DIABETES MELLITUS

INTEGRATED THERAPEUTICS I

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 OUTLINE
Introduction
Epidemiology
Etiology
Pathophysiology
Clinical Presentation & Diagnosis
Treatment
Monitoring & Evaluation
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 INTRODUCTION
Diabetes Mellitus (DM)
»A diverse group of metabolic disorders collectively
characterized by chronic hyperglycemia
»Can lead to various acute & chronic complications
»A major risk factor for CVD & CV events
»The two most common types
• Type 2 DM (>90%)
• Type 1 DM (<10%)
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 EPIDEMIOLOGY
DM worldwide in 2021
»~537 million adults (20–79 years) had DM (~10%)
• Predicted to rise to 643 M by 2030 & 783 M by 2045

»~1.2 million children & adolescents had type 1 DM

»~6.7 million adults (20–79) died related to DM
»~541 million adults had impaired glucose tolerance
DM in Ethiopia in 2021
»~1.9 million adults (20-79 years) had DM (3.3%)
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 ETIOLOGY
Most Common Causes of DM
»Type 1 DM
• Autoimmune destruction of the pancreatic β-cells
• Usually leading to absolute β-cells failure

»Type 2 DM
• Non-autoimmune progressive β-cell dysfunction
• On the background of
• Insulin resistance &

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• Metabolic syndrome 5
 Risk Factors for Type 2 Diabetes

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 PATHOPHYSIOLOGY
Type 1 DM
Genetic
»Autoimmune β-cell destruction Predisposition

• Deficiency of +
• Insulin Immunologic
Trigger
• Amylin
• Hyperglycemia
Autoimmune
• When 60%-90% β-cells are destroyed
Process
»The “honeymoon” Phase
• Occasional period of transient remission β-cell
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• After the initial diagnosis
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Clinical Course of Type 1 DM 8
 Pathophysiology
Insulin & glucagon & amylin
»Produced by the pancreatic islets of Langerhans cells
• β-cells (70-90%): Produce insulin & amylin
• α-cells: Produce glucagon

»Insulin decreases BGLs vs. Glucagon increases BGLs

»Amylin:
• Suppresses inappropriate glucagon secretion,
• Slows gastric emptying, & centrally mediated satiety

»Maintain fasting blood glucose values 79-99 mg/dL

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 Pathophysiology
Insulin Action
»Fasting insulin levels: 43–186 pmol/L (6–26 IU/mL)
»Food → BGL rise → Insulin-secretion response (biphasic)
• 1st-phase: Initial burst, bolus insulin, lasts 5-10 minutes
• Suppress hepatic glucose production
• Cause insulin-mediated glucose disposal in adipose tissue
• Minimizes hyperglycemia during meals & postprandial
• 2nd phase: Gradual increase, basal insulin, lasts 1-2 hour
• Stimulates glucose uptake by the muscle
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• Maintains normal FBG levels
 Pathophysiology
Type 2 DM
»Multiple defects impact plasma glucose regulation
1. Impaired insulin secretion
2. Decreased incretin effect
3. Insulin resistance involving muscle, liver, & adipocytes
4. Excess glucagon secretion
5. Increased hepatic glucose production
6. Upregulation of the SGLT-2 in the kidney
7. Systemic inflammation
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8. Diminished satiety
 2
3

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6

Pathophysiology
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of Type 2DM: Ominous Octet!: Rx Targets
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 Pathophysiology
Type 2 DM
»Impaired insulin secretion
• Requisite for the development of type 2 DM
• Impaired β-cell function
• Reduced ability to produce a 1st-phase insulin response
• Compensatory increase in the 2nd-phase insulin-secretion
• In order to normalize glucose levels
• Patients lose ~5% to 7% of β-cell function per year
• Eventual pancreatic burnout & severe hyperglycemia
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 Pathophysiology
Type 2 DM
»Decreased incretin effect
• Deficiency & resistance to incretin hormones
• Incretin hormones: GLP-1 & GIP
• Stimulate insulin secretion when nutrients enter the GI
• Glucagon-like peptide-1 (GLP-1)
• Secreted by the L cells of the ileum & colon primarily
• Blood levels rise rapidly w/n minutes of food ingestion

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• Cleaved by the dipeptidyl peptidase-4 (DPP-4) enzyme
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 Pathophysiology
Type 2 DM
»Upregulation of the SGLT-2
• Due to increased renal tubular glucose load
• Leading to increased renal glucose reabsorption
• SGLT- 2
• A Na+-glucose symporter
• Primarily expressed in the kidney
• Localized in the apical brush border of the proximal
convoluted tubule of the nephron
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• Mediates the renal reabsorption of 9o% of filtered glucose
 Pathophysiology
Type 2 DM
»Metabolic Syndrome
• The clustering of CV risk factors

Abdominal obesity:
>102 cm (M) & >88 cm (F)
+
2 of
• TGs ≥150 mg/dL or treated
• HDL-C <40 mg/dL (M) or <50 mg/dL (W) or treated
• BP ≥130/85 mm Hg or treated
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• FBS ≥100 mg/dL or diagnosed type 2 DM 16
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Natural history of type 2 DM 17
 Pathophysiology
Complications of DM
»Chronic complications
• Chronic hyperglycemia → Vascular & tissue damage
• Macrovascular complications:
• Atherosclerotic cardiovascular disease (ASCVD)
• Microvascular complications:
• Nephropathy → Renal failure or ESRD
• Retinopathy → Loss of vision
• Neuropathy → Peripheral neuropathy, ED

