Pharmacology · Diabetes Pharmacology

Special Clinical Contexts in Diabetes Pharmacology

Drug selection by comorbidity — preferred agents and agents to avoid

In patients with established atherosclerotic cardiovascular disease or high ASCVD risk, the ADA Standards of Care prioritize a GLP-1 receptor agonist with proven MACE reduction (liraglutide, semaglutide, or dulaglutide) or an SGLT-2 inhibitor with proven MACE reduction (empagliflozin or canagliflozin) as the second agent after metformin — the selection hierarchy is driven by outcomes evidence rather than glycemic efficacy alone.
CKD changes the entire drug selection framework: metformin is contraindicated below eGFR 30; sulfonylureas accumulate active metabolites and cause prolonged hypoglycemia as GFR falls (glyburide is particularly dangerous at any level of renal impairment); SGLT-2 inhibitors lose glucose-lowering efficacy below eGFR 45 but retain cardiorenal protection down to eGFR 20–30 and should be continued specifically for that indication, not for glucose lowering.
GLP-1 receptor agonists are not recommended in advanced heart failure with reduced ejection fraction — the FIGHT trial showed that liraglutide worsened outcomes in patients with advanced HFrEF (NYHA class III–IV), likely because the tachycardia and increased myocardial oxygen demand associated with GLP-1 receptor activation offset any benefit; SGLT-2 inhibitors are the preferred agents for heart failure regardless of ejection fraction.
Insulin is the only proven-safe antihyperglycemic in pregnancy: it does not cross the placenta, has decades of human safety data, and is the only agent with sufficient flexibility to achieve the tighter glycemic targets required in pregnancy (fasting below 95, 1-hour below 140, 2-hour below 120 mg/dL); metformin and glyburide are used in gestational diabetes mellitus in some guidelines but cross the placenta and have long-term offspring data that remains under evaluation.
Older adults with diabetes require individualized glycemic targets based on functional status and life expectancy — the Beers Criteria specifically flag glyburide as a potentially inappropriate medication in patients over 65 due to prolonged hypoglycemia risk; DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors are generally safer choices in the elderly, though SGLT-2 inhibitors require attention to volume depletion and falls risk in frail patients.

Abbreviations: ASCVD = atherosclerotic cardiovascular disease · CKD = chronic kidney disease · HFrEF = heart failure with reduced ejection fraction · HFpEF = heart failure with preserved ejection fraction · GDM = gestational diabetes mellitus · eGFR = estimated glomerular filtration rate · NYHA = New York Heart Association · ADA = American Diabetes Association

Drug Selection by Comorbidity

Comorbidity	Preferred Agents	Agents to Avoid / Caution
Established ASCVD or High CV Risk	GLP-1 agonist with MACE benefit (liraglutide, semaglutide, dulaglutide); SGLT-2 inhibitor with MACE benefit (empagliflozin, canagliflozin)	Avoid saxagliptin in patients with HF — SAVOR-TIMI HF hospitalization signal
CKD (eGFR 30–60)	SGLT-2 inhibitors (cardiorenal protection to eGFR ~20–30); DPP-4 inhibitors (dose-adjust most agents; linagliptin — no renal dose adjustment); GLP-1 agonists	Metformin: hold if eGFR <30; caution 30–45; Glyburide: avoid — prolonged hypoglycemia risk; Sulfonylureas in general: accumulate; dose reduce
Heart Failure (HFrEF or HFpEF)	SGLT-2 inhibitors: empagliflozin or dapagliflozin — benefit across full EF spectrum; effective regardless of diabetes status	GLP-1 agonists: avoid in advanced HFrEF (NYHA III–IV) — FIGHT trial showed harm; TZDs: absolutely contraindicated in NYHA III–IV — fluid retention worsens HF
Pregnancy / GDM	Insulin: only proven-safe agent; does not cross placenta; full dose flexibility; preferred in all trimesters	All other antihyperglycemics: insufficient human safety data; GLP-1 agonists, SGLT-2 inhibitors, DPP-4 inhibitors: contraindicated; Metformin and glyburide: cross placenta — used in GDM at some centers but not preferred
Older Adults (≥65)	DPP-4 inhibitors: well tolerated, no hypoglycemia; SGLT-2 inhibitors: cardiorenal benefit (monitor for volume depletion and falls risk); GLP-1 agonists: no hypoglycemia, weight benefit	Glyburide: Beers Criteria flag — prolonged hypoglycemia, active metabolites, renally cleared; Long-acting sulfonylureas: prefer shorter-acting alternatives if needed; Tight glycemic targets: individualize — HbA1c 7.5–8.5% acceptable in frail elderly

