Type 2 Diabetes Mellitus: Pharmacology & Management (ADA 2026 Standards)

from reportlab.lib.pagesizes import A4, landscape
from reportlab.lib import colors
from reportlab.lib.units import mm, cm
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_RIGHT
from reportlab.platypus import (
    SimpleDocTemplate, Table, TableStyle, Paragraph, Spacer,
    HRFlowable, KeepTogether, PageBreak
)
from reportlab.graphics.shapes import Drawing, Rect, String
from reportlab.graphics import renderPDF
from reportlab.pdfbase import pdfmetrics
import datetime

OUTPUT = "/home/daytona/workspace/t2dm-guide/T2DM_Quick_Reference_Guide.pdf"

# ── Colour palette ──────────────────────────────────────────────────────────
NAVY      = colors.HexColor("#1A3A5C")
TEAL      = colors.HexColor("#0B7D8A")
TEAL_LIGHT= colors.HexColor("#E0F4F6")
ORANGE    = colors.HexColor("#E8621A")
ORANGE_LT = colors.HexColor("#FEF0E8")
GREEN     = colors.HexColor("#1E7C45")
GREEN_LT  = colors.HexColor("#E5F5EC")
PURPLE    = colors.HexColor("#5A3E8E")
PURPLE_LT = colors.HexColor("#EDE8F8")
RED_LT    = colors.HexColor("#FDECEA")
RED       = colors.HexColor("#C0392B")
YELLOW_LT = colors.HexColor("#FEFAE0")
YELLOW    = colors.HexColor("#D4AC0D")
GREY_DARK = colors.HexColor("#2C3E50")
GREY_MID  = colors.HexColor("#7F8C8D")
GREY_LIGHT= colors.HexColor("#F2F4F4")
GREY_LINE = colors.HexColor("#D5D8DC")
WHITE     = colors.white
BLACK     = colors.black

# ── Styles ───────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

def S(name, **kw):
    return ParagraphStyle(name, **kw)

TITLE_STYLE = S("title_s",
    fontName="Helvetica-Bold", fontSize=22, textColor=WHITE,
    alignment=TA_CENTER, spaceAfter=2)

SUBTITLE_STYLE = S("sub_s",
    fontName="Helvetica", fontSize=10, textColor=colors.HexColor("#BDC3C7"),
    alignment=TA_CENTER, spaceAfter=0)

SECTION_STYLE = S("section_s",
    fontName="Helvetica-Bold", fontSize=12, textColor=WHITE,
    alignment=TA_LEFT, spaceBefore=4, spaceAfter=4,
    leftIndent=8)

BODY = S("body_s",
    fontName="Helvetica", fontSize=7.5, textColor=GREY_DARK,
    leading=10, alignment=TA_LEFT)

BODY_BOLD = S("body_bold",
    fontName="Helvetica-Bold", fontSize=7.5, textColor=GREY_DARK,
    leading=10, alignment=TA_LEFT)

CELL = S("cell_s",
    fontName="Helvetica", fontSize=7, textColor=GREY_DARK,
    leading=9, alignment=TA_LEFT)

CELL_BOLD = S("cell_bold",
    fontName="Helvetica-Bold", fontSize=7, textColor=GREY_DARK,
    leading=9, alignment=TA_LEFT)

CELL_CENTER = S("cell_center",
    fontName="Helvetica", fontSize=7, textColor=GREY_DARK,
    leading=9, alignment=TA_CENTER)

CELL_BOLD_CENTER = S("cell_bold_c",
    fontName="Helvetica-Bold", fontSize=7.2, textColor=WHITE,
    leading=9, alignment=TA_CENTER)

NOTE_STYLE = S("note_s",
    fontName="Helvetica-Oblique", fontSize=6.5, textColor=GREY_MID,
    leading=8, alignment=TA_LEFT)

FOOTNOTE = S("footnote",
    fontName="Helvetica", fontSize=6, textColor=GREY_MID,
    leading=7.5, alignment=TA_LEFT)

# ── Helper: coloured section header bar ─────────────────────────────────────
def section_header(text, bg=NAVY, width=None):
    return Table(
        [[Paragraph(text, SECTION_STYLE)]],
        colWidths=[width or 260*mm],
        style=TableStyle([
            ("BACKGROUND", (0,0), (-1,-1), bg),
            ("TOPPADDING",    (0,0), (-1,-1), 5),
            ("BOTTOMPADDING", (0,0), (-1,-1), 5),
            ("LEFTPADDING",   (0,0), (-1,-1), 8),
            ("RIGHTPADDING",  (0,0), (-1,-1), 8),
            ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
        ])
    )

def badge(text, bg, fg=WHITE, width=30*mm):
    style = S("badge", fontName="Helvetica-Bold", fontSize=6.5,
              textColor=fg, alignment=TA_CENTER, leading=8)
    return Table([[Paragraph(text, style)]],
        colWidths=[width],
        style=TableStyle([
            ("BACKGROUND", (0,0), (-1,-1), bg),
            ("TOPPADDING",    (0,0), (-1,-1), 2),
            ("BOTTOMPADDING", (0,0), (-1,-1), 2),
            ("LEFTPADDING",   (0,0), (-1,-1), 3),
            ("RIGHTPADDING",  (0,0), (-1,-1), 3),
            ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
            ("BOX", (0,0), (-1,-1), 0.3, bg),
        ])
    )