»Acute complications: Acute hyperglycemia, DKA, HHS

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CLINICAL PRESENTATION & Dx
Clinical presentation

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 Clinical Presentation & Diagnosis
Clinical presentation

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Clinical Presentation & Diagnosis
Diagnosis
»A diagnosis of DM is made in anyone of the cases of
• HbA1C ≥6.5%
• Fasting plasma glucose (FPG) ≥126 mg/dL
• OGTT: 2-hr plasma glucose ≥200 mg/dL
• A random plasma glucose (RPG) ≥200 mg/dL + Classic
symptoms of hyperglycemia
• Polyuria, polydipsia, polyphagia, Wt. loss, & fatigue
• Hyperglycemic crisis: DKA &/or HHS
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 TREATMENT
Goals of Therapy of DM
»To delay the onset & progression of the long-term
macrovascular & microvascular complications
»To alleviate symptoms of hyperglycemia
»To minimize hypoglycemia & other adverse effects
»To minimize treatment burden
»To maintain quality of life

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 Treatment
Glycemic Control
»Reduces both short- & long-term DM complications
Glycemic Targets: Must Be Individualized
»Adults
• HbA1C <7.0%
• FBS = 80-130 mg/dL
• RBS <180 mg/dL
• TIR; % of CGM readings & time 70-180 mg/dL >70%
• TBR; % of CGM readings & time <70 mg/dL <4%
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• Glycemic variability (%CV) <36%
Ambulatory
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Glucose Profile Report From A CGM Device
24
 CV = 53%

Glycemic
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Variability
25
 Treatment
Glycemic Targets
»Adolescents & Children
• HbA1C <7.0%
• FBS = 90-130 mg/dL
• Bedtime or overnight glucose = 90-150 mg/dL

»Pregnant women
• HbA1C <6.5%
• FBS <95 mg/dL
• PPG: 1 hour <140 mg/dL or 2 hour <120 mg/dL
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 Treatment
Glycemic Targets
»Older Adults
• Healthy (few comorbidities, intact cognitive & functional status)
• A1C <7.0-7.5%
• FPG = 80-130 mg/dL
• Bedtime glucose = 80-180 mg/dL
• Complex/moderate (multiple comorbidities, some impairments)
• A1C <8.0%
• FPG = 90-150 mg/dL
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• Bedtime glucose = 100-180 mg/dL 27
 Treatment
Glycemic Targets
»Older Adults
• Very complex/poor health
• Health status
• Life-threatening condition or end-stage chronic illness,
• Moderate to severe cognitive impairment, or
• 2+ activities of daily living dependencies
• Avoid reliance on A1C
• FPG = 100-180 mg/dL
• Bedtime glucose = 110-200 mg/dL
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 Approach to Individualizing Glycemic Targets
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 Treatment
Nonpharmacologic Therapy of DM
»A cornerstone of treatment for all patients with DM
• Medical nutrition therapy
• Physical activity
• Glucose monitoring
• Diabetes self-management education & support

»All healthcare professionals must be well-versed

• In the educational needs
• To provide education & reinforcement
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 Treatment
Medical nutrition therapy
»Using an individually tailored nutrition plan
»Patients should realize the interrelationships b/n
CHO intake, medications, Wt., & glucose control
»A healthy meal plan is recommended
• Moderate in calories & carbohydrates & low in saturated
fat, with all of the essential vitamins & minerals

»A Mediterranean-style diet rich in mono- & poly-

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unsaturated fats could be considered
 Treatment
Physical activity
»Aerobic exercise
• Improves insulin sensitivity
• Modestly improves glycemic control in the majority
• Reduces CV risk
• Contributes to weight loss or maintenance
• Improves well-being

»Patients should choose activities they enjoy & do

»Start exercise slowly in sedentary patients
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 Treatment
Physical activity
»Screening: In patients with
• Long-standing disease (≥10 years)
• Multiple CV risk factors
• Microvascular disease (especially kidney disease)
• Evidence of atherosclerotic disease

»Restrictions: If the patient has

• Uncontrolled hypertension, autonomic neuropathy,
• Insensate feet, or proliferative retinopathy
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 Treatment
Physical activity
»Moderate intensity exercise
• 50%-70% maximal heart rate
• At least 150 minutes per week
• Spread over at least 3 days a week
• No more than 2 days between activities

»Resistance/strength training
• At least two times a week as long as the patient does not

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have proliferative diabetic retinopathy 34
 Treatment
Glucose monitoring
»DM patients should be reassessed every 3-6 months
• An A1C should be drawn

»BGM & CGM: Patients on intensive insulin therapy

• Before meals & at bedtime, before exercise/critical tasks
• To detect & prevent acute complications
• Crucial during times of inter-current illness
• Occasionally testing 2 hours after meals
• For insulin dose calculations
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 Treatment
Diabetes self-management education & support
»All patients should have access to DSME/S programs
»Four critical times to evaluate the need for DSME/S:
1. At diagnosis
2. Annually
3. When complicating factors arise
4. When transitions in care occur

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 Treatment
Diabetes self-management education & support
»Self-care behaviors that can be targeted by DSME/S
1. Healthy eating
2. Being active
3. Monitoring
4. Taking medications
5. Problem-solving
6. Reducing risk
7. Healthy coping
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 Treatment
Diabetes self-management education & support
»The decision-making process must involve patients
»Emphasize that complications can be prevented or
minimized with
• Good glycemic control & managing RFs for ASCVD