Key Clinical Decision Points

CKD — Renal Dose Landscape

Dosing by eGFR

eGFR ≥60: most agents acceptable; full doses
eGFR 45–60: reduce metformin dose; caution with sulfonylureas; SGLT-2 inhibitors usable
eGFR 30–45: avoid sulfonylureas; metformin with caution; SGLT-2 inhibitors for CKD/HF benefit (not glucose)
eGFR <30: insulin preferred; linagliptin (no renal dose adjust); SGLT-2 inhibitors may be continued for CKD benefit per agent label; metformin contraindicated
Finerenone: add in CKD with albuminuria on max SGLT-2 inhibitor + RAS blocker (FIDELIO-DKD)

Pregnancy Management

Diabetes in Pregnancy

Insulin: lispro and aspart preferred for bolus; detemir for basal — most pregnancy safety data
Glycemic targets: fasting <95 mg/dL; 1-hour <140; 2-hour <120
Requirements double in 3rd trimester — anticipate dose escalation
Metformin (GDM): crosses placenta; used at some centers per MiG Trial — long-term offspring data still accumulating
Glyburide (GDM): also crosses placenta; higher neonatal hypoglycemia risk vs. insulin

Frail Elderly

Older Adults — Deprescribing

Glyburide: Beers Criteria 2023 — explicitly flagged; avoid in patients ≥65; substitute shorter-acting agents
Relaxed HbA1c target: 7.5–8.5% acceptable in frail patients — hypoglycemia risk outweighs tight control benefit
Deprescribing candidates: prolonged hypoglycemia, cognitive impairment, limited life expectancy — reduce insulin and sulfonylureas first
SGLT-2 inhibitors and DPP-4 inhibitors: generally safe to continue for cardiorenal protection — no hypoglycemia risk

Diabetes Pharmacology — Chapter Synthesis

Modern diabetes pharmacology has been reorganized by large outcome trials. The question is no longer simply "which agent lowers glucose best" but "which agent best protects the organs most at risk for this patient." For a patient with established ASCVD or high cardiovascular risk: a GLP-1 receptor agonist with MACE reduction plus an SGLT-2 inhibitor with MACE reduction and metformin — three different mechanisms, three different organ protections. For a patient with CKD and albuminuria: SGLT-2 inhibitor plus finerenone plus RAS blockade, titrated to the lowest tolerated eGFR. For a patient with heart failure: SGLT-2 inhibitor across the ejection fraction spectrum, regardless of diabetes status.

The pharmacological classes covered in this chapter — insulin, secretagogues, metformin, TZDs, DPP-4 inhibitors, alpha-glucosidase inhibitors, GLP-1 receptor agonists, GLP-1/GIP dual agonists, and SGLT-2 inhibitors — represent nine distinct mechanisms acting on beta cell function, peripheral insulin resistance, hepatic glucose output, renal glucose reabsorption, and incretin signaling. No other therapeutic area in pharmacology has seen a more rapid transformation from symptom management to organ-level protection in the past decade.

Suggested References

Author / Source	Title	Publication
Katzung BG, ed.	Basic and Clinical Pharmacology, 15th ed. — Chapter 41: Pancreatic Hormones and Antidiabetic Drugs	McGraw-Hill; 2021
Brunton L, Knollmann B, Hilal-Dandan R, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed. — Chapter 45: Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia	McGraw-Hill; 2023
American Diabetes Association	Standards of Care in Diabetes—2024	Diabetes Care. 2024;47(Suppl 1):S1–S321
Marso SP et al (LEADER)	Liraglutide and cardiovascular outcomes in type 2 diabetes	N Engl J Med. 2016;375(4):311–322
Zinman B et al (EMPA-REG OUTCOME)	Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes	N Engl J Med. 2015;373(22):2117–2128
Moen MF et al	Frequency of hypoglycemia and its significance in chronic kidney disease	Clin J Am Soc Nephrol. 2009;4(6):1121–1127
Perkovic V et al (CREDENCE)	Canagliflozin and renal outcomes in type 2 diabetes and nephropathy	N Engl J Med. 2019;380(24):2295–2306
Bakris GL et al (FIDELIO-DKD)	Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes	N Engl J Med. 2020;383(23):2219–2229
McMurray JJV et al (DAPA-HF)	Dapagliflozin in patients with heart failure and reduced ejection fraction	N Engl J Med. 2019;381(21):1995–2008
Scirica BM et al (SAVOR-TIMI 53)	Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus	N Engl J Med. 2013;369(14):1317–1326
Margulies KB et al (FIGHT)	Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction	JAMA. 2016;316(5):500–508
American College of Obstetricians and Gynecologists	ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus	Obstet Gynecol. 2018;131(2):e49–e64
Rowan JA et al (MiG Trial)	Metformin versus insulin for the treatment of gestational diabetes	N Engl J Med. 2008;358(19):2003–2015
American Diabetes Association	Older Adults: Standards of Care in Diabetes—2024	Diabetes Care. 2024;47(Suppl 1):S244–S257
American Geriatrics Society	2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults	J Am Geriatr Soc. 2023;71(7):2052–2081