# ── Document setup (landscape A4) ──────────────────────────────────────────
doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=landscape(A4),
    leftMargin=12*mm, rightMargin=12*mm,
    topMargin=12*mm, bottomMargin=14*mm,
    title="T2DM Quick Reference Guide",
    author="Orris Medical Reference",
    subject="Type 2 Diabetes Mellitus – Drug Comparison & Monitoring"
)

W, H = landscape(A4)
PAGE_W = W - 24*mm   # usable width

story = []

# ══════════════════════════════════════════════════════════════════════════════
# HEADER BANNER
# ══════════════════════════════════════════════════════════════════════════════
banner_data = [[
    Paragraph("TYPE 2 DIABETES MELLITUS", TITLE_STYLE),
    Paragraph("Quick Reference Guide — Drugs, Dosing & Monitoring  |  Based on ADA 2026 Standards of Care", SUBTITLE_STYLE),
]]
banner = Table(banner_data, colWidths=[PAGE_W],
    style=TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), NAVY),
        ("TOPPADDING",    (0,0), (-1,-1), 12),
        ("BOTTOMPADDING", (0,0), (-1,-1), 10),
        ("LEFTPADDING",   (0,0), (-1,-1), 12),
        ("RIGHTPADDING",  (0,0), (-1,-1), 12),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
        ("SPAN", (0,0), (-1,-1)),
    ])
)
story.append(banner)
story.append(Spacer(1, 4*mm))

# ══════════════════════════════════════════════════════════════════════════════
# SECTION 1 – MAIN DRUG COMPARISON TABLE
# ══════════════════════════════════════════════════════════════════════════════
story.append(section_header("① DRUG CLASS COMPARISON — MECHANISMS, DOSING & KEY PROPERTIES", TEAL, PAGE_W))
story.append(Spacer(1, 2*mm))

COL_DRUG    = 38*mm
COL_MECH    = 50*mm
COL_DOSE    = 46*mm
COL_HBA1C   = 18*mm
COL_WT      = 16*mm
COL_HYPO    = 14*mm
COL_CV      = 22*mm
COL_RENAL   = 22*mm
COL_ADR     = 40*mm
TOTAL = COL_DRUG+COL_MECH+COL_DOSE+COL_HBA1C+COL_WT+COL_HYPO+COL_CV+COL_RENAL+COL_ADR

def H(t): return Paragraph(t, CELL_BOLD_CENTER)
def C(t, bold=False): return Paragraph(t, CELL_BOLD if bold else CELL)
def CC(t): return Paragraph(t, CELL_CENTER)

main_table_data = [
    # Header row
    [H("DRUG CLASS / Agents"), H("Mechanism of Action"), H("Typical Dosing"),
     H("HbA1c\nReduction"), H("Weight\nEffect"), H("Hypo\nRisk"),
     H("CV / Cardiac\nBenefit"), H("Renal\nConsiderations"), H("Key ADRs / Precautions")],

    # ── Metformin ──
    [C("BIGUANIDE\nMetformin\n(Glucophage)", bold=True),
     C("↓ Hepatic gluconeogenesis (AMPK activation); slows intestinal glucose absorption; improves peripheral insulin sensitivity"),
     C("500–1000 mg PO BID with meals\nMax: 2550 mg/day\nER: 500–2000 mg QD with evening meal"),
     CC("↓ 1–2%"),
     CC("Neutral /\nSlight ↓"),
     CC("None"),
     CC("Possible CV benefit (UKPDS);\nWeight neutral"),
     C("HOLD if eGFR <30\nUse caution 30–45\nHold before IV contrast"),
     C("GI (N/V/D) – dose with food\nLactic acidosis (rare, mainly eGFR<30)\nVit B12 depletion (monitor annually)")],

