Lecture 27/28 - Type 2 Diabetes Prevention/Initial Oral Therapy

what is the main pathophysiology of type 2 diabetes

predominantly insulin resistance

predominantly insulin secretory deficit

most people exhibit abdominal obesity - major contributor to insulin resistance

what are type 2 diabetes related complications

neuropathy (neuropathic pain, gastroparesis, cardiac autonomic neuropathy)

anxiety and depression

erectile dysfunction 

foot ulcers

periordontal disease

vision loss

cardiovascular disease

CKD

lower limb amputation

what are the common causes of death for type 2 diabetes

heart disease/stroke

cancer

what are the core defects that contribute to hyperglycemia in diabetes

insulin resistance in muscle and liver

impaired insulin secretion from pancreatic beta cells

what are additional defects that contribute to hyperglycemia in diabetes

increased hepatic glucose production

decreased GLP-1 secretion from small intestine

increased lipolysis (increases plasma free fatty acids)

increased glucagon secretion from pancreatic alpha cells

increased renal glucose reabsorption by SGLT2

neurotransmitter dysfunction and resistance to appetite-suppressive effects of insulin, GLP-1 and other neurotransmitters

what are newer mechanisms of defects that contribute to hyperglycemia in diabetes

inflammation

vascular insulin resistance

what is the first and ongoing step in type 2 diabetes prevention

lifestyle intervention

reduces progression to diabetes by 58% in patients with impaired glucose tolerance

weight loss can improve insulin sensitivity, lower blood glucose, improve lipids and blood pressure

what are the 4 older agents testes to reduce the risk of progressing from pre-diabetes to type 2 diabetes 

metformin

acarbose

pioglitazone

rosiglitazone 

what is the only older agent used to prevent type 2 diabetes

metformin

what are the 3 modern incretin and anti-obesity therapies

liraglutide

semaglutide

tirzepatide

what is important to know about incretin and anti-obesity therapies in a canadian context 

they reduce the risk of diabetes progression in high-risk population largely via weight loss, but is NOT guideline endorsed in canada → used off label

why are metformin and GLP-1 agonist not commonly used to prevent the development of type 2 diabetes

a significant portion of patients treated with these therapies may never develop diabetes → unnecessary medication exposure

where do GLP-1 agonists act to treat insulin resistance

pancreatic beta cells

liver

small intestine

pancreatic alpha cells

brain

where do DPP4 inhibitors act to treat insulin resistance 

pancreatic beta cells 

liver

small intestine

pancreatic alpha cells 

where does metformin act to treat insulin resistance

possible in liver

where do SGLT2i act to treat insulin resistance

kidney

where does insulin act to treat insulin resistance 

pancreatic beta cells 

what are the goals of therapy for type 2 diabetes

reduce the risk of microvascular and macrovascular complications of diabetes

maintain glycemic treatment targets

• A1c around 7%

• fasting and pre-meal blood glucose (4-7 mmol/L)

• 2 hour post prandial blood glucose (5-10 mmol/L)

minimize the risk of hypoglycemia

maintain treatment targets for cardiovascular risk factors

what is the recommended initial antihyperglycemic medication for type 2 diabetes 

metformin

initial dose: 250-500 mg bid with meals 

effective in lowering A1c, negligible risk for hypoglycemia or weight gain, mild side effect profile, long-term track record, affordability 

GI upset usually goes away after 2-3 weeks 

when should metformin be combined with a second antihyperglycemic agent for initial therapy

if A1c is ≥ 1.5% above the target at diagnosis

(metformin only decreases A1c by 1-1.5%)

what is the recommendation for patient with metabolic decompensation (marked hyperglycemia, ketosis or unintentional weight loss)

insulin with or without metformin to correct the relative insulin deficiency

what is the preferred second line therapy for most patients 

SGLT2i

what are adverse effects to metformin

GI side effects - N/V, flatulence, abdominal discomfort

metallic taste (will not go away unless patient discontinues)

renal impairment

what are reasonable alternatives to metformin

DPP4 inhibitors

SGLT2i

GLP-1 agonists

what is important to know about combination therapy

using combinations at submaximal doses is more effective than using 1 therapy at maximal doses