»Use motivational interviewing techniques

• Asking open-ended questions
• Encourage patients to identify & acknowledge barriers
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• Work to address them with the educator’s guidance
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 Treatment
Pharmacotherapy of DM
»Antidiabetic Medications
• Insulin • α-Glucosidase Inhibitors
• Biguanides • Meglitinides
• SGLT-2 Inhibitors • Bile Acid Sequestrants
• GLP-1 Receptor Agonists • Dopamine Agonists
• DPP-4 Inhibitors • Amylin Analogs
• TZDs
• Sulfonylureas
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 Treatment
Insulin
»Insulin products
• Contain only the active insulin peptide
• Manufactured using rDNA technology
• “Human” insulins: Human rDNA insulin (NPH, regular)
• Insulin analogs: Have had amino acids substitutions
• That change the onset or duration of action
• Most administered SC for the chronic therapy of DM
• Except inhaled: A dry powder of human regular insulin
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• U-100 is the most commonly used insulin concentration
 Treatment
Insulin
»The PK & PD of insulin products
• Characterized by the onset, peak, & duration of action
• Absorption of insulin from a SC depot is dependent on
• Source of insulin
• Concentration of insulin
• Additives: zinc, protamine
• Blood flow to the area
• Injection site
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 Treatment
Insulin
»Basal insulin: AKA background insulin
• Longer acting insulins
• Regulate BG levels in b/n meals
• By suppressing hepatic glucose production
• Maintaining near-normal glycemia in the fasting state
• The most convenient initial insulin in type 2 DM patients
• NPH, detemir, glargine U-100, glargine U-300, degludec
U-100, or degludec U-200
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 Treatment
Insulin
»Bolus insulin
• Short- or rapid-acting insulins
• Cover meal (prandial) or glycemic excursions (correction)
• Short-acting: Regular
• Rapid-acting: Aspart, lispro, & glulisine
• Ultra-rapid: Inhaler, fast-acting aspart, & insulin lispro aabc

»Combination of basal & bolus insulin

• Required in type 1 DM for adequate glycemic control

»Dose must be individualized

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Pharmacodynamics of Insulin Preparations

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 Treatment
Insulin
»Effectiveness highly dependent on its proper use
• Product selection, education & training, & reinforcement
• Counseling must include
• Proper administration: Dose, injection technique, timing
• Glycemic targets
• BGM
• Dose titration or adjustment
• Storage
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• Prevention, detection, & treatment of hypoglycemia 49
 Treatment
Insulin
»Merits
• It can achieve a wide range of glucose targets
• The dose can be individualized based on glycemic levels

»Demerits
• The risk of hypoglycemia
• The need for injection/s
• Weight gain: Dose-dependent, mainly in truncal fat
• Treatment burden
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 Treatment
Biguanides: Metformin
»Enhanced insulin sensitivity in peripheral tissues
»The initial DOC for glucose lowering in type 2 DM
• Extensive experience
• High efficacy
• Minimal hypoglycemia risk
• Positive or neutral effects on weight
• Potential positive impact on CV risk
• Manageable side effect profile
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• Low cost
 Treatment
Biguanides: Metformin
»Consistently reduces A1C & FPG in naïve patients
• A1C levels by 1.5% to 2.0%
• FPG levels by 60 to 80 mg/dL

»May lead to a modest (2-3 kg) weight loss

»Has a low risk of hypoglycemia
»Decreases TGs & LDL-C by 8% to 15%
»Modestly increases HDL-C by 2%
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 Treatment
Biguanides: Metformin
»Dosing
• Metformin
• Starting Dose: 500 mg QD/BID or 850 mg QD
• Usual Recommended Dose: 1 g BID
• Maximal Dose: 2550 mg/day
• Metformin XR
• Starting Dose: 500 mg – 1 g QD
• Usual Recommended Dose: 2 g QD
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• Maximal Dose: 2550 mg/day 53
 Treatment
Biguanides: Metformin
»Adverse effects
• GI: Diarrhea, abdominal discomfort, stomach upset
• Usually dose-dependent, transient, mild
• Metallic taste
• May lower vitamin B12 concentrations
• Lactic acidosis

»CI in patients with an eGFR <30 mL/min/1.73 m2

»Withheld for 2-3 days when using IV contrast dye
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 Treatment
SGLT-2 Inhibitors
»AKA the “gliflozins”
»Reduce plasma glucose levels
• Through a non-insulin-dependent mechanism
• By inhibiting the SGLT-2
• Block the active renal tubular reabsorption of glucose
• Leading to increased glucosuria

»Can lower both FPG & PPG

»Effective even in the absolute absence of insulin 55
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 Treatment
SGLT-2 Inhibitors
»Have intermediate A1C-lowering efficacy (0.5-1%)
»More efficacious in those with higher baseline A1C
»Efficacy decreases in renal impairment
»Promote weight loss 1 to 5 kg
»Can result in modest BP reductions 3-4/1-2 mm Hg
»Unlikely to cause hypoglycemia alone
»Improve CV, HF, & CKD outcomes
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 Treatment
SGLT-2 Inhibitors
»Adverse effects
• Genital mycotic infections
• Polyuria
• Dehydration
• Dizziness
• Hypotension
• Ketoacidosis, amputations, fractures, Fournier gangrene

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 Treatment
Glucagon-Like Peptide-1 Receptor Agonists
»Mimics the action of endogenous GLP-1
»Stimulate insulin secretion depending on glucose
»Reduce inappropriately elevated levels of glucagon
»Slow gastric emptying meal glucose excursions
»Agents that penetrate the BBB increase satiety
»Potentially preserve β-cell function & protect
against cytokine-induced apoptosis
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 Treatment
GLP-1 RAs
»Resistant to the rapid degradation by the DPP-4
»A1C-lowering efficacy considered high
• Depends on baseline glycemic control, background
therapy, & the specific agent used