    # ── GLP-1 RA ──
    [C("GLP-1 RECEPTOR\nAGONISTS\nSemaglutide (Ozempic/Rybelsus)\nLiraglutide (Victoza)\nDulaglutide (Trulicity)\nExenatide (Byetta/Bydureon)\nTirzepatide* (Mounjaro)", bold=True),
     C("Mimic incretin effect: ↑ glucose-dependent insulin secretion, ↓ glucagon, delay gastric emptying, ↑ satiety. Tirzepatide: dual GIP+GLP-1 agonist"),
     C("Semaglutide SC: 0.25mg QW→1mg QW (up to 2mg)\nSemaglutide PO: 3mg QD→14mg QD\nLiraglutide: 0.6→1.2→1.8 mg SC QD\nDulaglutide: 0.75→1.5mg SC QW\nExenatide ER: 2mg SC QW\nTirzepatide: 2.5mg QW→max 15mg QW"),
     CC("↓ 1–1.8%\n(*Tirzepatide\nup to 2.4%)"),
     CC("↓↓\n(2–7 kg;\ntirzepatide\n>10%)"),
     CC("Minimal\n(glucose-\ndependent)"),
     C("✓ Proven MACE reduction (LEADER, SUSTAIN-6, REWIND, SOUL trials)\nBenefit in HFpEF (tirzepatide/sema)\n✓ Approved for weight loss"),
     C("No dose adjustment for most agents\nCan initiate/continue in advanced CKD (ADA 2026)\nExenatide avoid if eGFR <30"),
     C("N/V/D common at start (transient)\nPancreatitis (rare – monitor)\nThyroid C-cell tumors: CONTRAINDICATED in MEN2 / MTC hx\nInjection site reactions\nDelayed gastric emptying – drug interactions")],

    # ── SGLT2i ──
    [C("SGLT2 INHIBITORS\nEmpagliflozin (Jardiance)\nDapagliflozin (Farxiga)\nCanagliflozin (Invokana)\nErtugliflozin (Steglatro)", bold=True),
     C("Inhibit SGLT2 in proximal tubule → glycosuria (lowers glucose threshold 180→40 mg/dL); osmotic diuresis; ↓ renal sodium reabsorption"),
     C("Empagliflozin: 10–25 mg PO QD\nDapagliflozin: 10 mg PO QD\n  (5 mg if hepatic impairment)\nCanagliflozin: 100–300 mg PO QD\nErtugliflozin: 5–15 mg PO QD\n(All taken in AM before first meal)"),
     CC("↓ 0.5–1%"),
     CC("↓\n(2–5 kg)"),
     CC("Low"),
     C("✓ Reduced HF hospitalisations (HFrEF & HFpEF)\n✓ Slows CKD progression\nEmpagliflozin: ↓ CV mortality (EMPA-REG)\nDapa: DAPA-HF, DAPA-CKD"),
     C("eGFR 20–45: limited glycemic effect but cardioprotection preserved\nStop if eGFR <20 for glycemic use\nADA 2026: combine with finerenone (nsMRA) if ACR ≥100 & eGFR 30–90"),
     C("Genital mycotic infections ↑↑\nUTI ↑\nVolume depletion / hypotension\nEuglycemic DKA (rare in T2DM)\nFournier's gangrene (rare)\nCanagliflozin: ↑ amputation risk (lower limb)")],

    # ── DPP-4i ──
    [C("DPP-4 INHIBITORS\nSitagliptin (Januvia)\nLinagliptin (Tradjenta)\nSaxagliptin (Onglyza)\nAlogliptin (Nesina)\nVildagliptin (not in US)", bold=True),
     C("Inhibit DPP-4 enzyme → prevent degradation of endogenous GLP-1 & GIP → prolonged incretin effect → ↑ glucose-dependent insulin, ↓ glucagon"),
     C("Sitagliptin: 100 mg PO QD\n  (50 mg if eGFR 30–45; 25 mg if <30)\nLinagliptin: 5 mg PO QD\n  (NO renal dose adjustment – biliary)\nSaxagliptin: 2.5–5 mg PO QD\n  (2.5 mg if eGFR ≤50)\nAlogliptin: 25 mg PO QD\n  (renal dose if eGFR <60)"),
     CC("↓ 0.4–0.8%"),
     CC("Neutral"),
     CC("Minimal"),
     C("Cardioneutral overall\nSaxagliptin & alogliptin: possible ↑ HF hospitalization (use caution in HF)"),
     C("Linagliptin: safe in all CKD stages\nOthers: dose-reduce per eGFR\nSitagliptin safest in renal impairment after linagliptin"),
     C("Nasopharyngitis / URTI\nPancreatitis (rare)\nHypersensitivity: angioedema, SJS (rare)\nJoint pain (FDA warning – reversible)\nAlogliptin: rare hepatic failure")],

