylureas 1–2 Yes Gain
Biguanides 1–2 No Neutral/loss
Meglitinides 0.5 – 1.5 Yes Gain
Thiazolidinediones 0.5 – 1.4 low Gain
GLP-1 agonists 0.5 – 1 No Modest loss
DPP-4 inhibitors 0.5 – 0.8 No Neutral
Amylin mimetics 0.5 – 1 No Loss
SGLT-2 inhibitors 0.3 - 1 low loss

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Table 7: Class Disadvantages of anti-DM drugs
Class Disadvantages

Sulfonylureas Photosensitivity, hypersensitivity to sulfonamide, renal impairment (use

glipizide)
B12 deficiency, rare lactic acidosis, monitor renal function (SCr < 1.4 mg% and
Biguanides 1.5 mg% for men/women respectively, GIT upset (take with food)

Meglitinides Frequent dosing, flu-like respiratory symptoms

Effects take 2-3 to be noticed, fluid retention, hepatoxicity osteoporosis, CI in
Thiazolidinediones NYHA III or IV

GLP-1 agonists Injection (SC), thyroid cell tumor, pancreatitis

DPP-4 inhibitors Angioedema, pancreatitis, respiratory tract infections

Amylin mimetics CI: gastroparesis, A1C > 9%, patients prone to hypoglyceamia

SGLT-2 inhibitors Requires renal adjustment, hyperkalemia, hypotension, CI if CrC < 45ml/min
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 Table 8:Therapy implementation Scheme (Diabetic care standard,
2015)
• First step: Monotherapy with Metformin with lifestyle modifications
• or if metformin is CI / not tolerated then any of Sulf., Meglt., TZD (pioglitazone), DPP-4
inhibitor

• Second step: Dual therapy (metformin + any of Sulf., TZD, DPP-4 inhibitor,
Meglt.,GLP-1 agonist, SGLT-2 inhibitor)

• Third step: Triple therapy (see attached DM treatment Scheme)

• Combination injectable therapy (Metformin + Insulin (basal or + mealtime) or +

GLP-1
NB: Intensification of therapy from one stage to the next is based on non-reaching
target blood glucose after 3 months of treatment
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 Hypoglyceamia
• BG < 70 mg%
• Major adverse effect & cause of sudden deaths of DM treatment
• Caused by skipped meals, little meal, too much insulin or
hypoglyceamic agents, more intense exercise than usual
• Signs/symptoms of hypoglyceamia
• Sweating (wet skin), tremor, tachycardia, dizziness, blurred vision, hunger,
weakness, irritability
• Beware of signs/symptoms of hyperglyceamia so that you did not
misdiagnose or mistreat
• Signs/symptoms of hyperglyceamia
• Extreme thirst, dry skin, hungry, blurred vision, drowsiness, polyuria

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Treatment of hypoglyceamia
• Conscious patient: give Oral 15 g of carbohydrate
• 4 – 8 oz fruit juice (1 oz = 2.69 ml)
• 3 – 4 glucose tabs or 3 – 5 hard candies
• 1/2 bottles dextrose liquid
• Unconscious patient: give intravenous glucose
• IV 50% dextrose 25 ml start then 5% dextrose water infusion
• Unconscious patient without I.V line access: give glucagon injection
• Glucagon 1 mg I.M once
• Check glucose level 15 minutes after treatment and if still low (or still
having symptoms) treat again, then check again after 15 minutes, if it
persists call healthcare provider or go to healthcare facility

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