»Can lead to weight loss of 1-3kg

• Depend on the agent & dose used

»Improve CV & CKD outcomes

»Adverse effects: NVD
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GLP-1 RAs

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 Treatment
Dipeptidyl Peptidase-4 Inhibitors
»Inhibit the rapid degradation of GLP-1 & GIP
»Increase glucose-dependent insulin secretion
»Reduce inappropriate PP glucagon secretion
»Lower BGLs without an increase in hypoglycemia
»Have a neutral impact on weight
»Have moderate glucose-lowering efficacy
• An average reduction in A1C of 0.5% to 0.9%
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 Dosing Recommendations
for DPP-4 inhibitors

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 Treatment
DPP-4 inhibitors
»Adverse effects
• Upper respiratory tract infections
• Urinary tract infections
• Headaches
• Nasopharyngitis

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 Treatment
Thiazolidinediones (TZDs)
»Work by binding to the peroxisome proliferator
activator receptor-γ (PPAR-γ)
• A nuclear receptor
• Predominantly located on fat cells & vascular cells

»Activation of PPAR-γ
• Alters the transcription of several genes involved in
• Glucose & lipid metabolism
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 Treatment
TZDs
»Boost insulin sensitivity at muscle, liver, & fat tissues
• Maturation of preadipocytes in SC fat stores
• Small fat cells:
• More sensitive to insulin & more able to store FFAs
• Allows a flux of FFAs
• Out of the plasma, visceral fat, & liver
• Into SC fat, a less insulin-resistant storage tissue
• Muscle IC fat products, w/c add to insulin resistance, decline
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 Treatment
TZDs
»Affect adipokines w/c can positively affect insulin
sensitivity, endothelial function, & inflammation
• Adiponectin
• Reduced with obesity & DM
• Increased with TZD therapy
• Improves endothelial function, insulin sensitivity, &
has a potent anti-inflammatory effect
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 Treatment
TZDs
»Glycemic lowering efficacy
• High at maximal doses
• Reduce A1C levels by 1.0-1.5%
• FPG levels by 60 to 70 mg/dL
• With high durability over time
• With slow onset 3-4 months to maximal effects

»Pioglitazone consistently decreases TGs by 10-20%

»LDL-C tend to increase with rosiglitazone (5-15%)
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 Treatment
TZDs
»Appear to convert small, dense LDL particles, to
large, buoyant LDL particles
• From more to less atherogenic LDL particles

»Increase HDL: Pioglitazone > Rosiglitazone

»2nd-line treatment choices for type 2 DM
• Can be used in combination with metformin & 2nd-lines
• A compelling need to reduce cost or avoid hypoglycemia
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 Initial Dose Usual Maximum
TZDs
Range daily

dose

Pioglitazone 15 mg PO QD 30 mg QD 45 mg

Rosiglitazone 4 mg PO QD 4 mg QD 8 mg
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 Treatment
TZDs
»Adverse effects
• Fluid retention
• Due to peripheral vasodilation & improved renal insulin
sensitization → Increased renal Na+ & H2O retention
• Resulting in
• Peripheral edema
• New-onset or worsening of preexisting HF
• Hemodilution of hemoglobin & hematocrit
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• Weight gain 71
 Treatment
TZDs
»Adverse effects
• HF
• TZDs are contraindicated in patients Class III-IV HF
• Great caution used in those with Class I-II HF
• Edema: Dose-related
• A dose reduction may help in no severe cases
• Weight gain: Dose-related
• A a result of fluid retention & fat accumulation
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• Higher gains may necessitate discontinuation of therapy
 Treatment
TZDs
»Adverse effects
• Fracture
• In the upper & lower limbs of postmenopausal women
• The risk may relate to TZDs’ effect
• On the pluripotent stem cell
• Shunting of new cells to fat instead of osteocytes
• Altering osteoblasts/osteoclasts
• A patient’s RFs are considered before selecting a TZD
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 Treatment
TZDs
»Have been linked to bladder ca
• Excess risk, if present, appears to be mostly in men & smokers,
& is dose & duration associated
• TZDs should not be used in patients with active bladder ca
• The benefits & risks should be carefully considered before
using pioglitazone in patients with a history of bladder ca

»Premenopausal anovulatory may resume ovulation

• Adequate pregnancy & contraception precautions
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• Explained to all women capable of becoming pregnant
 Treatment
Sulfonylureas
»Oral hypoglycemic agents
»Enhance insulin secretion
• By binding to their specific receptor on pancreatic β-cells
• Tachyphylaxis develops after time

»Classified as 1st-generation & 2nd-generation agents

• The 1st-generation agents
• Lower in relative potency
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 Treatment
Sulfonylureas
»BG-lowering efficacy
• All agents are equally effective in equipotent doses
• Dependent on baseline values & duration of DM
• In drug-naïve patients
• A1C reductions of 1.5% to 2%
• FPG reductions of 60 to 70 mg/dL