    # ── Sulfonylureas ──
    [C("SULFONYLUREAS\nGlimepiride (Amaryl)\nGlipizide (Glucotrol)\nGlyburide (DiaBeta)\n[2nd gen preferred]", bold=True),
     C("Close K⁺-ATP channels on pancreatic β cells → membrane depolarisation → Ca²⁺ influx → insulin secretion (GLUCOSE-INDEPENDENT – hence hypoglycemia risk)"),
     C("Glimepiride: 1–8 mg PO QD with breakfast\nGlipizide: 5–40 mg PO QD-BID (IR);\n  5–20 mg PO QD (XL)\nGlyburide: 1.25–20 mg PO QD-BID\n(Start low, titrate every 1–2 weeks)\n⚠ Avoid glyburide in elderly/CKD"),
     CC("↓ 1–1.5%"),
     CC("↑\n(1–4 kg)"),
     CC("SIGNIFICANT\n(glucose-\nindependent)"),
     C("No established CV benefit\nOlder agents: possible ↑ CV risk\nNow second-line/cost-driven choice"),
     C("Glipizide preferred in CKD\nGlyburide AVOID in eGFR <60 (active metabolites → hypoglycemia)\nGlimepiride: use caution if eGFR <60"),
     C("HYPOGLYCEMIA (main concern – prolonged with glyburide)\nWeight gain\nPhotodermatitis\nDisulfiram-like reaction (glyburide)\nBeta-cell exhaustion over time")],

    # ── TZDs ──
    [C("THIAZOLIDINEDIONES (TZDs)\nPioglitazone (Actos)\nRosiglitazone (Avandia)\n[Pioglitazone preferred]", bold=True),
     C("PPAR-γ agonists → ↑ transcription of insulin-responsive genes → ↑ peripheral insulin sensitivity in adipose, muscle, liver; ↓ hepatic glucose production"),
     C("Pioglitazone: 15–45 mg PO QD\n  (no food restriction)\nRosiglitazone: 4–8 mg PO QD/BID\n  (restricted use – CV concerns)\nFull effect takes 8–12 weeks"),
     CC("↓ 0.5–1.4%"),
     CC("↑\n(fluid +\nfat)"),
     CC("None"),
     C("Pioglitazone: modest ↓ MACE (PROactive trial)\nROSIGLITAZONE: ↑ MI risk (restricted/banned in some countries)\nPioglitazone beneficial in MASH/NAFLD (ADA 2026)"),
     C("No dose adjustment in CKD\nUse with caution if fluid retention concerns\nContraindicated: active/hx bladder cancer"),
     C("Edema / fluid retention ↑↑\nHF exacerbation (CONTRAINDICATED NYHA III-IV)\nWeight gain\nFractures ↑ (esp. women – distal)\nBladder cancer risk (pioglitazone – long term)\nMacular edema (rare)")],

    # ── Meglitinides ──
    [C("MEGLITINIDES\nRepaglinide (Prandin)\nNateglinide (Starlix)", bold=True),
     C("Close K⁺-ATP channels on β cells (same as SUs) but shorter duration of action → rapid, short-burst insulin release for meal coverage"),
     C("Repaglinide: 0.5–4 mg PO with each meal\n  (up to 3x/day with meals; skip dose if skipping meal)\nNateglinide: 60–120 mg PO TID with meals\n(Take 0–30 min before each meal)"),
     CC("↓ 0.5–1.5%"),
     CC("↑\n(modest)"),
     CC("Moderate\n(less than\nSUs)"),
     C("No proven CV benefit"),
     C("Repaglinide: can use in CKD (hepatic metabolism)\nNateglinide: caution in severe renal impairment"),
     C("Hypoglycemia (less than SUs; flexible dosing)\nWeight gain\nFlexible dosing for irregular meal schedules\nNot cost-effective vs SUs in most settings")],

    # ── Alpha-glucosidase ──
    [C("α-GLUCOSIDASE\nINHIBITORS\nAcarbose (Precose)\nMiglitol (Glyset)", bold=True),
     C("Inhibit intestinal alpha-glucosidases (maltase, sucrase, glucoamylase) → delayed CHO digestion & glucose absorption → ↓ postprandial glucose spikes"),
     C("Acarbose: 25 mg PO TID with first bite of meals → titrate to 50–100 mg TID over weeks\nMiglitol: 25–100 mg PO TID with meals\nMax: 100 mg TID\nStart low to minimize GI side effects"),
     CC("↓ 0.5–0.8%"),
     CC("Neutral"),
     CC("None"),
     C("No proven CV benefit\nMay offer modest benefit in IGT progression"),
     C("Avoid if eGFR <25 (acarbose)\nMiglitol: avoid in significant renal impairment"),
     C("GI: flatulence, bloating, diarrhea, abdominal cramps (often limits use)\nHypoglycemia: does not cause alone; if combined with SU/insulin use GLUCOSE (not sucrose) to treat\nLiver enzyme elevation (rare – high dose acarbose)")],