»Do not increase macrovascular outcomes or all-

cause mortality compared to other active agents78
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 Treatment
Sulfonylureas
»Adverse effects
• Hypoglycemia
• Higher with glyburide; lower with glipizide & glimepiride
• Lower initial dose or switch therapy in high-risk patients
• Avoid or use with extreme caution in older adults
• Avoid long-acting agents or those with active metabolites
in elderly & renal insufficiency
• Weight gain is common (typically 1 to 2 kg)
• Avoid if a history of anaphylaxis reactions to sulfa
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 Treatment
α-Glucosidase Inhibitors
»Inhibit maltase, isomaltase, sucrase, & glucoamylase
in the small intestine
»Reduce the PPG levels by 40 to 50 mg/dL
»A1C-lowering efficacy is modest
»For patients with desired A1C & FPG but high PPG
»Acarbose/miglitol 25-50mg PO TID with meals
• Max. 300 mg/day; Avoid if CrCl <25 mL/min

»S/Es: Flatulence, abdominal pain, diarrhea

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 Treatment
Meglitinides
»Stimulate insulin secretion from the β-cells
»Reduce PPG excursions & A1C (by 0.8-1%)
»May be used in patients with kidney insufficiency
»A good option for those with erratic meal schedules
»Nateglinide 120 mg PO TID before meals
»Repaglinide 1-2mg PO TID (max. 16mg) before meals
• Initiate 0.5 mg if A1C<8% or if CrCl 20-40 mL/min

»Main side effects are hypoglycemia & Wt. gain

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 Treatment
Bile Acid Sequestrants
»Colesevelam
• Approved for the treatment of type 2 DM
• Decreases the bile acid pool for reabsorption
• Lowers plasma glucose & LDL-C
• A1C-lowering efficacy is modest
• Not been proven to prevent CV morbidity or mortality
• Colesevelam 1.875 g PO BID or 3.75 g PO QD
• Weight neutral & has a low risk of hypoglycemia
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 Treatment
Dopamine Agonists
»Bromocriptine mesylate
• A quick-release formulation of the dopamine agonist
• Approved for the treatment of type 2 DM
• Low hypothalamic dopamine, mainly upon waking are
augmented, w/c may decrease sympathetic tone & output
• Speculated to improve hepatic insulin sensitivity and
decrease hepatic glucose output
• A1C-lowering efficacy is modest
• Bromocriptine 0.8 mg/day (1.6-4.8 mg/day maximum)
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 Treatment
Amylin Analogs
»Pramlintide
• A synthetic analog of amylin
• Regulates glucose by 3 key mechanisms
1. Reduces glucagon secretion
2. Slows gastric emptying
3. Increases satiety
• Lowers PPG & A1C (by 0.6%), & can decrease weight
• May allow for lower mealtime insulin doses
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 Treatment
Amylin Analogs
»Pramlintide
• Mainly used as adjunctive therapy in type 1 DM patients
• Not achieving PPG goal despite max mealtime insulin dose
• Dosing
• In type 1 DM: Initial 15 𝜇g SC before meals
• Titrated to 60-mcg as tolerated & based on PPG
• In type 2 DM: Initial 60 𝜇g SC before meals
• Titrated to 120-mcg as tolerated & based on PPG
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 Treatment
Amylin Analogs
»Pramlintide
• Adverse effects
• Most commonly GI: Nausea, vomiting, anorexia
• Decrease over time & are dose-related
• Start with a low dose & titrate slow as tolerated
• Hypoglycemia
• Can occur in patients on insulin
• Mealtime insulin dose should be reduced by 30-50%
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• When pramlintide is initiated
 Treatment
Type 1 DM
»Insulin therapy
• Exogenous insulin therapy is a requirement

• Intensive insulin therapy

• Using multiple daily injection or insulin pump therapy
• Usually required to achieve adequate glycemic control
• Designed to mimics normal physiologic insulin secretion
• Basal insulin: Consistent insulin secretion throughout the day
• To manage glucose levels overnight & in b/n meals
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• Prandial insulin: Bursts in response to prandial glucose rise
87
Relationship
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b/n Insulin & Glucose Over the Course of a Day
88
 Treatment
Type 1 DM
»Insulin therapy
• Multiple daily injection
• An injection of LA insulin & 3 injections of RA insulin
• A common MDI approach
• 2 injections of IA insulin & 2 injections of SA insulin
• A less expensive option
• RA insulins in place of the SA insulin
• Recommended in most patients
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• To reduce the risk of hypoglycemia
 Meals

A. An injection of LA insulin & 3 injections of RA insulin

Meals

B. 2 injections of IA insulin & 2 injections of RA insulin

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 Treatment
Type 1 DM
»Insulin therapy
• Insulin pump therapy
• Continuous SC insulin infusion (CSII) via an insulin pump
• Infuses RA insulin to cover both the basal & prandial needs
• Infuses a basal rate constantly throughout the day
• Allows the patient to give bolus doses using a calculator
• Based on current BGLs, CHO, & insulin on board
• Can provide more precise glucose control
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• Allow more flexibility and fine-tune tailoring 91
Insulin Administration By An Insulin Infusion Device
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 Treatment
Type 1 DM
»Insulin therapy
• Initiation
• Starting dose
• Insulin 0.4 to 1.0 units/kg/day
• ½ as basal insulin
• ½ as prandial insulin (distributed across meals)
• Dose adjustment

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• Based on BGL monitoring data 93
 Treatment
Type 1 DM
»Insulin therapy
• Bolus insulin doses can be better individualized using
• The carbohydrate to insulin ratio (C:I ratios)
• To estimate CHO grams each unit of RA insulin will cover
• A typical C:I ratio for a patient with type 1 DM is 15:1
• An initial C:I ratio is estimated: 550/the total daily dose

• The correction factor (CF)

• Expected gs that 1U will decrease under normal conditions
• To reduce high glucose levels detected before meals
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• The initial CF is estimated as 1,650/the total daily dose
 Treatment
Type 1 DM
»Lifestyle modifications differ b/n type 1 & 2 DM
• Patients with type 2 DM are often encouraged to “count
carbs” as a way to prevent glucose excursions after meals
• This involves limiting carbohydrates to 45-75 g/meal or
limiting starches/grains to ¼ of a 23 cm plate
• Type 1 DM patients count carbs to match their prandial
insulin dose with their CHO intake using a C:I ratio
• Requires much more accurate estimations of carbohydrate
12/28/2024 95
content than what is needed for type 2 DM
 Treatment
Type 1 DM
»Pramlintide
• An amylin agonist adjuvant therapy for patients who are not
achieving glycemic targets despite optimal mealtime insulin
• May improve glycemic control & minimize Wt. gain by insulin
• Use is limited by
• Adverse effects such as nausea and vomiting
• Modest glucose improvements
• Increased injections and cost
12/28/2024 • Increased risk of hypoglycemia 96
 Treatment
Type 2 DM
»Lifestyle modifications
• Comprehensive lifestyle modifications
• Medical nutrition therapy
• Physical activity
Could be considered initial treatment if
• Weight loss • The A1C is close to goal (e.g. <7.5%) &
• The patient is motivated to LSMs
• Smoking cessation
• Psychological support
• Implemented at diagnosis & reinforced at every visit
• Patients need access to ongoing DSME/S programs
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 Treatment
Type 2 DM
»Pharmacotherapy: Initial monotherapy
• Metformin
• Along with comprehensive lifestyle modification
• As a 1st-line treatment
• In those w/o contraindications or intolerances
• At a low starting dose
• Titrated gradually to the maximum effective dose

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 Treatment
Type 2 DM
»Pharmacotherapy: Initial combination therapy
• Starting two medications: Metformin + a 2nd agent
• If the initial A1C is over 1.5% higher than the target
• Basal insulin should be considered in patients with
• Very high A1C levels (>10%),
• Symptoms of hyperglycemia, or
• Evidence of catabolism (eg, weight loss)

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 Treatment
Type 2 DM
»Pharmacotherapy: Stepwise addition of agents
• Intensification beyond metformin monotherapy
• Requires careful consideration of key factors
• Patient-specific factors
• Individualized A1C target
• Presence of comorbidities or compelling indications
• Drug-specific factors
• Glucose-lowering efficacy, Impact on comorbidities
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• Impact on Wt. & hypoglycemia, S/E, ease of use, & cost
 Treatment
Type 2 DM
»Pharmacotherapy: Stepwise addition of agents
• In patients with high risk or established ASCVD
• SGLT-2 inhibitors: Canagliflozin or empagliflozin
• GLP-1 RAs: Dulaglutide, liraglutide, or SC semaglutide
• In patients with coexisting HF
• SGLT-2 I: Empagliflozin, canagliflozin, or dapagliflozin
• In patients with coexisting CKD
• SGLT-2 inhibitors: Canagliflozin or dapagliflozin
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• GLP-1 RAs If an SGLT-2i is contraindicated or not tolerated
 Treatment
Type 2 DM
»Pharmacotherapy: Stepwise addition of agents
• A compelling need to abate Wt. gain or help Wt. loss
• GLP-1 RAs or SGLT-2 inhibitors are preferred
• DPP-4 inhibitor if the preferred agents cannot be used
• A compelling need to minimize hypoglycemia
• DPP-4 inhibitors, GLP-1 RAs, SGLT-2 Is, or TZDs
• DPP-4 inhibitors & GLP-1 RAs should not be combined
• If there is a compelling need to minimize cost
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• Sulfonylureas or TZDs
 Treatment
Type 2 DM
»Pharmacotherapy: Addition of injectable agents
• Insulin is recommended for patients with
• Extreme (A1C >10%) or symptomatic hyperglycemia
• Basal insulin
• Started at a low dose: 10U QD or 0.1-0.2 U/kg/day
• Titrated slowly, until target FPG or 0.7-1.0 units/kg/day
• The 3-0-3 method
• Increase dose by 3 units if mean of 3-day FPG >130 mg/dL
12/28/2024 • Decrease by 3 units if unexplained hypoglycemia occurs
103
 Treatment
Type 2 DM
»Pharmacotherapy
• Addition of injectable medications
• Prandial insulin
• Starting with 4 units or 10% of the basal dose with the
largest meal of the day
• If the A1C is <8%, the basal dose can be decreased by
the same amount to avoid hypoglycemia
• The dose should be titrated over time to achieve
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target PPG levels <180mg/dL
 Treatment
Type 2 DM
»Pharmacotherapy
• Addition of injectable medications
• When insulin is started
• Metformin should be continued
• TZDs should be stopped or dose should be reduced
• Sulfonylureas should be stopped or the dose reduced
• SGLT-2 inhibitors can be continued
• DPP-4 inhibitors can be continued
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 Treatment
Hypoglycemia
»Abnormally low BG that can range in severity
• Level 1: BGL ≤70 mg/dL; Alert, may be asymptomatic
• Level 2: BGL <54 mg/dL; Serious, clinically significant
• Level 3: Severe hypoglycemia; Can be life-threatening