    # ── Insulin ──
    [C("INSULIN THERAPY\nRapid: Lispro, Aspart, Glulisine\nShort: Regular\nIntermediate: NPH\nLong-acting: Glargine, Detemir\nUltra-long: Degludec\nCombinations: IDegLira, iGlarLixi", bold=True),
     C("Replaces endogenous insulin: ↑ glucose uptake (muscle/adipose), ↓ hepatic glucose output, ↑ glycogen synthesis, ↓ lipolysis, ↓ glucagon"),
     C("Basal START: Glargine/Degludec 10 U SC QHS\n  Titrate: ↑2U q3 days until FBG 80–130\nRapid: 4U per meal (titrate)\nRule of 1500/1800 for correction dose\nRapid onset: 15 min before meal\nRegular: 30 min before meal\n2026: AID systems preferred if on insulin"),
     CC("Variable\n(1–3%+\ndepending\non dose)"),
     CC("↑↑\n(2–8 kg)"),
     CC("YES –\nSIGNIFICANT"),
     C("Neutral CV effect (ORIGIN trial)\nFlexible in all patients\nAID (automated insulin delivery) recommended by ADA 2026"),
     C("Dose not restricted by renal function per se\nBut hypoglycemia risk ↑ in CKD\nInsulin requirements may fall with worsening CKD\nDegludec: more stable profile"),
     C("Hypoglycemia (main risk)\nWeight gain\nInjection site: lipohypertrophy, lipoatrophy\nEdema at initiation\nInsulin resistance with high doses\nHypoglycemia unawareness (with chronic use)")],
]

main_tbl = Table(main_table_data,
    colWidths=[COL_DRUG, COL_MECH, COL_DOSE, COL_HBA1C, COL_WT, COL_HYPO, COL_CV, COL_RENAL, COL_ADR],
    repeatRows=1)

# Build alternating row colours and header style
tbl_style = [
    # Header
    ("BACKGROUND", (0,0), (-1,0), TEAL),
    ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
    ("FONTNAME",   (0,0), (-1,0), "Helvetica-Bold"),
    ("FONTSIZE",   (0,0), (-1,0), 7),
    ("ALIGN",      (0,0), (-1,0), "CENTER"),
    ("VALIGN",     (0,0), (-1,-1), "TOP"),
    # Grid
    ("GRID",       (0,0), (-1,-1), 0.3, GREY_LINE),
    ("LINEBELOW",  (0,0), (-1,0), 1, TEAL),
    # Padding
    ("TOPPADDING",    (0,0), (-1,-1), 4),
    ("BOTTOMPADDING", (0,0), (-1,-1), 4),
    ("LEFTPADDING",   (0,0), (-1,-1), 4),
    ("RIGHTPADDING",  (0,0), (-1,-1), 4),
]

# Alternating row bg + drug class colour coding
row_colours = [
    TEAL_LIGHT,   # metformin
    GREEN_LT,     # GLP-1
    colors.HexColor("#E8F0FE"),  # SGLT2
    YELLOW_LT,    # DPP4
    ORANGE_LT,    # SU
    PURPLE_LT,    # TZD
    RED_LT,       # meglitinides
    colors.HexColor("#F0FFF4"),  # alpha-gluc
    colors.HexColor("#F5F0FF"),  # insulin
]

for i, clr in enumerate(row_colours):
    tbl_style.append(("BACKGROUND", (0, i+1), (-1, i+1), clr))

# First col bold
for r in range(1, len(main_table_data)):
    tbl_style.append(("FONTNAME", (0, r), (0, r), "Helvetica-Bold"))
    tbl_style.append(("FONTSIZE", (0, r), (0, r), 6.8))

main_tbl.setStyle(TableStyle(tbl_style))
story.append(main_tbl)
story.append(Spacer(1, 3*mm))

# ══════════════════════════════════════════════════════════════════════════════
# PAGE 2
# ══════════════════════════════════════════════════════════════════════════════
story.append(PageBreak())

# PAGE 2 BANNER
banner2 = Table([[Paragraph("TYPE 2 DIABETES MELLITUS — Monitoring, Targets &amp; Clinical Decision Framework", TITLE_STYLE)]],
    colWidths=[PAGE_W],
    style=TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), NAVY),
        ("TOPPADDING",    (0,0), (-1,-1), 10),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
        ("LEFTPADDING",   (0,0), (-1,-1), 12),
    ]))
story.append(banner2)
story.append(Spacer(1, 4*mm))