»A common complication of insulin, SU, meglitinides

»A major limiting factor to optimal glycemic control
• Associated with falls, injury, accidents, decreased QOL,
12/28/2024 increased risk of CV events, QT-P, arrhythmias, & death106
 Treatment
Hypoglycemia
»Symptoms
• Autonomic symptoms:
• Early warning symptoms
• Tachycardia, palpitations, sweating, tremors, & hunger
• Neuroglycopenic symptoms:
• Often occurs when BG is <60 mg/dL
• Cognitive impairment, confusion, behavioral changes,
anger, irritability, blurred vision, headache, seizure, & LOC
12/28/2024 107
 Treatment
Hypoglycemia
»Prevention
• Patients must be educated
• To identify the early warning symptoms & take apt actions
• To realize & manage situations that can increase their risk
• Including fasting or missing or delaying meals
• BGM may not be regular enough to detect hypoglycemia
• CGM provides the patient with glucose trends
• Patients can adjust their management decisions in advance
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• Patients should always carry a source of fast-acting CHOs
 Treatment
Hypoglycemia
»The “rule of 15”
• Perform BGM to confirm a BG <70 mg/dL
• Ingest 15 g of fast-acting carbohydrates
• ½ cup (125mL) of milk, juice, or soda, or a tablespoon
of honey, hard candy, jelly beans, or glucose tablet/gel
• Repeat BGM in 15 minutes
• Repeat the process if the BG remains <70 mg/dL
• Once the BG is normalized, the patient should eat
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• A snack/meal including complex carbohydrates & protein
 Treatment
Hypoglycemia
»Unconscious patient
• IV glucose
• IM/IN glucagon
• In situations IV glucose cannot be rapidly administered
• Should be readily available to all patients on insulin & at
high risk or with a history of severe case
• Subordinates should be educated about the administration
• Position the patient on the side with the head tilted
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slightly downward to avoid aspiration from vomiting
 Treatment
Hypoglycemia
»Clinicians should inquire about hypoglycemia at
every visit
• The frequency, severity
• The timing of hypoglycemic events
• The need for assistance by a third party
• The need to administer glucagon

»Patients experiencing frequent or severe case should

have their treatment regimen re-evaluated
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 Treatment
Macrovascular complications
»Managing CV RFs will reduce macrovascular events
• In DM patients with established ASCVD
• Antiplatelet therapy: Aspirin 75-162 mg daily
• Good glycemic control: Consider a SGLT-2i or GLP-1 RA
• β-blocker therapy following MI
• BP control using LSMs ± 1st-line antihypertensive agents
• High-intensity statin therapy
• Smoking cessation
12/28/2024 112
• PAD: LSM, statin, good glycemic control, aspirin, cilostazole
 Treatment
Microvascular complications
»Glycemic control reduces the risk & progression
»Diabetes Nephropathy
• Albuminuria
• A marker of kidney damage & a strong predictor of ESKD
in patients with type 1 DM
• A strong risk factor for macrovascular disease but a weaker
predictor for ESKD in patients with type 2 DM
• Glucose & BP control are key for preventing & retarding
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the progression of nephropathy
 Treatment
Microvascular complications
»Diabetes Nephropathy
• SGLT-2 inhibitors
• Reduce the decline in kidney function in CKD patients
• Preferred in type 2 DM patients with CKD
• Specifically in those with eGFR 30-60 mL/min/1.73 m2
& a UACR >300 mg/g
• Glucose-lowering effects are substantially reduced when
the patient’s eGFR is <45 mL/min/1.73 m2
12/28/2024 • But not the renoprotective effects 114
 Treatment
Microvascular complications
»Diabetes Nephropathy
• ACE inhibitors or ARBs
• Can slow the progression of diabetic renal disease
• ≥3 agents are often needed to reach goal BP
• BP <140/90 mm Hg
• BP <130/80 mm Hg w/o undue burden or side effects
• Diuretics
• Recommended second-line therapy
12/28/2024
• Due to the volume-expanded state of patients with CKD
115
 Treatment
Microvascular complications
»Diabetes Retinopathy
• Improved glycemia & BP may reverse early background RP
• Advanced retinopathy wont fully regress with better BG
• Aggressive BG reductions may acutely worsen retinopathy
• Laser photocoagulation for sight preservation
• In those with macular edema & proliferative retinopathy
• Intravitreal anti-VEGF therapy: Effectively preserve sight
• Bevacizumab & ranibizumab
12/28/2024 116
• Aflibercept: A VEGF decoy receptor
 Treatment
Microvascular complications
»Diabetes Neuropathy
• Can manifest as
• Peripheral neuropathy
• Autonomic neuropathy
• Focal neuropathies