# ── Layout: 3-column grid ───────────────────────────────────────────────────
COL3 = (PAGE_W - 6*mm) / 3

# ── Column 1: Monitoring Targets ─────────────────────────────────────────────
def monitoring_table():
    rows = [
        [Paragraph("PARAMETER", CELL_BOLD_CENTER), Paragraph("TARGET (GENERAL)", CELL_BOLD_CENTER), Paragraph("NOTES", CELL_BOLD_CENTER)],
        [C("HbA1c"), CC("<7.0%"), C("< 8% for elderly/frail/limited life expectancy\n> 6.5% acceptable in young/short duration")],
        [C("Fasting glucose"), CC("80–130 mg/dL"), C("Adjust target to individual")],
        [C("2-hr postprandial"), CC("< 180 mg/dL"), C("Postprandial monitoring important with prandial insulin or SU")],
        [C("Blood pressure"), CC("< 130/80 mmHg"), C("ADA 2026: target SBP < 120 mmHg where feasible")],
        [C("LDL cholesterol"), CC("< 70 mg/dL"), C("< 55 mg/dL if very high CV risk\nStatin therapy for most with T2DM age > 40")],
        [C("Triglycerides"), CC("< 150 mg/dL"), C("Fibrate or icosapentaenoic acid (REDUCE-IT) if > 200")],
        [C("eGFR / Creatinine"), CC("Monitor annually"), C("More frequent if declining; adjust drug doses")],
        [C("Urine ACR"), CC("< 30 mg/g"), C("If ≥ 30: start SGLT2i + ACE/ARB\nIf ≥ 100 + eGFR 30–90: add finerenone")],
        [C("BMI / Weight"), CC("Monitor each visit"), C("Target ≥ 5–10% weight loss if overweight\nConsider GLP-1 RA / bariatric surgery")],
        [C("HbA1c frequency"), CC("Q3 months (unstable)\nQ6 months (stable)"), C("CGM preferred over SMBG if on insulin (ADA 2026)")],
        [C("Eye exam"), CC("Annually"), C("Dilated fundus exam; telemedicine retinal imaging acceptable")],
        [C("Foot exam"), CC("Annually (+ each visit if high risk)"), C("Inspect for neuropathy, PVD, ulcers")],
        [C("Dental / psych"), CC("Regularly"), C("Dental disease common; screen for diabetes distress")],
        [C("Vitamin B12"), CC("Annually if on metformin"), C("Long-term metformin → B12 depletion; supplement if low")],
    ]
    t = Table(rows, colWidths=[COL3*0.38, COL3*0.28, COL3*0.34])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), TEAL),
        ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        ("GRID", (0,0), (-1,-1), 0.3, GREY_LINE),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
        ("TOPPADDING",    (0,0), (-1,-1), 3),
        ("BOTTOMPADDING", (0,0), (-1,-1), 3),
        ("LEFTPADDING",   (0,0), (-1,-1), 4),
        ("RIGHTPADDING",  (0,0), (-1,-1), 4),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, GREY_LIGHT]),
    ]))
    return t

# ── Column 2: Drug choice by comorbidity ──────────────────────────────────────
def comorbidity_table():
    rows = [
        [Paragraph("COMORBIDITY / SITUATION", CELL_BOLD_CENTER), Paragraph("PREFERRED AGENTS", CELL_BOLD_CENTER)],
        [C("Established ASCVD / High CV risk", bold=True), C("GLP-1 RA with proven MACE benefit\n(liraglutide, semaglutide, dulaglutide)\nOR SGLT2i")],
        [C("Heart Failure (HFrEF or HFpEF)", bold=True), C("SGLT2i first\nFor HFpEF: tirzepatide or GLP-1 RA\n(ADA 2026 Rec 9.9a/9.9b)")],
        [C("CKD (eGFR 20–90)", bold=True), C("SGLT2i + ACE/ARB (eGFR ≥30)\nGLP-1 RA (can continue in advanced CKD)\nFinerenone if ACR ≥100")],
        [C("Obesity / Weight loss priority", bold=True), C("Tirzepatide (highest weight loss)\nor semaglutide 2.4 mg (Wegovy)\nConsider bariatric surgery if BMI ≥35")],
        [C("MASLD / MASH", bold=True), C("Semaglutide (preferred GLP-1 RA)\nPioglitazone (biopsy-proven MASH)\nTirzepatide – potential MASH benefit")],
        [C("Hypoglycemia risk", bold=True), C("GLP-1 RA, SGLT2i, DPP-4i\nAvoid sulfonylureas / meglitinides")],
        [C("Cost constraint", bold=True), C("Metformin + sulfonylurea (glipizide)\n+ NPH insulin\n(Avoid glyburide in elderly)")],
        [C("Pregnancy (T2DM)", bold=True), C("Insulin preferred (all trimesters)\nMetformin may be used\nAvoid GLP-1 RA, SGLT2i in pregnancy")],
        [C("Post-transplant diabetes", bold=True), C("Insulin preferred perioperatively\n(DPP-4i for mild hyperglycemia)\nLong-term: noninsulin options; GLP-1 RA for cardiometabolic benefit")],
        [C("Elderly (>75 y / frail)", bold=True), C("DPP-4i (safe, well tolerated)\nAvoid glyburide, meglitinides\nRelax HbA1c target to <8%")],
        [C("Hepatic impairment", bold=True), C("Avoid metformin in severe hepatic failure\nDapagliflozin: 5 mg starting dose\nInsulin or DPP-4i generally safe")],
        [C("High HbA1c at diagnosis (≥10%)", bold=True), C("Consider insulin initiation\nOR GLP-1 RA + metformin\nReassess once stabilised")],
    ]
    t = Table(rows, colWidths=[COL3*0.46, COL3*0.54])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), ORANGE),
        ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        ("GRID", (0,0), (-1,-1), 0.3, GREY_LINE),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("TOPPADDING",    (0,0), (-1,-1), 3),
        ("BOTTOMPADDING", (0,0), (-1,-1), 3),
        ("LEFTPADDING",   (0,0), (-1,-1), 4),
        ("RIGHTPADDING",  (0,0), (-1,-1), 4),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, ORANGE_LT]),
    ]))
    return t

# ── Column 3: Insulin types + ADA step algorithm ─────────────────────────────
def insulin_table():
    rows = [
        [Paragraph("INSULIN TYPE", CELL_BOLD_CENTER), Paragraph("ONSET", CELL_BOLD_CENTER),
         Paragraph("PEAK", CELL_BOLD_CENTER), Paragraph("DURATION", CELL_BOLD_CENTER)],
        [C("Rapid-acting\n(Lispro, Aspart,\nGlulisine)"), CC("5–15 min"), CC("30–90 min"), CC("3–5 hr")],
        [C("Short-acting\n(Regular)"), CC("30–60 min"), CC("2–4 hr"), CC("6–10 hr")],
        [C("Intermediate\n(NPH)"), CC("2–4 hr"), CC("4–10 hr"), CC("12–18 hr")],
        [C("Long-acting\n(Glargine, Detemir)"), CC("1–2 hr"), CC("Peakless"), CC("20–24 hr")],
        [C("Ultra-long\n(Degludec)"), CC("30–90 min"), CC("Peakless"), CC(">42 hr")],
    ]
    t = Table(rows, colWidths=[COL3*0.38, COL3*0.2, COL3*0.2, COL3*0.22])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,0), PURPLE),
        ("TEXTCOLOR",  (0,0), (-1,0), WHITE),
        ("GRID", (0,0), (-1,-1), 0.3, GREY_LINE),
        ("VALIGN", (0,0), (-1,-1), "MIDDLE"),
        ("TOPPADDING",    (0,0), (-1,-1), 3),
        ("BOTTOMPADDING", (0,0), (-1,-1), 3),
        ("LEFTPADDING",   (0,0), (-1,-1), 4),
        ("RIGHTPADDING",  (0,0), (-1,-1), 4),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, PURPLE_LT]),
    ]))
    return t

def step_algo():
    steps = [
        ("STEP 1\nDIAGNOSIS", "Lifestyle modification (MNT, exercise, weight)\n+ Metformin\n+ Consider GLP-1 RA or SGLT2i\n  if CVD / HF / CKD present", TEAL),
        ("STEP 2\n3 MONTHS", "If HbA1c still above target:\nAdd GLP-1 RA (weight ↑, CVD)\nor SGLT2i (HF, CKD, weight)\nor DPP-4i (well tolerated, neutral)\nor SU (if cost is barrier)", GREEN),
        ("STEP 3\n3–6 MO", "Triple therapy:\nCombine agents from different classes\nConsider tirzepatide (dual GIP/GLP-1)\nfor maximum weight + glucose lowering", ORANGE),
        ("STEP 4\nBASAL INS.", "Add basal insulin (glargine/degludec)\n10U QHS; titrate by 2U q3 days\nTarget FBG 80–130 mg/dL\nContinue non-insulin agents if possible", PURPLE),
        ("STEP 5\nINTENSIFY", "Basal-bolus insulin\nor AID system (preferred 2026)\nIDegLira / iGlarLixi: reduce\nhypoglycemia + weight gain", RED),
    ]
    data = []
    for label, text, clr in steps:
        data.append([
            Paragraph(label, S("steplabel", fontName="Helvetica-Bold", fontSize=6.5,
                               textColor=WHITE, alignment=TA_CENTER, leading=8)),
            Paragraph(text, CELL)
        ])
    t = Table(data, colWidths=[COL3*0.27, COL3*0.73])
    style = [
        ("GRID", (0,0), (-1,-1), 0.3, GREY_LINE),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
        ("TOPPADDING",    (0,0), (-1,-1), 4),
        ("BOTTOMPADDING", (0,0), (-1,-1), 4),
        ("LEFTPADDING",   (0,0), (-1,-1), 4),
        ("RIGHTPADDING",  (0,0), (-1,-1), 4),
    ]
    clrs = [TEAL, GREEN, ORANGE, PURPLE, RED]
    for i, clr in enumerate(clrs):
        style.append(("BACKGROUND", (0, i), (0, i), clr))
        style.append(("BACKGROUND", (1, i), (1, i), WHITE if i % 2 == 0 else GREY_LIGHT))
    t.setStyle(TableStyle(style))
    return t