12/28/2024 117
 Treatment
Microvascular complications
»Diabetes Neuropathy: Peripheral neuropathy
• Distal, symmetrical, peripheral neuropathy is the most
common complication seen in type 2 DM patients
• Predominant symptoms
• Paresthesias
• Perceived hot or cold
• Numbness
• Pain
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• The feet are involved far more often than the hands
 Treatment
Microvascular complications
»Diabetes Neuropathy: Peripheral neuropathy
• Efforts to improve glycemic control
• The primary treatment strategy
• May alleviate some of the symptoms
• Symptomatic (pain) treatments
• No medication has been shown to be clearly superior
• The selection should be based on safety, cost, convenience
• TCA (nortriptyline/desipramine), duloxetine, gabapentin,
12/28/2024
pregabalin, venlafaxine, topical capsaicin, tramadol 119
 Treatment
Microvascular complications
»Diabetes Neuropathy: Autonomic neuropathy
• Impacts the ANS & can lead to
• Resting tachycardia
• Orthostatic hypotension
• Chronic constipation
• Gastroparesis
• Erectile dysfunction
• Anhidrosis, heat intolerance, gustatory sweating, dry skin,
12/28/2024 & hypoglycemic unawareness 120
 Treatment
Microvascular complications
»Diabetes Neuropathy: Autonomic neuropathy
• Gastroparesis
• Improved glycemic control, d/c drugs that slow gastric
motility, metoclopramide or low-dose erythromycin
• Tachyphylaxis develops within days or weeks
• Gastric pacemakers if symptoms are severe & persistent
• Domperidone may also be considered
• Doxycycline or metronidazole 10-14 days for diarrhea
12/28/2024 • Octreotide in more unresponsive diabetic diarrhea 121
 Treatment
Microvascular complications
»Diabetes Neuropathy: Autonomic neuropathy
• Orthostatic Hypotension
• Antihypertensive agents should be discontinued
• Dietary sodium intake should be liberalized
• Mineralocorticoids (eg, fludocortisone)
• Adrenergic agonist agents (eg, midodrine)
• Supine hypertension: Sleep in sitting or semi-recumbent
• Erectile dysfunction
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• A PDE type 5 inhibitor (highest dose) trial prior to referral
122
 Treatment
Microvascular complications
»Diabetes Neuropathy: Autonomic neuropathy
• Sudomotor dysfunction
• May cause reduced sweating & dry, cracked skin
• Requires hydrating creams & ointments
• Gustatory sweating after eating
• Antiperspirants or anticholinergics for excess sweating
• Hypoglycemic unawareness
• Requires the patient to avoid hypoglycemia
12/28/2024 123
 Treatment
Microvascular complications
»Diabetes Neuropathy: Focal neuropathy
• Most often in older patients with poorly controlled DM
• CN III, IV, & VI neuropathies & Bell’s palsy
• Usually self-limited
• Partial/full recovery in a few weeks to months
• Diabetic amyotrophy can be very debilitating
• Carpal tunnel syndrome
• Caused by radial nerve entrapment
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• Tarsal tunnel syndrome may cause foot paresthesias
 Treatment
Special Populations
»Prediabetes & Preventing Type 2 DM
• The lifestyle pillars for treatment & prevention of T2DM
1. Weight loss
2. Regular aerobic activity
3. Increased fiber intake
4. Limiting fat consumption
• Metformin, with LSM, to delay DM onset in prediabetes
• BMI >35 kg/m2, <60 y/o, & women with GDM history
• Liraglutide & once-weekly semaglutide are alternatives
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 Treatment
Special Populations
»Children & Adolescents with Type 2 DM
• Extraordinary efforts should be made to assist the child
• The family adopt lifestyle changes that normalize BG
• Metformin, liraglutide & exenatide XR
• Approved for use in children (≥10 years of age)
• Sulfonylureas: Commonly used
• TZDs: Improve glycemic control when added to metformin
• Insulin therapy: The standard of care when glycemic goals
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cannot be achieved or maintained with metformin
 Treatment
Special Populations
»Older Adults with DM
• Less able to adopt healthy lifestyle behaviors
• More likely to experience medication adverse effects
• A patient-centered approach is recommended as several
factors influence glycemic goals & treatment selection
• The number & severity of comorbid conditions,
• Renal dysfunction, ability to engage in self-care,
• Nutritional status, social support
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• The risk of falls, life expectancy
 Treatment
Special Populations
»Older Adults with DM
• Over-treatment of DM should be avoided
• De-escalation should severe or frequent hypoglycemia
• Metformin
• A decline in renal function may preclude its use
• Lower doses may be used
• Coupled with frequent monitoring (every 3-month)
• When the eGFR is consistently >30 mL/min/1.73 m2
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 Treatment
Special Populations
»Older Adults with DM
• SGLT-2 inhibitors
• Efficacy declines with renal function
• Can cause orthostatic hypotension & falls
• Sulfonylureas: Particularly LA agents should be avoided
• TZDs: Often cause fluid retention & increase the risk of CHF
• DPP-4 Is: Don’t cause hypoglycemia, generally well-tolerated
• 𝛂-glucosidase inhibitors are generally safe & may be used
12/28/2024 129
 Treatment
Special Populations
»Older Adults with DM
• GLP-1 RAs & SGLT-2 Is: Can be useful in overweight cases
• Simple insulin regimens
• A single daily basal insulin dose
• If tight glycemic control is not the goal
• Injectable GLP-1 RAs & insulin therapy
• Require adequate motor skills & visual acuity
• To self-administer doses
12/28/2024 130
 Treatment
Special Populations
»Pregnant Women with DM
• Preconception planning & glycemic control are critical
• Insulin therapy
• NPH remains the recommended basal insulin
• Insulin detemir appears to be safe
• Insulin pump therapy: Excellent glycemic control
• Glyburide or metformin use is justified in T2DM patients
• For whom insulin therapy is too complex or refuses insulin
12/28/2024 131
• GDM cases should have BG test ~6 weeks after delivery
 Treatment
Special Populations
»Patients with DM + HIV
• Metformin
• The drug of choice as weight gain can be minimized
• Check lactate levels in patients taking D4T, AZT, DDI
• Consider alternative if lactate levels >2x normal
• A chosen TZD can be used if excess visceral adiposity
• Drugs helping weight loss should also be considered
• Significant DDIs may also be present
12/28/2024 132
 MONITORING & EVALUATION
Glycemic control
»FPG, PPG
»BGM
»A1C
»CGM & Glycemic variability
Disease progression: Complications
Medication adverse effects
Medication adherence
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