# ── Build 3-column layout ────────────────────────────────────────────────────
def col_header(text, bg):
    return Table([[Paragraph(f"<b>{text}</b>",
        S("ch", fontName="Helvetica-Bold", fontSize=8, textColor=WHITE,
          alignment=TA_CENTER))]],
        colWidths=[COL3],
        style=TableStyle([
            ("BACKGROUND", (0,0), (-1,-1), bg),
            ("TOPPADDING",    (0,0), (-1,-1), 5),
            ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ]))

col1_content = [
    col_header("② MONITORING TARGETS & FREQUENCY", TEAL),
    monitoring_table(),
]
col2_content = [
    col_header("③ DRUG CHOICE BY COMORBIDITY (ADA 2026)", ORANGE),
    comorbidity_table(),
]
col3_content = [
    col_header("④ INSULIN REFERENCE", PURPLE),
    insulin_table(),
    Spacer(1, 3*mm),
    col_header("⑤ ADA 2026 STEPWISE MANAGEMENT ALGORITHM", GREEN),
    step_algo(),
]

from reportlab.platypus import KeepInFrame

def wrap_col(items, width, height=175*mm):
    frame_content = []
    for item in items:
        frame_content.append(item)
        frame_content.append(Spacer(1, 2*mm))
    kif = KeepInFrame(width, height, frame_content, mode='shrink')
    return kif

grid_data = [[
    wrap_col(col1_content, COL3),
    wrap_col(col2_content, COL3),
    wrap_col(col3_content, COL3),
]]

grid = Table(grid_data, colWidths=[COL3, COL3, COL3],
    style=TableStyle([
        ("VALIGN",      (0,0), (-1,-1), "TOP"),
        ("LEFTPADDING", (0,0), (-1,-1), 0),
        ("RIGHTPADDING",(0,0), (-1,-1), 3),
        ("TOPPADDING",  (0,0), (-1,-1), 0),
        ("BOTTOMPADDING",(0,0), (-1,-1), 0),
    ]))
story.append(grid)

story.append(Spacer(1, 3*mm))
story.append(HRFlowable(width=PAGE_W, thickness=0.5, color=GREY_LINE))
story.append(Spacer(1, 2*mm))

# ── ADA 2026 Highlights box ──────────────────────────────────────────────────
highlights = [
    "⭐ <b>GLP-1 RAs & SGLT2i now recommended from point of T2DM diagnosis</b> – not only after metformin failure",
    "⭐ <b>Tirzepatide (dual GIP/GLP-1)</b> – for HFpEF, MASH, and maximum weight loss",
    "⭐ <b>SGLT2i + finerenone</b> simultaneous initiation endorsed for CKD (ACR ≥100 mg/g, eGFR 30–90, on RAS inhibitor)",
    "⭐ <b>BP target</b>: SBP < 120 mmHg where feasible  |  ⭐ <b>AID systems</b> preferred for insulin-requiring T2DM",
    "⭐ <b>GLP-1 RA</b> can now be continued / initiated in <b>advanced CKD</b>  |  ⭐ Holistic care: liver, cognition, bone now addressed",
]
hi_text = "   ".join(highlights)
hi_para = Paragraph(hi_text, S("hi", fontName="Helvetica", fontSize=6.5, textColor=NAVY,
                                leading=9, alignment=TA_LEFT))
hi_box = Table([[hi_para]], colWidths=[PAGE_W],
    style=TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), colors.HexColor("#EBF5FB")),
        ("BOX", (0,0), (-1,-1), 1, TEAL),
        ("TOPPADDING",    (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING",   (0,0), (-1,-1), 8),
        ("RIGHTPADDING",  (0,0), (-1,-1), 8),
    ]))
story.append(hi_box)
story.append(Spacer(1, 2*mm))

# Footer
footer_text = (
    f"Generated by Orris Medical Reference  |  Based on ADA Standards of Care in Diabetes 2026  |  "
    f"Sources: Lippincott Pharmacology, Katzung's Basic & Clinical Pharmacology 16e, Goodman & Gilman's  |  "
    f"Date: {datetime.date.today().strftime('%B %d, %Y')}  |  "
    "⚠ For clinical decision support only – always verify with current guidelines and patient-specific factors"
)
story.append(Paragraph(footer_text, FOOTNOTE))

# ── Build ─────────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF generated: {OUTPUT}")